{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Nicotinamide mononucleotide supplementation improves physical function in older adults.", "entry_form": "claim", "gradeable_restatement": "Nicotinamide mononucleotide supplementation improves physical function in older adults.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Baseline age, disease, physical function, sex, exact formulation/dose, assigned exposure and follow-up; no NAD responder or favorable endpoint subset defines eligibility.", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "NAD Boosters and Human Function", "central_claim": "Nicotinamide mononucleotide supplementation improves physical function in older adults.", "proposed_mechanism": "Nicotinamide mononucleotide supplementation improves physical function in older adults.", "claimed_scope": "NMN versus matched placebo for strength, gait or exercise capacity in adults aged at least 60 over at least eight weeks, with baseline health/function fixed. Blood NAD, young runners, shorter exposure, other molecules and human longevity remain separate claims.", "claimed_level": [ "response" ], "is_conjunctive": false, "conjunctive_note": "The precise lead clinical proposition is SC2. Mechanism, competing-cause, generalization and safety companions remain separately reported; they do not replace the primary clinical endpoint." }, "rubric_routing": { "primary_rubric": "06-metabolism-aging.md", "secondary_rubrics": [], "index_notes_applied": [ "The precise lead clinical proposition is SC2. Mechanism, competing-cause, generalization and safety companions remain separately reported; they do not replace the primary clinical endpoint." ], "rubric_fit_note": "Rubric06 separates NAD/mitochondrial markers, function, healthspan and lifespan. The explicit clinical adaptation treats measured gait/strength/capacity as the registered physical phenotype rather than demanding a lifespan result for a non-lifespan claim. A randomized genuine secondary function endpoint may cross the first threshold with appropriate confidence and multiplicity limits; a null study primary does not automatically erase every secondary clinical signal. Human function is not inferred from animal/cell markers, and molecule-specific treatment benefit is not mediator necessity." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "NMN supplementation increases NAD-related exposure markers.", "subclaim_type": "mechanism", "scope": "Exact NMN formulation, age and duration specified", "claimed_scope": "Exact NMN formulation, age and duration specified", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Controlled pharmacodynamic studies", "hsef_level": "Γ", "confidence": "Low", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "NMN reliably changes blood NAD-related exposure measures across several controlled formulations. These are genuine pharmacodynamic effects, not proof that muscle NAD was functionally limiting or that NAD itself is the necessary mediator. Different salvage routes and compartments prevent direct uptake and functional-aging inference; marker-only support retains Γ.", "rubric_adaptation": "Target-marker rise is real but remains physiological support rather than function or isolated mediator proof." }, { "id": "SC2", "statement": "NMN improves physical function against placebo in older adults.", "subclaim_type": "sufficiency", "scope": "Adults aged at least 60 with baseline health and function measured; strength, gait or exercise capacity; at least 8 weeks", "claimed_scope": "Adults aged at least 60 with baseline health and function measured; strength, gait or exercise capacity; at least 8 weeks", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Controlled functional-outcome trials", "hsef_level": "Δ", "confidence": "Low", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "A twelve-week placebo-controlled trial in baseline age65–75 reports a baseline-adjusted secondary four-metre gait-time difference, and the smaller older-men trial has nominal gait signals with substantial allocation errors and uncorrected exploratory testing. Our registered gate permits gait outcomes and does not secretly require a study-primary endpoint. The direct functional contrast therefore supports a tentative first clinical crossing, Δ, with Low confidence. Stepping, grip, SPPB, chair-stand and older-diabetic primary nulls remain explicit. This is not established broad functional improvement or mechanistic proof; multiplicity and disrupted balance leave the tentative crossing vulnerable.", "rubric_adaptation": "Assess actual placebo-controlled function in the fixed ≥60, ≥eight-week gate; retain exact endpoint hierarchy and correct between-group contrasts, and avoid an added posthoc requirement that every endpoint be positive." }, { "id": "SC3", "statement": "Functional benefit establishes slower aging or longer human lifespan.", "subclaim_type": "generalization", "scope": "Disease incidence and lifespan independently measured", "claimed_scope": "Disease incidence and lifespan independently measured", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Prospective clinical healthspan and survival tests", "hsef_level": "Γ", "confidence": "Low", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "A true short-term gait effect does not itself establish slower biological aging, disease prevention or longer human lifespan. No qualifying NMN clinical aging-trajectory/survival set was examined. Animal physiology, NAD markers and algorithmic biological-age scores are separate outcomes and systems; cap 4 blocks their promotion to the broad longevity inference.", "rubric_adaptation": "Require separately measured human disease trajectory or survival rather than translate gait, NAD or trained-age scores into longevity." }, { "id": "SC4", "statement": "Nicotinamide riboside and metformin have equivalent healthy-aging benefits.", "subclaim_type": "generalization", "scope": "Exact molecule and baseline diabetes or disease status separated", "claimed_scope": "Exact molecule and baseline diabetes or disease status separated", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Molecule-specific clinical trials", "hsef_level": "Α", "confidence": "Low", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "NR and metformin are distinct exposures with different disease-specific successes and nulls, not clinically established equivalent healthy-aging interventions. NR has a genuine PAD walking trial positive, while metformin frailty, PAD and lifestyle-additive function trials have context-specific nulls and some exercise interactions. A knee-OA adjunct metformin positive is also retained. No direct equivalence or common healthy-aging efficacy experiment establishes the proposed equality; this unsupported generalization is Α rather than a declaration that either molecule is universally ineffective.", "rubric_adaptation": "Require molecule-specific clinical comparisons or a valid equivalence design; class analogies and shared aging language do not establish equal effects." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "The precise lead clinical proposition is SC2. Mechanism, competing-cause, generalization and safety companions remain separately reported; they do not replace the primary clinical endpoint.", "primary_subclaim_id": "SC2", "aggregation_derivation": "Primary SC2 tentatively crosses Δ, with Low confidence, because the registered physical-function gate includes a genuine assigned secondary gait contrast. The quality concerns—multiple endpoints, incomplete twelve-week observations, an older trial allocation error and exploratory testing—are not hidden or converted into an unstated primary-endpoint requirement. Functional benefit is inconsistent across measures and contexts, and a separate emerging longer-dose trial adds a null boundary. Evidence does not establish broad strength/exercise efficacy, isolated NAD necessity or human longevity. SC1/SC3 marker-to-clinical inference and SC4 molecule equivalence remain separately bounded.", "aggregation_alternatives": { "weakest_link_would_return": "Α", "primary_subclaim_would_return": "Δ", "scope_matched_would_return": "Δ", "note": "Separate narrow successes do not replace the preregistered full-scope gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 2, "model_id": "M1", "is_nominal": true, "name": "NMN restores a functionally limiting NAD pathway", "core_claim": "NMN exposure can improve selected older-adult performance by restoring a limiting pathway.", "explains_what_nominal_does_not": "NMN exposure can improve selected older-adult performance by restoring a limiting pathway.", "strongest_supporting_evidence": [ "A genuine secondary gait contrast and nominal older-men gait signals provide tentative clinical support." ], "strongest_contradictory_evidence": [ "Blood markers do not prove tissue limitation or mediator necessity; many physical measures and clinical contexts remain null." ], "hsef_level_for_this_model": "Δ", "rationale": "A genuine secondary gait contrast and nominal older-men gait signals provide tentative clinical support. Blood markers do not prove tissue limitation or mediator necessity; many physical measures and clinical contexts remain null." }, { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Exposure and functional response are partly dissociated", "core_claim": "NMN raises NAD while clinical effects vary by measure, baseline physiology and trial context.", "explains_what_nominal_does_not": "NMN raises NAD while clinical effects vary by measure, baseline physiology and trial context.", "strongest_supporting_evidence": [ "Controlled NAD rise coexists with stepping, strength, aerobic and disease-specific nulls; direct gait positives remain bounded." ], "strongest_contradictory_evidence": [ "Dissociation does not demonstrate which pathway causes every genuine positive or that all supplementation is ineffective." ], "hsef_level_for_this_model": "Δ", "rationale": "Controlled NAD rise coexists with stepping, strength, aerobic and disease-specific nulls; direct gait positives remain bounded. Dissociation does not demonstrate which pathway causes every genuine positive or that all supplementation is ineffective." }, { "rank_in_tournament": 3, "model_id": "M3", "is_nominal": false, "name": "Secondary testing and study conduct contribute to apparent benefit", "core_claim": "Practice, multiple outcomes, incomplete data and disrupted allocation can generate nominal signals.", "explains_what_nominal_does_not": "Practice, multiple outcomes, incomplete data and disrupted allocation can generate nominal signals.", "strongest_supporting_evidence": [ "All-group within improvements, uncorrected exploratory outcomes and the22-person supplier cross-switch are concrete concerns." ], "strongest_contradictory_evidence": [ "A baseline-adjusted controlled gait contrast is not merely within-arm improvement and cannot be dismissed solely because it is secondary." ], "hsef_level_for_this_model": "Γ", "rationale": "All-group within improvements, uncorrected exploratory outcomes and the22-person supplier cross-switch are concrete concerns. A baseline-adjusted controlled gait contrast is not merely within-arm improvement and cannot be dismissed solely because it is secondary." }, { "rank_in_tournament": 4, "model_id": "M4", "is_nominal": false, "name": "Distinct molecules and disease states have distinct effects", "core_claim": "NR, NMN and metformin act through overlapping but non-equivalent pathways and patient settings.", "explains_what_nominal_does_not": "NR, NMN and metformin act through overlapping but non-equivalent pathways and patient settings.", "strongest_supporting_evidence": [ "NR-PAD walking benefit, metformin-PAD/frailty nulls and specific adjunct successes distinguish outcomes." ], "strongest_contradictory_evidence": [ "Cross-trial comparisons do not constitute randomized drug equivalence or prove every molecular mediator." ], "hsef_level_for_this_model": "Γ", "rationale": "NR-PAD walking benefit, metformin-PAD/frailty nulls and specific adjunct successes distinguish outcomes. Cross-trial comparisons do not constitute randomized drug equivalence or prove every molecular mediator." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. PMID38789831 original M/R gives a genuine secondary baseline-adjusted gait-time contrast alongside null stepping/grip/SPPB, while PMID35215405 shows within-group sit-to-stand improvement in every arm. These separate a specific tentative clinical signal from a blanket function claim or a largest-within-arm effect interpretation.", "study_separating_rank1_from_rank2": "PMID38789831 original M/R gives a genuine secondary baseline-adjusted gait-time contrast alongside null stepping/grip/SPPB, while PMID35215405 shows within-group sit-to-stand improvement in every arm. These separate a specific tentative clinical signal from a blanket function claim or a largest-within-arm effect interpretation.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "38789831", "title": "Ingestion of β-nicotinamide mononucleotide increased blood NAD levels, maintained walking speed, and improved sleep quality in older adults in a double-blind randomized, placebo-controlled study.", "citation": "Morifuji M, Higashi S, Ebihara S et al. Ingestion of β-nicotinamide mononucleotide increased blood NAD levels, maintained walking speed, and improved sleep quality in older adults in a double-blind randomized, placebo-controlled study. GeroScience. 2024.", "doi": "10.1007/s11357-024-01204-1", "pmcid": "PMC11336149", "url": "https://pubmed.ncbi.nlm.nih.gov/38789831/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38789831/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NMN-UMIN000047871", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: Original PDF Methods page3/table1; web lines136-174, Original PDF Methods/Results pages6-7; web lines403-445, Original PDF Results figure2 page11; web lines670-674. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Actual original PDF Methods/Results confirm age65–75, twelve-week assigned NMN, null stepping/grip/SPPB scores and a baseline-adjusted positive secondary four-metre time.", "what_it_does_not_show": "Multiple endpoint testing and selective four-week follow-up limit certainty; two placebo twelve-week observations were missing, and NAD correlation is not mediator necessity or lifespan.", "confounders_present": [ "Multiple endpoint testing and selective four-week follow-up limit certainty; two placebo twelve-week observations were missing, and NAD correlation is not mediator necessity or lifespan." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 2, "pmid": "35215405", "title": "Effect of 12-Week Intake of Nicotinamide Mononucleotide on Sleep Quality, Fatigue, and Physical Performance in Older Japanese Adults: A Randomized, Double-Blind Placebo-Controlled Study.", "citation": "Kim M, Seol J, Sato T et al. Effect of 12-Week Intake of Nicotinamide Mononucleotide on Sleep Quality, Fatigue, and Physical Performance in Older Japanese Adults: A Randomized, Double-Blind Placebo-Controlled Study. Nutrients. 2022.", "doi": "10.3390/nu14040755", "pmcid": "PMC8877443", "url": "https://pubmed.ncbi.nlm.nih.gov/35215405/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35215405/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NMN-UMIN000038097", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:2. Materials and Methods:paragraph0, 1:2. Materials and Methods:paragraph1, 1:2. Materials and Methods:paragraph2, 1:2. Materials and Methods:paragraph3, 1:2. Materials and Methods:paragraph7, 1:2. Materials and Methods:paragraph8, 2:3. Results:paragraph0, 2:3. Results:paragraph1, 2:3. Results:paragraph2, 2:3. Results:paragraph3. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Actual Methods/Results confirm ≥65, twelve-week four-arm timing assignment, secondary physical outcomes and a nominal sit-to-stand interaction.", "what_it_does_not_show": "Bonferroni posthoc reports improvement within every group rather than demonstrated NMN-placebo pair superiority; largest within-group effect is not treatment efficacy, and primary sleep interaction was null.", "confounders_present": [ "Bonferroni posthoc reports improvement within every group rather than demonstrated NMN-placebo pair superiority; largest within-group effect is not treatment efficacy, and primary sleep interaction was null." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 3, "pmid": "36740954", "title": "Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study.", "citation": "Pencina KM, Valderrabano R, Wipper B et al. Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study. The Journal of clinical endocrinology and metabolism. 2023.", "doi": "10.1210/clinem/dgad027", "pmcid": "PMC11491622", "url": "https://pubmed.ncbi.nlm.nih.gov/36740954/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36740954/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36740954", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Twenty-eight-day MIB-626 in 30 overweight adults raised NAD and improved selected weight/lipid/BP measures but not strength, fatigability, aerobic capacity or stair power.", "what_it_does_not_show": "Under-eight-week mixed-age physiological trial is outside registered functional scope; markers and cardiometabolic changes cannot replace older-adult function.", "confounders_present": [ "Under-eight-week mixed-age physiological trial is outside registered functional scope; markers and cardiometabolic changes cannot replace older-adult function." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 4, "pmid": "35182418", "title": "MIB-626, an Oral Formulation of a Microcrystalline Unique Polymorph of β-Nicotinamide Mononucleotide, Increases Circulating Nicotinamide Adenine Dinucleotide and its Metabolome in Middle-Aged and Older Adults.", "citation": "Pencina KM, Lavu S, Dos Santos M et al. MIB-626, an Oral Formulation of a Microcrystalline Unique Polymorph of β-Nicotinamide Mononucleotide, Increases Circulating Nicotinamide Adenine Dinucleotide and its Metabolome in Middle-Aged and Older Adults. The journals of gerontology. Series A, Biological sciences and medical sciences. 2023.", "doi": "10.1093/gerona/glac049", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35182418/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35182418/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID35182418", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Fourteen-day microcrystalline NMN dose assignment increased blood NMN/NAD and metabolome measures in 32 adults aged 55–80.", "what_it_does_not_show": "Pharmacodynamic exposure and short observed tolerability do not establish older-adult eight-week function, formulation interchangeability or lifespan.", "confounders_present": [ "Pharmacodynamic exposure and short observed tolerability do not establish older-adult eight-week function, formulation interchangeability or lifespan." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 5, "pmid": "36443648", "title": "Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study.", "citation": "Akasaka H, Nakagami H, Sugimoto K et al. Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study. Geriatrics & gerontology international. 2023.", "doi": "10.1111/ggi.14513", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36443648/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36443648/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36443648", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "Fourteen older diabetic men with impaired baseline function had no between-group grip or walking benefit after 24 weeks of 250 mg NMN.", "what_it_does_not_show": "Small sample limits precision; borderline exploratory frailty/retinal measures do not rescue primary nulls, and healthy versus diabetic baseline context remains distinct.", "confounders_present": [ "Small sample limits precision; borderline exploratory frailty/retinal measures do not rescue primary nulls, and healthy versus diabetic baseline context remains distinct." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 6, "pmid": "38871717", "title": "Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial.", "citation": "McDermott MM, Martens CR, Domanchuk KJ et al. Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial. Nature communications. 2024.", "doi": "10.1038/s41467-024-49092-5", "pmcid": "PMC11176364", "url": "https://pubmed.ncbi.nlm.nih.gov/38871717/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38871717/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID39134546" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID38871717", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "NICE randomized 90 PAD adults and found a six-month NR six-minute-walk benefit, while resveratrol added no benefit.", "what_it_does_not_show": "NR differs from NMN; one-sided 90% interval and adherence-selected analyses require clear labeling, and an indexed erratum remains linked without detailed correction audit.", "confounders_present": [ "NR differs from NMN; one-sided 90% interval and adherence-selected analyses require clear labeling, and an indexed erratum remains linked without detailed correction audit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 7, "pmid": "29599478", "title": "Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults.", "citation": "Martens CR, Denman BA, Mazzo MR et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature communications. 2018.", "doi": "10.1038/s41467-018-03421-7", "pmcid": "PMC5876407", "url": "https://pubmed.ncbi.nlm.nih.gov/29599478/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29599478/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NR-NCT02921659", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Six-week NR crossover in middle-aged/older adults increased NAD metabolism and reported selected vascular physiology leads.", "what_it_does_not_show": "Different molecule, mixed age and short follow-up do not establish registered NMN physical function or human aging/lifespan.", "confounders_present": [ "Different molecule, mixed age and short follow-up do not establish registered NMN physical function or human aging/lifespan." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 8, "pmid": "37994989", "title": "A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment.", "citation": "Orr ME, Kotkowski E, Ramirez P et al. A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. GeroScience. 2024.", "doi": "10.1007/s11357-023-00999-9", "pmcid": "PMC10828186", "url": "https://pubmed.ncbi.nlm.nih.gov/37994989/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37994989/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37994989", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Ten-week NR in 20 MCI adults increased NAD and selected clocks while cognition remained stable.", "what_it_does_not_show": "Uncorrected CBF signals and exploratory clock movement do not establish function or slower aging; drug and disease differ from NMN scope.", "confounders_present": [ "Uncorrected CBF signals and exploratory clock movement do not establish function or slower aging; drug and disease differ from NMN scope." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 9, "pmid": "31278280", "title": "Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults.", "citation": "Conze D, Brenner C, Kruger CL. Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Scientific reports. 2019.", "doi": "10.1038/s41598-019-46120-z", "pmcid": "PMC6611812", "url": "https://pubmed.ncbi.nlm.nih.gov/31278280/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31278280/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID31278280", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Eight-week NR dose assignment increased blood NAD with no observed dose-related adverse-event differences.", "what_it_does_not_show": "Tolerability and pharmacodynamics are not equivalence to NMN, physical benefit or lifetime healthy-aging safety.", "confounders_present": [ "Tolerability and pharmacodynamics are not equivalence to NMN, physical benefit or lifetime healthy-aging safety." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 10, "pmid": "32320006", "title": "Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans.", "citation": "Remie CME, Roumans KHM, Moonen MPB et al. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. The American journal of clinical nutrition. 2020.", "doi": "10.1093/ajcn/nqaa072", "pmcid": "PMC7398770", "url": "https://pubmed.ncbi.nlm.nih.gov/32320006/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32320006/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NR-NCT02835664", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "NR crossover changed selected muscle metabolites/body composition but not insulin sensitivity, mitochondrial function or most metabolic endpoints.", "what_it_does_not_show": "Minor fat-free-mass change is not measured strength; six-week obese mixed-age NR exposure cannot replace older NMN function.", "confounders_present": [ "Minor fat-free-mass change is not measured strength; six-week obese mixed-age NR exposure cannot replace older NMN function." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 11, "pmid": "40770531", "title": "Nicotinamide riboside combined with exercise to treat hypertension in middle-aged and older adults: a pilot randomized clinical trial.", "citation": "Lin Y, Zeidan RS, Lapierre-Nguyen S et al. Nicotinamide riboside combined with exercise to treat hypertension in middle-aged and older adults: a pilot randomized clinical trial. GeroScience. 2025.", "doi": "10.1007/s11357-025-01815-2", "pmcid": "PMC12638573", "url": "https://pubmed.ncbi.nlm.nih.gov/40770531/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40770531/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID40770531", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "NR plus exercise did not improve daytime BP more than placebo plus exercise despite higher NAD catabolites.", "what_it_does_not_show": "Short hypertensive trial and posthoc medication-free nighttime trends are distinct from verified physical function or a confirmed baseline subgroup.", "confounders_present": [ "Short hypertensive trial and posthoc medication-free nighttime trends are distinct from verified physical function or a confirmed baseline subgroup." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 12, "pmid": "42478598", "title": "A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment.", "citation": "Martens CR, Decker KP, DeConne TM et al. A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2026.", "doi": "10.1002/alz.71605", "pmcid": "PMC13386481", "url": "https://pubmed.ncbi.nlm.nih.gov/42478598/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42478598/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42478598", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "A 12-week NR MCI pilot doubled NAD without improved cognitive primary, total CBF or BP.", "what_it_does_not_show": "Exploratory regional-CBF hypotheses do not overturn the primary null or establish NMN function and human longevity.", "confounders_present": [ "Exploratory regional-CBF hypotheses do not overturn the primary null or establish NMN function and human longevity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 13, "pmid": "32791973", "title": "Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI.", "citation": "Simic P, Vela Parada XF, Parikh SM et al. Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI. BMC nephrology. 2020.", "doi": "10.1186/s12882-020-02006-1", "pmcid": "PMC7427083", "url": "https://pubmed.ncbi.nlm.nih.gov/32791973/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32791973/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID32791973", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Two-day NR/pterostilbene escalation in hospitalized AKI patients increased selected NAD measures with variable response and short safety observations.", "what_it_does_not_show": "Combination exposure, acute disease and biomarker endpoint do not establish older-adult function, recovery efficacy or healthy-aging equivalence.", "confounders_present": [ "Combination exposure, acute disease and biomarker endpoint do not establish older-adult function, recovery efficacy or healthy-aging equivalence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 14, "pmid": "41512967", "title": "Energy-replenishing, mitochondria-targeted hydrogel microspheres mitigate sarcopenia via cellular senescence amelioration.", "citation": "Bao W, Liu S, Du C et al. Energy-replenishing, mitochondria-targeted hydrogel microspheres mitigate sarcopenia via cellular senescence amelioration. Journal of controlled release : official journal of the Controlled Release Society. 2026.", "doi": "10.1016/j.jconrel.2025.114595", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/41512967/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41512967/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID41512967", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Local mitochondria-targeted NMN hydrogel reduced dexamethasone muscle-cell senescence/mitochondrial abnormalities in preclinical experiments.", "what_it_does_not_show": "Delivery includes SS-31/liposome/scaffold coeffects and induced disease; markers and local injections cannot establish oral human functional efficacy or lifespan.", "confounders_present": [ "Delivery includes SS-31/liposome/scaffold coeffects and induced disease; markers and local injections cannot establish oral human functional efficacy or lifespan." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 15, "pmid": "39424071", "title": "Long-Term Administration of Nicotinamide Mononucleotide Mitigates High-Fat-Diet-Induced Physiological Decline in Aging Mice.", "citation": "Zhou AJ, Xiong ZE, Wang L et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates High-Fat-Diet-Induced Physiological Decline in Aging Mice. The Journal of nutrition. 2025.", "doi": "10.1016/j.tjnut.2024.10.017", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39424071/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39424071/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID39424071", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Seven-month NMN in aging high-fat-diet mice improved selected grip/locomotor and metabolic/organ measures.", "what_it_does_not_show": "High dose, diet, species and autophagy correlations differ from human trials; physiological benefit is not examined human or necessarily mouse lifespan extension.", "confounders_present": [ "High dose, diet, species and autophagy correlations differ from human trials; physiological benefit is not examined human or necessarily mouse lifespan extension." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 16, "pmid": "41205146", "title": "Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease: The PERMET Randomized Clinical Trial.", "citation": "McDermott MM, Domanchuk KJ, Tian L et al. Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease: The PERMET Randomized Clinical Trial. JAMA. 2026.", "doi": "10.1001/jama.2025.21358", "pmcid": "PMC12596744", "url": "https://pubmed.ncbi.nlm.nih.gov/41205146/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41205146/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID41205146", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "PERMET found no six-month metformin six-minute-walk or secondary functional advantage in 202 PAD adults without diabetes.", "what_it_does_not_show": "Metformin and PAD are distinct from NMN; gastrointestinal events and follow-up attrition matter, and nulls do not negate metformin's established other indications.", "confounders_present": [ "Metformin and PAD are distinct from NMN; gastrointestinal events and follow-up attrition matter, and nulls do not negate metformin's established other indications." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 17, "pmid": "40147475", "title": "Metformin and physical performance in older people with probable sarcopenia and physical prefrailty or frailty in England (MET-PREVENT): a double-blind, randomised, placebo-controlled trial.", "citation": "Witham MD, McDonald C, Wilson N et al. Metformin and physical performance in older people with probable sarcopenia and physical prefrailty or frailty in England (MET-PREVENT): a double-blind, randomised, placebo-controlled trial. The lancet. Healthy longevity. 2025.", "doi": "10.1016/j.lanhl.2025.100695", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/40147475/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40147475/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID40147475", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "MET-PREVENT found no four-month metformin gait benefit in 72 frail/sarcopenic older adults, with poor tolerability and more admissions.", "what_it_does_not_show": "Exact older frailty context is bounded; admissions are observed harms requiring attribution rather than proof of every metformin risk, and this is not NMN.", "confounders_present": [ "Exact older frailty context is bounded; admissions are observed harms requiring attribution rather than proof of every metformin risk, and this is not NMN." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 18, "pmid": "39744353", "title": "Long-term impact of Diabetes Prevention Program interventions on walking endurance.", "citation": "Munshi MN, Venditti EM, Tjaden AH et al. Long-term impact of Diabetes Prevention Program interventions on walking endurance. Frontiers in public health. 2024.", "doi": "10.3389/fpubh.2024.1470035", "pmcid": "PMC11688401", "url": "https://pubmed.ncbi.nlm.nih.gov/39744353/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39744353/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "DPP-DPPOS", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Long-term DPPOS original-group analysis found no sustained walking-endurance differences about 20 years after randomization.", "what_it_does_not_show": "Later shared interventions and survival/completer selection differ from maintained blinded treatment; one DPP parent is not new clinical longevity proof.", "confounders_present": [ "Later shared interventions and survival/completer selection differ from maintained blinded treatment; one DPP parent is not new clinical longevity proof." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 19, "pmid": "36792952", "title": "Association Between Metformin Use and Cognitive and Physical Function in Persons with HIV and Diabetes.", "citation": "Masters MC, Granche J, Yang J et al. Association Between Metformin Use and Cognitive and Physical Function in Persons with HIV and Diabetes. AIDS research and human retroviruses. 2023.", "doi": "10.1089/AID.2022.0129", "pmcid": "PMC10278023", "url": "https://pubmed.ncbi.nlm.nih.gov/36792952/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36792952/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36792952", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "null", "what_it_shows": "Small older HIV/diabetes cohort found no metformin association with measured cognition, frailty or physical function.", "what_it_does_not_show": "Observational prescribing, restricted disease and low precision do not establish causal absence or equivalence to NMN.", "confounders_present": [ "Observational prescribing, restricted disease and low precision do not establish causal absence or equivalence to NMN." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 20, "pmid": "34920739", "title": "An epigenetic aging analysis of randomized metformin and weight loss interventions in overweight postmenopausal breast cancer survivors.", "citation": "Nwanaji-Enwerem JC, Chung FF, Van der Laan L et al. An epigenetic aging analysis of randomized metformin and weight loss interventions in overweight postmenopausal breast cancer survivors. Clinical epigenetics. 2021.", "doi": "10.1186/s13148-021-01218-y", "pmcid": "PMC8684118", "url": "https://pubmed.ncbi.nlm.nih.gov/34920739/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34920739/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID34920739", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Posthoc metformin/weight-loss factorial trial in breast-cancer survivors found no significant epigenetic-age assignment effects at six months.", "what_it_does_not_show": "Clock null does not by itself establish absent clinical benefit; disease and exposure differ from NMN and human life extension remains unmeasured.", "confounders_present": [ "Clock null does not by itself establish absent clinical benefit; disease and exposure differ from NMN and human life extension remains unmeasured." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 21, "pmid": "42551713", "title": "Lung function after randomization to metformin, lifestyle intervention or placebo in the Diabetes Prevention Program Outcomes Study (DPPOS).", "citation": "Pistenmaa CL, Doherty L, Hermann EA et al. Lung function after randomization to metformin, lifestyle intervention or placebo in the Diabetes Prevention Program Outcomes Study (DPPOS). Respiratory medicine. 2026.", "doi": "10.1016/j.rmed.2026.109077", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42551713/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42551713/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "DPP-DPPOS", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "DPPOS long-term original assignments were not associated with spirometry or respiratory-symptom differences.", "what_it_does_not_show": "Shared DPP cohort with later open-label/cointervention exposure is not independent continuous-dose or NMN evidence.", "confounders_present": [ "Shared DPP cohort with later open-label/cointervention exposure is not independent continuous-dose or NMN evidence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 22, "pmid": "35405248", "title": "Short-term exposure to a clinical dose of metformin increases skeletal muscle mitochondrial H2O2 emission and production in healthy, older adults: A randomized controlled trial.", "citation": "McKenzie AI, Mahmassani ZS, Petrocelli JJ et al. Short-term exposure to a clinical dose of metformin increases skeletal muscle mitochondrial H2O2 emission and production in healthy, older adults: A randomized controlled trial. Experimental gerontology. 2022.", "doi": "10.1016/j.exger.2022.111804", "pmcid": "PMC9237837", "url": "https://pubmed.ncbi.nlm.nih.gov/35405248/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35405248/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID35405248", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Two-week metformin in 16 older adults increased muscle H2O2 measures without altering maximal mitochondrial respiration.", "what_it_does_not_show": "ROS/biopsy markers and short exposure are not organismal aging or physical benefit; correlations do not establish free-radical causal primacy.", "confounders_present": [ "ROS/biopsy markers and short exposure are not organismal aging or physical benefit; correlations do not establish free-radical causal primacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 23, "pmid": "28681986", "title": "Metformin-associated prevention of weight gain in insulin-treated type 2 diabetic patients cannot be explained by decreased energy intake: A post hoc analysis of a randomized placebo-controlled 4.3-year trial.", "citation": "Out M, Miedema I, Jager-Wittenaar H et al. Metformin-associated prevention of weight gain in insulin-treated type 2 diabetic patients cannot be explained by decreased energy intake: A post hoc analysis of a randomized placebo-controlled 4.3-year trial. Diabetes, obesity & metabolism. 2018.", "doi": "10.1111/dom.13054", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28681986/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28681986/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID28681986", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "HOME posthoc analysis found less weight gain with metformin but no reported dietary-energy explanation over 4.3 years.", "what_it_does_not_show": "Selected completed diet histories and self-reported intake cannot prove mediator absence; diabetic weight effect is not NMN function or nondiabetic longevity.", "confounders_present": [ "Selected completed diet histories and self-reported intake cannot prove mediator absence; diabetic weight effect is not NMN function or nondiabetic longevity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 24, "pmid": "37486024", "title": "Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment.", "citation": "Petrocelli JJ, McKenzie AI, de Hart NMMP et al. Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment. Aging cell. 2023.", "doi": "10.1111/acel.13936", "pmcid": "PMC10652302", "url": "https://pubmed.ncbi.nlm.nih.gov/37486024/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37486024/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37486024", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Metformin pretreatment during brief bedrest altered older-adult muscle atrophy/fibrosis and senescence measures in recovery.", "what_it_does_not_show": "Short induced disuse and histology markers do not establish long-term gait, general healthy aging or NMN efficacy; candidate SASP mediation is not isolated.", "confounders_present": [ "Short induced disuse and histology markers do not establish long-term gait, general healthy aging or NMN efficacy; candidate SASP mediation is not isolated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 25, "pmid": "26789348", "title": "METFORMIN-SUSTAINED WEIGHT LOSS AND REDUCED ANDROID FAT TISSUE AT 12 MONTHS IN EMPOWIR (ENHANCE THE METABOLIC PROFILE OF WOMEN WITH INSULIN RESISTANCE): A DOUBLE BLIND, PLACEBO-CONTROLLED, RANDOMIZED TRIAL OF NORMOGLYCEMIC WOMEN WITH MIDLIFE WEIGHT GAIN.", "citation": "Mogul H, Freeman R, Nguyen K. METFORMIN-SUSTAINED WEIGHT LOSS AND REDUCED ANDROID FAT TISSUE AT 12 MONTHS IN EMPOWIR (ENHANCE THE METABOLIC PROFILE OF WOMEN WITH INSULIN RESISTANCE): A DOUBLE BLIND, PLACEBO-CONTROLLED, RANDOMIZED TRIAL OF NORMOGLYCEMIC WOMEN WITH MIDLIFE WEIGHT GAIN. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2016.", "doi": "10.4158/EP151087.OR", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26789348/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26789348/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID26789348", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "EMPOWIR diet plus metformin improved selected weight/fat measures in midlife hyperinsulinemic women with completed follow-up.", "what_it_does_not_show": "Mixed treatment/rerandomization and body composition are not older physical function or life extension; marker and outcome-specific positives remain bounded.", "confounders_present": [ "Mixed treatment/rerandomization and body composition are not older physical function or life extension; marker and outcome-specific positives remain bounded." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 26, "pmid": "31557380", "title": "Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial.", "citation": "Walton RG, Dungan CM, Long DE et al. Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial. Aging cell. 2019.", "doi": "10.1111/acel.13039", "pmcid": "PMC6826125", "url": "https://pubmed.ncbi.nlm.nih.gov/31557380/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31557380/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID32141718" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "MASTERS-NCT02308228", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "MASTERS metformin blunted resistance-training muscle growth, with a nonsignificant trend in strength gains.", "what_it_does_not_show": "Lean-mass/hypertrophy and strength are distinct; the adverse exercise interaction does not quantify NMN efficacy, and an erratum remains attached.", "confounders_present": [ "Lean-mass/hypertrophy and strength are distinct; the adverse exercise interaction does not quantify NMN efficacy, and an erratum remains attached." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 27, "pmid": "40965862", "title": "Metformin and the Development of Age-Related Macular Degeneration.", "citation": "Jindal DA, Hanna J, Shaia JK et al. Metformin and the Development of Age-Related Macular Degeneration. JAMA ophthalmology. 2025.", "doi": "10.1001/jamaophthalmol.2025.3070", "pmcid": "PMC12447287", "url": "https://pubmed.ncbi.nlm.nih.gov/40965862/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40965862/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID40965862", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Large matched metformin AMD cohorts found comparable development/progression under their clinical-significance criterion.", "what_it_does_not_show": "Some confidence intervals exclude unity despite authors' equivalence-style criterion; do not conflate statistical and meaningful significance or infer NMN equivalence.", "confounders_present": [ "Some confidence intervals exclude unity despite authors' equivalence-style criterion; do not conflate statistical and meaningful significance or infer NMN equivalence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 28, "pmid": "41603726", "title": "Metformin Does Not Significantly Alter Longitudinal Dynamics of Clonal Hematopoiesis.", "citation": "Pareek E, Pershad Y, Zhao K et al. Metformin Does Not Significantly Alter Longitudinal Dynamics of Clonal Hematopoiesis. Clinical cancer research : an official journal of the American Association for Cancer Research. 2026.", "doi": "10.1158/1078-0432.CCR-25-3606", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/41603726/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41603726/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID41603726", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Longitudinal diabetic metformin cohorts showed no significant individual-cohort clonal-growth effect but a small pooled association.", "what_it_does_not_show": "Small molecular clone-rate association is not clinically established protection or NMN longevity; two cohorts remain components of one reported analysis.", "confounders_present": [ "Small molecular clone-rate association is not clinically established protection or NMN longevity; two cohorts remain components of one reported analysis." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 29, "pmid": "36287641", "title": "Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study.", "citation": "Keys MT, Thinggaard M, Larsen LA et al. Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study. International journal of epidemiology. 2022.", "doi": "10.1093/ije/dyac200", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36287641/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36287641/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36287641", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "contradicts", "what_it_shows": "Danish singleton/twin analyses did not reproduce superior survival of metformin-treated diabetes relative to nondiabetic controls.", "what_it_does_not_show": "Diabetes status and prescribing confounding prevent inference that metformin causes excess mortality; comparator choice does not establish healthy-person longevity efficacy.", "confounders_present": [ "Diabetes status and prescribing confounding prevent inference that metformin causes excess mortality; comparator choice does not establish healthy-person longevity efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 30, "pmid": "26022641", "title": "Association of Geroprotective Effects of Metformin and Risk of Open-Angle Glaucoma in Persons With Diabetes Mellitus.", "citation": "Lin HC, Stein JD, Nan B et al. Association of Geroprotective Effects of Metformin and Risk of Open-Angle Glaucoma in Persons With Diabetes Mellitus. JAMA ophthalmology. 2015.", "doi": "10.1001/jamaophthalmol.2015.1440", "pmcid": "PMC4537372", "url": "https://pubmed.ncbi.nlm.nih.gov/26022641/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26022641/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID26022641", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Diabetic metformin exposure was associated with lower open-angle-glaucoma incidence in a retrospective cohort.", "what_it_does_not_show": "Exposure-dose association and model projections are not randomized prevention, human lifespan or equivalence to NAD precursors.", "confounders_present": [ "Exposure-dose association and model projections are not randomized prevention, human lifespan or equivalence to NAD precursors." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 31, "pmid": "28190681", "title": "Differential effects of metformin on age related comorbidities in older men with type 2 diabetes.", "citation": "Wang CP, Lorenzo C, Habib SL et al. Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. Journal of diabetes and its complications. 2017.", "doi": "10.1016/j.jdiacomp.2017.01.013", "pmcid": "PMC5654524", "url": "https://pubmed.ncbi.nlm.nih.gov/28190681/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28190681/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID28190681", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Older diabetic-veteran metformin use associated with selected lower age-related comorbidity patterns.", "what_it_does_not_show": "Latent classes partly defined by outcomes and residual prescribing confounding cannot establish causal baseline subtypes or nondiabetic geroprotection.", "confounders_present": [ "Latent classes partly defined by outcomes and residual prescribing confounding cannot establish causal baseline subtypes or nondiabetic geroprotection." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 32, "pmid": "33462708", "title": "Associations of muscle lipid content with physical function and resistance training outcomes in older adults: altered responses with metformin.", "citation": "Long DE, Peck BD, Tuggle SC et al. Associations of muscle lipid content with physical function and resistance training outcomes in older adults: altered responses with metformin. GeroScience. 2021.", "doi": "10.1007/s11357-020-00315-9", "pmcid": "PMC8110673", "url": "https://pubmed.ncbi.nlm.nih.gov/33462708/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33462708/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "MASTERS-NCT02308228", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "MASTERS secondary analysis linked muscle density with performance and selected metformin exercise-response patterns.", "what_it_does_not_show": "Shared parent and baseline/subgroup associations are not independent causal lines or proof that mass or lipid density is the necessary mediator.", "confounders_present": [ "Shared parent and baseline/subgroup associations are not independent causal lines or proof that mass or lipid density is the necessary mediator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 33, "pmid": "25506599", "title": "Frailty Attenuates the Impact of Metformin on Reducing Mortality in Older Adults with Type 2 Diabetes.", "citation": "Wang CP, Lorenzo C, Espinoza SE. Frailty Attenuates the Impact of Metformin on Reducing Mortality in Older Adults with Type 2 Diabetes. Journal of endocrinology, diabetes & obesity. 2014.", "doi": "", "pmcid": "PMC4264048", "url": "https://pubmed.ncbi.nlm.nih.gov/25506599/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25506599/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID25506599", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Older diabetic veterans had a metformin-versus-sulfonylurea survival association differing by frailty context.", "what_it_does_not_show": "Active-drug selection and diabetes indication do not establish healthy-person life extension or NMN equivalence; frailty association is not randomized prevention.", "confounders_present": [ "Active-drug selection and diabetes indication do not establish healthy-person life extension or NMN equivalence; frailty association is not randomized prevention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 34, "pmid": "36482258", "title": "The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial.", "citation": "Yi L, Maier AB, Tao R et al. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. GeroScience. 2023.", "doi": "10.1007/s11357-022-00705-1", "pmcid": "PMC9735188", "url": "https://pubmed.ncbi.nlm.nih.gov/36482258/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36482258/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NMN-NCT04823260", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "An 80-person 60-day NMN dose trial increased NAD and six-minute-walk response in adults aged 40–65, with no HOMA-IR difference.", "what_it_does_not_show": "Mixed middle age is outside the full registered at-least-60 population; algorithmic biological-age score and PP analysis do not establish lifespan or isolated NAD mediation.", "confounders_present": [ "Mixed middle age is outside the full registered at-least-60 population; algorithmic biological-age score and PP analysis do not establish lifespan or isolated NAD mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 35, "pmid": "33888596", "title": "Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women.", "citation": "Yoshino M, Yoshino J, Kayser BD et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science (New York, N.Y.). 2021.", "doi": "10.1126/science.abe9985", "pmcid": "PMC8550608", "url": "https://pubmed.ncbi.nlm.nih.gov/33888596/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33888596/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID33888596", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Ten-week NMN in overweight prediabetic postmenopausal women improved clamp muscle-insulin sensitivity and selected remodeling signals.", "what_it_does_not_show": "Clamp/metabolic physiology is not measured strength/gait/exercise capacity or human aging; population and mediators remain distinct.", "confounders_present": [ "Clamp/metabolic physiology is not measured strength/gait/exercise capacity or human aging; population and mediators remain distinct." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 36, "pmid": "35235774", "title": "The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.", "citation": "Brakedal B, Dölle C, Riemer F et al. The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease. Cell metabolism. 2022.", "doi": "10.1016/j.cmet.2022.02.001", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35235774/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35235774/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID35235774", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "NADPARK NR increased variable brain NAD and molecular measures, with clinical changes among NAD responders.", "what_it_does_not_show": "Responder-defined clinical association, one-month disease exposure and another precursor do not establish the NMN older-function gate or confirmed neuroprotection.", "confounders_present": [ "Responder-defined clinical association, one-month disease exposure and another precursor do not establish the NMN older-function gate or confirmed neuroprotection." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 37, "pmid": "27721479", "title": "Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.", "citation": "Trammell SA, Schmidt MS, Weidemann BJ et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nature communications. 2016.", "doi": "10.1038/ncomms12948", "pmcid": "PMC5062546", "url": "https://pubmed.ncbi.nlm.nih.gov/27721479/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27721479/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID27721479", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Early human NR dosing and mouse studies demonstrated NAD-related pharmacokinetics and sensitive NAAD readouts.", "what_it_does_not_show": "Single-person lead and short pharmacodynamics are not function/healthspan or proof that intact NR and NMN share identical tissue routes.", "confounders_present": [ "Single-person lead and short pharmacodynamics are not function/healthspan or proof that intact NR and NMN share identical tissue routes." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 38, "pmid": "40846977", "title": "NAD+ dyshomeostasis in RYR1-related myopathies.", "citation": "Lawal TA, Riekhof W, Groom L et al. NAD+ dyshomeostasis in RYR1-related myopathies. Skeletal muscle. 2025.", "doi": "10.1186/s13395-025-00390-6", "pmcid": "PMC12374369", "url": "https://pubmed.ncbi.nlm.nih.gov/40846977/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40846977/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID40846977", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "RYR1-myopathy patients had heterogeneous blood NAD dysregulation, and patient-cell NR changed selected energetic measures.", "what_it_does_not_show": "Disease deficiency and cultured myotube responses are not clinical treatment or age-related oral NMN benefit; mouse redox findings did not reproduce all human patterns.", "confounders_present": [ "Disease deficiency and cultured myotube responses are not clinical treatment or age-related oral NMN benefit; mouse redox findings did not reproduce all human patterns." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 39, "pmid": "37271226", "title": "The acute effect of different NAD+ precursors included in the combined metabolic activators.", "citation": "Li X, Yang H, Jin H et al. The acute effect of different NAD+ precursors included in the combined metabolic activators. Free radical biology & medicine. 2023.", "doi": "10.1016/j.freeradbiomed.2023.05.032", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37271226/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37271226/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37271226", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "One-day combined-activator precursor comparisons changed metabolomic NAD products with precursor-specific effects and niacin flushing.", "what_it_does_not_show": "Mixture, acute dosing and plasma products do not establish function or interchangeability; direct NMN uptake and health benefit cannot be inferred from ranks.", "confounders_present": [ "Mixture, acute dosing and plasma products do not establish function or interchangeability; direct NMN uptake and health benefit cannot be inferred from ranks." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 40, "pmid": "34238308", "title": "Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study.", "citation": "Liao B, Zhao Y, Wang D et al. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. Journal of the International Society of Sports Nutrition. 2021.", "doi": "10.1186/s12970-021-00442-4", "pmcid": "PMC8265078", "url": "https://pubmed.ncbi.nlm.nih.gov/34238308/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34238308/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID34238308", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Six-week NMN plus training improved selected ventilatory-threshold measures in younger/middle-aged runners, while VO2max and peak power did not differ.", "what_it_does_not_show": "Outside registered age/duration, training cointervention and outcome multiplicity; ventilatory threshold is not equivalent to peak aerobic capacity or slower aging.", "confounders_present": [ "Outside registered age/duration, training cointervention and outcome multiplicity; ventilatory threshold is not equivalent to peak aerobic capacity or slower aging." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 41, "pmid": "39548320", "title": "Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial.", "citation": "Norheim KL, Ben Ezra M, Heckenbach I et al. Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial. Nature aging. 2024.", "doi": "10.1038/s43587-024-00758-1", "pmcid": "PMC11645284", "url": "https://pubmed.ncbi.nlm.nih.gov/39548320/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39548320/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID39548320", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "NR in stable COPD lowered sputum IL8 and increased NAD, with selected persistent marker effects.", "what_it_does_not_show": "Inflammation and exploratory clock signatures do not establish pulmonary function, generalized aging or NMN efficacy; drug/disease/time differ.", "confounders_present": [ "Inflammation and exploratory clock signatures do not establish pulmonary function, generalized aging or NMN efficacy; drug/disease/time differ." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 42, "pmid": "31412242", "title": "Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures.", "citation": "Elhassan YS, Kluckova K, Fletcher RS et al. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell reports. 2019.", "doi": "10.1016/j.celrep.2019.07.043", "pmcid": "PMC6702140", "url": "https://pubmed.ncbi.nlm.nih.gov/31412242/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31412242/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID31412242", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Twenty-one-day NR in aged men increased muscle NAD metabolites and lowered selected inflammatory signatures without altered bioenergetics.", "what_it_does_not_show": "Target engagement is not physical-function efficacy; short other-precursor exposure cannot cross the registered NMN eight-week gate.", "confounders_present": [ "Target engagement is not physical-function efficacy; short other-precursor exposure cannot cross the registered NMN eight-week gate." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 43, "pmid": "35927255", "title": "Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men.", "citation": "Igarashi M, Nakagawa-Nagahama Y, Miura M et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. npj aging. 2022.", "doi": "10.1038/s41514-022-00084-z", "pmcid": "PMC9158788", "url": "https://pubmed.ncbi.nlm.nih.gov/35927255/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35927255/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NMN-UMIN000036321", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph10, 1:Results:paragraph11, 1:Results:paragraph133, 1:Results:paragraph214, 2:Discussion:paragraph9, 3:Methods:paragraph1, 3:Methods:paragraph2, 3:Methods:paragraph3, 3:Methods:paragraph4, 3:Methods:paragraph22, 3:Methods:paragraph23, 3:Methods:paragraph24. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Actual Methods/Results report nominal gait/left-grip signals, NAD augmentation and no mass effect; a supplier switched supplements in22of42 at week6, leaving ten per arm at week12.", "what_it_does_not_show": "Randomized balance was disrupted; every analysis was exploratory without P correction, and six-week left-grip/mixed-duration results cannot alone satisfy the registered ≥eight-week gate.", "confounders_present": [ "Randomized balance was disrupted; every analysis was exploratory without P correction, and six-week left-grip/mixed-duration results cannot alone satisfy the registered ≥eight-week gate." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 44, "pmid": "36499074", "title": "Nicotinamide Mononucleotide Supplementation Improves Mitochondrial Dysfunction and Rescues Cellular Senescence by NAD+/Sirt3 Pathway in Mesenchymal Stem Cells.", "citation": "Wang H, Sun Y, Pi C et al. Nicotinamide Mononucleotide Supplementation Improves Mitochondrial Dysfunction and Rescues Cellular Senescence by NAD+/Sirt3 Pathway in Mesenchymal Stem Cells. International journal of molecular sciences. 2022.", "doi": "10.3390/ijms232314739", "pmcid": "PMC9738479", "url": "https://pubmed.ncbi.nlm.nih.gov/36499074/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36499074/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36499074", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "NMN/Sirt3 manipulations changed cultured MSC mitochondrial and senescence measures.", "what_it_does_not_show": "Replicative-cell senescence, overexpression and inhibitor effects are not organismal aging or physical function in human recipients; pharmacological specificity remains bounded.", "confounders_present": [ "Replicative-cell senescence, overexpression and inhibitor effects are not organismal aging or physical function in human recipients; pharmacological specificity remains bounded." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 45, "pmid": "36515353", "title": "Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin.", "citation": "Vreones M, Mustapic M, Moaddel R et al. Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin. Aging cell. 2023.", "doi": "10.1111/acel.13754", "pmcid": "PMC9835564", "url": "https://pubmed.ncbi.nlm.nih.gov/36515353/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36515353/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NR-NCT02921659", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "NR-trial secondary neuronal-enriched-vesicle analysis changed NAD and selected pathology-associated markers.", "what_it_does_not_show": "Shared six-week precursor trial and vesicle enrichment do not establish actual brain function, neuron-specific origin certainty or prevented neurodegeneration.", "confounders_present": [ "Shared six-week precursor trial and vesicle enrichment do not establish actual brain function, neuron-specific origin certainty or prevented neurodegeneration." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 46, "pmid": "35479740", "title": "Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects.", "citation": "Okabe K, Yaku K, Uchida Y et al. Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects. Frontiers in nutrition. 2022.", "doi": "10.3389/fnut.2022.868640", "pmcid": "PMC9036060", "url": "https://pubmed.ncbi.nlm.nih.gov/35479740/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35479740/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID35479740", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Thirty healthy subjects receiving 12-week NMN had higher blood NAD/NAMN and no observed major laboratory abnormalities.", "what_it_does_not_show": "Pharmacodynamics and limited safety do not establish older-adult physical improvement, intact NMN uptake or lifetime healthy aging.", "confounders_present": [ "Pharmacodynamics and limited safety do not establish older-adult physical improvement, intact NMN uptake or lifetime healthy aging." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 47, "pmid": "37899683", "title": "Long-Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia.", "citation": "Presterud R, Deng WH, Wennerström AB et al. Long-Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia. Movement disorders : official journal of the Movement Disorder Society. 2024.", "doi": "10.1002/mds.29645", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37899683/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37899683/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37899683", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Long-term open-label NR in ataxia-telangiectasia showed selected coordination/eye-movement changes relative to historical expectations.", "what_it_does_not_show": "No concurrent randomized control, all-age rare disease and different molecule; historical trajectories and practice effects constrain causal transfer to NMN older adults.", "confounders_present": [ "No concurrent randomized control, all-age rare disease and different molecule; historical trajectories and practice effects constrain causal transfer to NMN older adults." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 48, "pmid": "36797393", "title": "Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial.", "citation": "Katayoshi T, Uehata S, Nakashima N et al. Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial. Scientific reports. 2023.", "doi": "10.1038/s41598-023-29787-3", "pmcid": "PMC9935856", "url": "https://pubmed.ncbi.nlm.nih.gov/36797393/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36797393/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36797393", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Twelve-week NMN increased serum nicotinamide in middle-aged adults, but arterial-stiffness between-group difference was nonsignificant.", "what_it_does_not_show": "Metabolite and trend are not proven function or age slowing; middle age and vascular outcome differ from the physical gate.", "confounders_present": [ "Metabolite and trend are not proven function or age slowing; middle age and vascular outcome differ from the physical gate." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 49, "pmid": "31685720", "title": "Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men.", "citation": "Irie J, Inagaki E, Fujita M et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocrine journal. 2020.", "doi": "10.1507/endocrj.EJ19-0313", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31685720/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31685720/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID31685720", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Single-dose NMN in ten men changed pharmacokinetic metabolites with no major short-term examined clinical effects.", "what_it_does_not_show": "Uncontrolled hours-long dosing does not establish eight-week function, durable safety or longevity.", "confounders_present": [ "Uncontrolled hours-long dosing does not establish eight-week function, durable safety or longevity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 50, "pmid": "36638183", "title": "Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study.", "citation": "Lapatto HAK, Kuusela M, Heikkinen A et al. Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study. Science advances. 2023.", "doi": "10.1126/sciadv.add5163", "pmcid": "PMC9839336", "url": "https://pubmed.ncbi.nlm.nih.gov/36638183/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36638183/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36638183", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Five-month NR twin study altered NAD, mitochondrial and stem-cell measures without improved adiposity/metabolic health.", "what_it_does_not_show": "Both twins received NR without placebo, and cellular mitochondrial function differs from measured physical performance; distinct precursor cannot establish NMN efficacy.", "confounders_present": [ "Both twins received NR without placebo, and cellular mitochondrial function differs from measured physical performance; distinct precursor cannot establish NMN efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 51, "pmid": "38016950", "title": "NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease.", "citation": "Berven H, Kverneng S, Sheard E et al. NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease. Nature communications. 2023.", "doi": "10.1038/s41467-023-43514-6", "pmcid": "PMC10684646", "url": "https://pubmed.ncbi.nlm.nih.gov/38016950/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38016950/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID38016950", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "NR-SAFE four-week high-dose NR increased NAD with no observed major safety problem and a clinical PD score signal.", "what_it_does_not_show": "Clinical change also tracked shorter levodopa-dose interval; short pharmacological timing confounding prevents unique NR or broader healthy-aging attribution.", "confounders_present": [ "Clinical change also tracked shorter levodopa-dose interval; short pharmacological timing confounding prevents unique NR or broader healthy-aging attribution." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 52, "pmid": "37159264", "title": "Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease.", "citation": "Ahmadi A, Begue G, Valencia AP et al. Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease. JCI insight. 2023.", "doi": "10.1172/jci.insight.167274", "pmcid": "PMC10393227", "url": "https://pubmed.ncbi.nlm.nih.gov/37159264/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37159264/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37159264", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "CKD crossover NR/CoQ10 altered metabolic/lipid measures without greater VO2peak, work or work efficiency.", "what_it_does_not_show": "Submaximal oxygen changes do not overturn primary exercise nulls; six-week disease-specific other-molecule results are not NMN efficacy.", "confounders_present": [ "Submaximal oxygen changes do not overturn primary exercise nulls; six-week disease-specific other-molecule results are not NMN efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 53, "pmid": "36703196", "title": "Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: a randomised, double-blinded, placebo-controlled phase-II trial.", "citation": "Yulug B, Altay O, Li X et al. Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: a randomised, double-blinded, placebo-controlled phase-II trial. Translational neurodegeneration. 2023.", "doi": "10.1186/s40035-023-00336-2", "pmcid": "PMC9879258", "url": "https://pubmed.ncbi.nlm.nih.gov/36703196/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36703196/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36703196", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "An AD combined-metabolic-activator trial reported within-group cognition change and a selected higher-baseline treatment contrast.", "what_it_does_not_show": "NR is one of four ingredients; subgroup and within-arm analyses do not establish component necessity or general healthy-aging benefit.", "confounders_present": [ "NR is one of four ingredients; subgroup and within-arm analyses do not establish component necessity or general healthy-aging benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 54, "pmid": "33524145", "title": "Nicotinamide Riboside Enhances In Vitro Beta-adrenergic Brown Adipose Tissue Activity in Humans.", "citation": "Nascimento EBM, Moonen MPB, Remie CME et al. Nicotinamide Riboside Enhances In Vitro Beta-adrenergic Brown Adipose Tissue Activity in Humans. The Journal of clinical endocrinology and metabolism. 2021.", "doi": "10.1210/clinem/dgaa960", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/33524145/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33524145/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NR-NCT02835664", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "NR stimulated cultured human BAT uncoupling but did not increase in vivo human BAT activity/thermogenesis.", "what_it_does_not_show": "Actual cell-to-human dissociation bounds translation; another precursor and brown-fat endpoint do not establish older NMN physical function.", "confounders_present": [ "Actual cell-to-human dissociation bounds translation; another precursor and brown-fat endpoint do not establish older NMN physical function." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 55, "pmid": "36652727", "title": "Nicotinamide Mononucleotide Alleviates Angiotensin II-Induced Human Aortic Smooth Muscle Cell Senescence in a Microphysiological Model.", "citation": "Yin X, Abudupataer M, Ming Y et al. Nicotinamide Mononucleotide Alleviates Angiotensin II-Induced Human Aortic Smooth Muscle Cell Senescence in a Microphysiological Model. Journal of cardiovascular pharmacology. 2023.", "doi": "10.1097/FJC.0000000000001400", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36652727/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36652727/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36652727", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "in vitro", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "NMN pretreatment increased NAD and reduced angiotensin-II smooth-muscle-cell senescence in a mechanically stimulated organ-on-chip.", "what_it_does_not_show": "A microphysiological induced-cell model is not prevented clinical aneurysm, human physical function or lifespan extension.", "confounders_present": [ "A microphysiological induced-cell model is not prevented clinical aneurysm, human physical function or lifespan extension." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 56, "pmid": "36002548", "title": "Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women.", "citation": "Fukamizu Y, Uchida Y, Shigekawa A et al. Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women. Scientific reports. 2022.", "doi": "10.1038/s41598-022-18272-y", "pmcid": "PMC9400576", "url": "https://pubmed.ncbi.nlm.nih.gov/36002548/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36002548/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36002548", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Four-week high-dose NMN in 31 adults aged 20–65 had no major examined safety abnormality.", "what_it_does_not_show": "Short mixed-age tolerability does not establish older function, long-term tumor risk or a universal safe dose.", "confounders_present": [ "Short mixed-age tolerability does not establish older function, long-term tumor risk or a universal safe dose." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 57, "pmid": "38430946", "title": "Towards personalized nicotinamide mononucleotide (NMN) supplementation: Nicotinamide adenine dinucleotide (NAD) concentration.", "citation": "Kuerec AH, Wang W, Yi L et al. Towards personalized nicotinamide mononucleotide (NMN) supplementation: Nicotinamide adenine dinucleotide (NAD) concentration. Mechanisms of ageing and development. 2024.", "doi": "10.1016/j.mad.2024.111917", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38430946/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38430946/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NMN-NCT04823260", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Shared 80-person NMN posthoc analysis associated NAD change with walk/SF36 response and modeled marker doses.", "what_it_does_not_show": "Achieved marker associations and selected response models do not randomize the NAD mediator, validate personalised dosing or add a causal trial.", "confounders_present": [ "Achieved marker associations and selected response models do not randomize the NAD mediator, validate personalised dosing or add a causal trial." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 58, "pmid": "42048163", "title": "NAD+ augmentation by nicotinamide riboside engages SLIT2/ROBO1 signaling to attenuate Th17 inflammation in psoriasis.", "citation": "Han K, Klein RJ, Recupero TC et al. NAD+ augmentation by nicotinamide riboside engages SLIT2/ROBO1 signaling to attenuate Th17 inflammation in psoriasis. JCI insight. 2026.", "doi": "10.1172/jci.insight.203826", "pmcid": "PMC13313537", "url": "https://pubmed.ncbi.nlm.nih.gov/42048163/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42048163/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42048163", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "NR psoriasis trial and cellular genetic/pharmacological work linked marker immune suppression to SLIT2/ROBO1 signaling.", "what_it_does_not_show": "Four-week immune pathway endpoints are not older physical healthspan; mechanism in psoriasis cannot supply NMN aging necessity or equivalence.", "confounders_present": [ "Four-week immune pathway endpoints are not older physical healthspan; mechanism in psoriasis cannot supply NMN aging necessity or equivalence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 59, "pmid": "35998039", "title": "A randomized placebo-controlled trial of nicotinamide riboside and pterostilbene supplementation in experimental muscle injury in elderly individuals.", "citation": "Jensen JB, Dollerup OL, Møller AB et al. A randomized placebo-controlled trial of nicotinamide riboside and pterostilbene supplementation in experimental muscle injury in elderly individuals. JCI insight. 2022.", "doi": "10.1172/jci.insight.158314", "pmcid": "PMC9675477", "url": "https://pubmed.ncbi.nlm.nih.gov/35998039/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35998039/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID35998039", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "NR/pterostilbene in an older induced-muscle-injury trial did not improve stem-cell recruitment or muscle-recovery measures.", "what_it_does_not_show": "Combination and injury model differ from chronic older NMN use; tissue changes and short follow-up need separate clinical interpretation.", "confounders_present": [ "Combination and injury model differ from chronic older NMN use; tissue changes and short follow-up need separate clinical interpretation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 60, "pmid": "37446292", "title": "Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD+ Biosynthesis in Whole Mice.", "citation": "Sauve AA, Wang Q, Zhang N et al. Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD+ Biosynthesis in Whole Mice. International journal of molecular sciences. 2023.", "doi": "10.3390/ijms241311114", "pmcid": "PMC10342116", "url": "https://pubmed.ncbi.nlm.nih.gov/37446292/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37446292/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37446292", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Triple-isotope mouse tracing indicated NMN-induced NAD largely arises through nicotinamide/NR salvage with little intact uptake.", "what_it_does_not_show": "Route/tissue mouse pharmacodynamics cannot establish identical human delivery or function and prevents assuming oral NMN directly enters every target cell.", "confounders_present": [ "Route/tissue mouse pharmacodynamics cannot establish identical human delivery or function and prevents assuming oral NMN directly enters every target cell." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 61, "pmid": "38871078", "title": "Metformin-induced changes in the gut microbiome and plasma metabolome are associated with cognition in men.", "citation": "Rosell-Díaz M, Petit-Gay A, Molas-Prat C et al. Metformin-induced changes in the gut microbiome and plasma metabolome are associated with cognition in men. Metabolism: clinical and experimental. 2024.", "doi": "10.1016/j.metabol.2024.155941", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38871078/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38871078/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID38871078", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Metformin cohorts and pilot samples associated microbiome/metabolite patterns with cognition mainly in a sex-stratified analysis.", "what_it_does_not_show": "Whole-cohort microbial ratio association was null; exploratory sex stratification and mixed designs do not isolate a necessary gut mediator or NMN equivalence.", "confounders_present": [ "Whole-cohort microbial ratio association was null; exploratory sex stratification and mixed designs do not isolate a necessary gut mediator or NMN equivalence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 62, "pmid": "38869746", "title": "Metformin as adjuvant therapy in obese knee osteoarthritis patients.", "citation": "Aiad AAE, El-Haggar SM, El-Barbary AM et al. Metformin as adjuvant therapy in obese knee osteoarthritis patients. Inflammopharmacology. 2024.", "doi": "10.1007/s10787-024-01495-y", "pmcid": "PMC11300470", "url": "https://pubmed.ncbi.nlm.nih.gov/38869746/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38869746/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID38869746", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Metformin added to celecoxib improved WOMAC pain/function and selected markers in obese knee-OA patients over twelve weeks.", "what_it_does_not_show": "A genuine disease-specific adjunct positive is retained, with retrospective registration; it is not equivalent to NMN physical-aging or life-extension evidence.", "confounders_present": [ "A genuine disease-specific adjunct positive is retained, with retrospective registration; it is not equivalent to NMN physical-aging or life-extension evidence." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 63, "pmid": "39363095", "title": "Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome.", "citation": "Vinicki M, Pribić T, Vučković F et al. Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome. GeroScience. 2025.", "doi": "10.1007/s11357-024-01349-z", "pmcid": "PMC11979073", "url": "https://pubmed.ncbi.nlm.nih.gov/39363095/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39363095/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID39363095", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "In younger men, testosterone changed IgG glycan measures while metformin did not significantly alter glycosylation.", "what_it_does_not_show": "GlycanAge and another age/molecule are not physical efficacy or human healthspan; null marker response does not prove all clinical effects absent.", "confounders_present": [ "GlycanAge and another age/molecule are not physical efficacy or human healthspan; null marker response does not prove all clinical effects absent." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 64, "pmid": "30548390", "title": "Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults.", "citation": "Konopka AR, Laurin JL, Schoenberg HM et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging cell. 2019.", "doi": "10.1111/acel.12880", "pmcid": "PMC6351883", "url": "https://pubmed.ncbi.nlm.nih.gov/30548390/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30548390/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID30548390", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Metformin attenuated exercise VO2max/insulin-sensitivity and mitochondrial adaptations in older adults despite training benefits.", "what_it_does_not_show": "Variable individual response is not a responder-defined efficacy scope; this exercise interaction does not negate established diabetic indications or determine NMN efficacy.", "confounders_present": [ "Variable individual response is not a responder-defined efficacy scope; this exercise interaction does not negate established diabetic indications or determine NMN efficacy." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 65, "pmid": "29383869", "title": "Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults.", "citation": "Kulkarni AS, Brutsaert EF, Anghel V et al. Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging cell. 2018.", "doi": "10.1111/acel.12723", "pmcid": "PMC5847877", "url": "https://pubmed.ncbi.nlm.nih.gov/29383869/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29383869/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID29383869", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Six-week metformin in about-70-year-old adults changed tissue gene pathways and selected postprandial metabolic responses.", "what_it_does_not_show": "Omics and physiology do not establish physical performance, slower aging or necessary mTOR/MYC mediation.", "confounders_present": [ "Omics and physiology do not establish physical performance, slower aging or necessary mTOR/MYC mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 66, "pmid": "42532077", "title": "Metformin added to lifestyle intervention for physical function in older adults with obesity (DEMFOS trial): a randomised controlled trial.", "citation": "Nava MLD, Viola V, Aguilar M et al. Metformin added to lifestyle intervention for physical function in older adults with obesity (DEMFOS trial): a randomised controlled trial. The lancet. Healthy longevity. 2026.", "doi": "10.1016/j.lanhl.2026.100883", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/42532077/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42532077/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42532077", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "DEMFOS found lifestyle-related performance benefit but no added six-month metformin effect over matched intensive lifestyle.", "what_it_does_not_show": "The correct randomized additive-drug contrast is null; benefit versus weaker lifestyle cannot be attributed to metformin or equivalent NMN action.", "confounders_present": [ "The correct randomized additive-drug contrast is null; benefit versus weaker lifestyle cannot be attributed to metformin or equivalent NMN action." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 67, "pmid": "35492586", "title": "Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals.", "citation": "Long DE, Kosmac K, Dungan CM et al. Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals. Frontiers in physiology. 2022.", "doi": "10.3389/fphys.2022.872745", "pmcid": "PMC9047873", "url": "https://pubmed.ncbi.nlm.nih.gov/35492586/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35492586/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "MASTERS-NCT02308228", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "MASTERS statin secondary analysis found an apparent growth-response modification but no significant strength benefit.", "what_it_does_not_show": "Shared parent and nonrandom baseline statin use cannot establish randomized drug synergy; hypertrophy does not equal strength or longevity.", "confounders_present": [ "Shared parent and nonrandom baseline statin use cannot establish randomized drug synergy; hypertrophy does not equal strength or longevity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 68, "pmid": "33428709", "title": "Association of Intensive Lifestyle and Metformin Interventions With Frailty in the Diabetes Prevention Program Outcomes Study.", "citation": "Hazuda HP, Pan Q, Florez H et al. Association of Intensive Lifestyle and Metformin Interventions With Frailty in the Diabetes Prevention Program Outcomes Study. The journals of gerontology. Series A, Biological sciences and medical sciences. 2021.", "doi": "10.1093/gerona/glaa295", "pmcid": "PMC8087265", "url": "https://pubmed.ncbi.nlm.nih.gov/33428709/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33428709/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "DPP-DPPOS", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "DPPOS follow-up found lower frailty odds after original lifestyle assignment but not metformin assignment.", "what_it_does_not_show": "Shared long-term parent and later cointerventions limit isolated maintenance effects; a genuine lifestyle signal does not prove metformin or NMN geroprotection.", "confounders_present": [ "Shared long-term parent and later cointerventions limit isolated maintenance effects; a genuine lifestyle signal does not prove metformin or NMN geroprotection." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 69, "pmid": "42023167", "title": "Metformin and epigenetic age in non-diabetic older people with HIV in Madrid (METFORAGING): a double-blind, randomised, placebo-controlled, pilot trial.", "citation": "Marcelo-Calvo C, Esteban-Cantos A, Jurado F et al. Metformin and epigenetic age in non-diabetic older people with HIV in Madrid (METFORAGING): a double-blind, randomised, placebo-controlled, pilot trial. EClinicalMedicine. 2026.", "doi": "10.1016/j.eclinm.2026.103874", "pmcid": "PMC13098334", "url": "https://pubmed.ncbi.nlm.nih.gov/42023167/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42023167/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42023167", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "METFORAGING found no significant 96-week primary PhenoAge difference in a small older-HIV metformin trial.", "what_it_does_not_show": "Under-recruited PP analysis, biomarkers and disease-specific population do not establish lifespan or equivalent healthy-aging benefit.", "confounders_present": [ "Under-recruited PP analysis, biomarkers and disease-specific population do not establish lifespan or equivalent healthy-aging benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 70, "pmid": "33071237", "title": "Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults.", "citation": "Kulkarni AS, Peck BD, Walton RG et al. Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults. Aging. 2020.", "doi": "10.18632/aging.104096", "pmcid": "PMC7655218", "url": "https://pubmed.ncbi.nlm.nih.gov/33071237/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33071237/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "MASTERS-NCT02308228", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2", "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "MASTERS transcriptomic secondary analysis found altered exercise/aging-signature pathways alongside the parent's blunted hypertrophy.", "what_it_does_not_show": "Youthful expression alongside adverse growth response illustrates marker/function separation; shared biopsies do not add an independent trial or unique mediator proof.", "confounders_present": [ "Youthful expression alongside adverse growth response illustrates marker/function separation; shared biopsies do not add an independent trial or unique mediator proof." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 75, "verified": 75, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Γ", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Biomarker change without functional/phenotypic change caps at Γ.", "specific_trigger": "NMN reliably changes blood NAD-related exposure measures across several controlled formulations. These are genuine pharmacodynamic effects, not proof that muscle NAD was functionally limiting or that NAD itself is the necessary mediator. Different salvage routes and compartments prevent direct uptake and functional-aging inference; marker-only support retains Γ.", "resulting_ceiling": "Γ" }, { "subclaim_id": "SC3", "cap": "Γ", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Biomarker change without functional/phenotypic change caps at Γ.", "specific_trigger": "A true short-term gait effect does not itself establish slower biological aging, disease prevention or longer human lifespan. No qualifying NMN clinical aging-trajectory/survival set was examined. Animal physiology, NAD markers and algorithmic biological-age scores are separate outcomes and systems; cap 4 blocks their promotion to the broad longevity inference.", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Nicotinamide mononucleotide supplementation improves physical function in older adults.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Universal marker cap4 binds NAD/clock-to-physical or physical-to-longevity inference, not measured gait itself. Association cap2 binds NAD-gait correlations and diabetic survival cohorts, not the randomized function contrast. Rubric06 clinical adaptation scores this non-lifespan physical claim on its declared phenotype. Full-body trial-conduct concerns lower confidence and constrain higher thresholds; they are not hidden changes to registration. No weakest clinical-null or biomarker leg is re-capped over an independently complementary same-scope set; no high-ladder convergent mediator set exists.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "NAD exposure is not functional benefit or mediator necessity." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "NMN reliably changes blood NAD-related exposure measures across several controlled formulations. These are genuine pharmacodynamic effects, not proof that muscle NAD was functionally limiting or that NAD itself is the necessary mediator. Different salvage routes and compartments prevent direct uptake and functional-aging inference; marker-only support retains Γ.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID38789831", "gamma_hard_rules_triggered": [ "Direct gait is a phenotype, not a NAD-only metric; confidence is Low because of endpoint multiplicity and study-conduct concerns." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "A twelve-week placebo-controlled trial in baseline age65–75 reports a baseline-adjusted secondary four-metre gait-time difference, and the smaller older-men trial has nominal gait signals with substantial allocation errors and uncorrected exploratory testing. Our registered gate permits gait outcomes and does not secretly require a study-primary endpoint. The direct functional contrast therefore supports a tentative first clinical crossing, Δ, with Low confidence. Stepping, grip, SPPB, chair-stand and older-diabetic primary nulls remain explicit. This is not established broad functional improvement or mechanistic proof; multiplicity and disrupted balance leave the tentative crossing vulnerable.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "Human aging/lifespan was not established from short function or markers." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "A true short-term gait effect does not itself establish slower biological aging, disease prevention or longer human lifespan. No qualifying NMN clinical aging-trajectory/survival set was examined. Animal physiology, NAD markers and algorithmic biological-age scores are separate outcomes and systems; cap 4 blocks their promotion to the broad longevity inference.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "No clinical equivalence crossing; genuine separate drug outcomes remain intact." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "NR and metformin are distinct exposures with different disease-specific successes and nulls, not clinically established equivalent healthy-aging interventions. NR has a genuine PAD walking trial positive, while metformin frailty, PAD and lifestyle-additive function trials have context-specific nulls and some exercise interactions. A knee-OA adjunct metformin positive is also retained. No direct equivalence or common healthy-aging efficacy experiment establishes the proposed equality; this unsupported generalization is Α rather than a declaration that either molecule is universally ineffective.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Demonstrate target-tissue NAD restoration and function with mechanism-specific perturbation/rescue, rather than peripheral exposure alone." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "yes", "supporting_evidence": [ "[1] Actual original PDF Methods/Results confirm age65–75, twelve-week assigned NMN, null stepping/grip/SPPB scores and a baseline-adjusted positive secondary four-metre time." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires causal effect in constrained contexts, backgrounds, or species.", "satisfied": "no", "supporting_evidence": [ "[1] Actual original PDF Methods/Results confirm age65–75, twelve-week assigned NMN, null stepping/grip/SPPB scores and a baseline-adjusted positive secondary four-metre time." ], "what_would_cross_it": "Independently replicate a prespecified functional estimand in a sufficiently powered exact-formulation trial with familywise control, proper allocation, complete follow-up and meaningful effect sizes. Map baseline disease/function and dose without selecting outcomes afterward." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Measure clinical disease-free/function trajectory or survival in long prospective human NMN work and isolate mediation, rather than infer longevity from a surrogate." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "Directly compare exact molecules or undertake separate adequately powered clinical trials with justified equivalence margins and matched population/outcomes." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "Morifuji stepping primary, grip and total SPPB null despite secondary gait and NAD positivity.", "Kim all-group sit-to-stand improvement and no demonstrated NMN-placebo pair superiority.", "Igarashi allocation error excludes22at week12, with uncorrected exploratory tests and limited remaining sample.", "Older diabetic impaired-function primary grip/walk null at24weeks.", "Short MIB626 strength/fatigue/aerobic/stair outcomes null despite NAD rise.", "Younger-runner ventilatory-threshold signals coexist with VO2max/peak-power nulls.", "NR-PAD benefit does not generalize to all NR disease trials or to metformin.", "Metformin training hypertrophy/fitness interactions show that biomarker-pathway effects need not improve function." ], "note": "Several baseline disease, age, duration, dose and endpoint contexts were examined; results are heterogeneous and cross-trial contrasts do not prove treatment-by-subgroup interactions. The tentative positive is fixed to actual age65–75 twelve-week assigned gait, rather than redefining the entire claim to NAD responders. It does not yet provide sufficiently secure replicated context causality for Ε. Younger or shorter trials remain adjacent evidence, not failures or successes inside SC2." }, "falsification_patterns_met": [ { "pattern": "Marker engagement does not uniformly improve function", "evidence": "Multiple controlled NMN/NR studies have exposure positives and physical/cognitive nulls. The cap bounds marker inference without cancelling the separately measured gait contrast.", "downgrade_applied": false }, { "pattern": "Dose/class generalization is not established", "evidence": "Exact disease/duration/molecule contrasts differ, with metformin nulls and NR-PAD positives. A class-wide or lifespan claim cannot borrow a narrow functional result.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Within-group change treated as randomized benefit", "where": "Kim all-arm sit-to-stand improvements and large NMN-PM Cohen d do not establish NMN-placebo superiority." }, { "pitfall": "Biomarker confirmation", "where": "NAD, mitochondrial and trained-age readouts do not establish physical benefit or life extension." }, { "pitfall": "Posthoc primary-endpoint gate", "where": "Our preregistered gate allows actual gait; absence of a trial-primary success is not automatic rejection of every controlled secondary signal." }, { "pitfall": "Multiplicity and allocation ignored", "where": "Nominal Pvalues, extensive exploratory testing and22-person supplier error lower certainty." }, { "pitfall": "Mechanism and molecule conflation", "where": "NR, NMN, mixtures and metformin are not interchangeable trials; target engagement is not necessary mediation." }, { "pitfall": "Study reports counted as independent lines", "where": "MASTERS, DPPOS and NMN dose-trial posthoc papers retain parent IDs." } ], "causal_tally_audit": { "tally_claimed_by_document": 1, "tally_after_audit": 1, "tally_unit": "Positive qualifying study units across scoped subclaims (one: the twelve-week randomized gait-time contrast supporting SC2), not independent causal lines or full-claim necessity/sufficiency.", "screened_discriminating_contrasts": 54, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "One positive qualifying source is counted for the tentative ≥eight-week primary gate; nominal six-week/pooled signals and marker trials are not added as strong independent crossings.", "NAD responder correlations, shared trials, other molecules and nonregistered age/duration do not add independent NMN functional causal units.", "Genuine other-molecule disease-specific positives and all measured nulls retain their scope without being loaned into NMN aging proof." ] }, "steelman": { "case_one_rung_higher": "Ε could be defended from two older-adult gait signals and null strength/disease boundaries. Its strongest version needs reproducible clinically credible positive context attribution. Supplier errors, uncorrected testing, a secondary endpoint and incomplete observations leave the present causality/context map too fragile for established context-specific efficacy.", "case_one_rung_lower": "Γ could be defended by treating the evidence as NAD markers plus exploratory functional leads. The strongest concern is real multiplicity/conduct uncertainty. However, actual Morifuji M/R give a randomized baseline-adjusted gait outcome under the registered age/duration gate; requiring a study-primary endpoint would add a new rule after seeing results. Δ with Low confidence preserves that tentative measured functional crossing while making fragility explicit.", "which_rejected": "Tentatively retainΔ Low. Reject a confidentΕ context claim because independent prespecified functional confirmation and clear context interactions are missing. Reject a blanketΓ marker-only account because one controlled actual gait phenotype meets our declared endpoint gate. A correction or failed credible replication could change the first-crossing assessment; source attribution and final clinical certainty remain distinct.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Randomize baseline-defined ≥60 adults to exact NMN formulation and matched placebo for24weeks, with gait/strength/capacity prespecified as primary or multiplicity-controlled co-primary, meaningful effect size and complete assignment-based analysis. Include prospectively defined healthy and impaired-function/diabetes strata with interaction testing, independent blinded assessors and proper allocation auditing. Measure muscle NAD and pathway controls separately, and extend functional/disease follow-up." }, "final_score": { "hsef_level": "Δ", "hsef_descriptor": "First field-valid causal perturbation crossed", "confidence": "Low", "confidence_rationale": "70 primary reports with 3 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Primary SC2 tentatively crosses Δ, with Low confidence, because the registered physical-function gate includes a genuine assigned secondary gait contrast. The quality concerns—multiple endpoints, incomplete twelve-week observations, an older trial allocation error and exploratory testing—are not hidden or converted into an unstated primary-endpoint requirement. Functional benefit is inconsistent across measures and contexts, and a separate emerging longer-dose trial adds a null boundary. Evidence does not establish broad strength/exercise efficacy, isolated NAD necessity or human longevity. SC1/SC3 marker-to-clinical inference and SC4 molecule equivalence remain separately bounded." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "Assigned NMN precedes target-marker and tentative functional changes. Necessity, initiation and rate limitation for human age-related functional decline are unproven. Other interventions modify function and several exposures change markers without benefit, so the role describes a possible trajectory modifier rather than a primary aging driver.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Recent clinical function trials and ongoing pharmacodynamic/pathway work are identified, but no reliably verified pending exact older-function result was established. UMIN000054187 targets the boundary yet has conflicting published/unpublished fields without an identified result; it is not asserted to be currently running. This coarse label records the limitation of the verified current-work inventory, not a denial of completed clinical causal research.", "justification": "Recent clinical function trials and ongoing pharmacodynamic/pathway work are identified, but no reliably verified pending exact older-function result was established. UMIN000054187 targets the boundary yet has conflicting published/unpublished fields without an identified result; it is not asserted to be currently running. This coarse label records the limitation of the verified current-work inventory, not a denial of completed clinical causal research." }, "stability": { "value": "Stable", "trigger": "No reliable named pending result was verified: the checked function registry has contradictory publication fields and no result link. Future independent replication could strengthen or overturn the tentative crossing, but a proposed study or ambiguous record is not a verified pending trigger.", "justification": "No reliable named pending result was verified: the checked function registry has contradictory publication fields and no result link. Future independent replication could strengthen or overturn the tentative crossing, but a proposed study or ambiguous record is not a verified pending trigger." }, "divergence": { "implied_level": null, "implied_level_basis": "Exposure, geroprotection, dose optimization and disease-specific trial claims imply different scopes; no measured field-implied score.", "assessed_level": "Δ", "gap_in_rungs": null, "value": "Contested", "justification": "The field framing is genuinely split and no single implied level applies: consumer and supplier framing of NMN implies a settled functional benefit well above the assessed level, while the clinical-trial literature itself presents a null-dominated picture at or below it. No single numerical belief gap is therefore inferred, and none is invented from supplement marketing or a provider strength label." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "none assigned", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": true, "new_level": "Δ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Randomize baseline-defined ≥60 adults to exact NMN formulation and matched placebo for24weeks, with gait/strength/capacity prespecified as primary or multiplicity-controlled co-primary, meaningful effect size and complete assignment-based analysis. Include prospectively defined healthy and impaired-function/diabetes strata with interaction testing, independent blinded assessors and proper allocation auditing. Measure muscle NAD and pathway controls separately, and extend functional/disease follow-up.", "readout": "Prespecified meaningful gait, grip/knee strength and exercise capacity, adverse events and durability; blood/tissue NAD as mechanistic secondary and lifespan/disease trajectory separate.", "critical_control": "Matched formulations, independent blinded function assessment and allocation audit, practice-effect/run-in measurement, full-population estimands, missing-data sensitivity, prospective multiplicity and baseline-stratum interaction.", "supporting_result": "A clear replicated functional treatment contrast with adequate precision would strengthen the tentative crossing and map context; mediation needs independently targeted pathway evidence.", "falsifying_result": "Exposure increase without multiplicity-controlled function leaves benefit unconfirmed in that context; no posthoc NAD-responder or favorable-test exclusion can rescue the assigned result." } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Adequate prespecified objective-function replication and clinically interpretable effect size.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Independent verification of exact formulations, target-tissue NAD and necessary functional mediator.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Prospective baseline disease/function/sex and dose interactions rather than cross-trial subgroup narratives.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Complete missing-data, allocation-error and multiplicity audits across older trials.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Longer clinical functional trajectory, disease incidence and survival rather than biological-age algorithms.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 6", "statement": "Long-term safety and drug/exercise interactions with molecule-specific attribution.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-13", "reviewer": "Codex", "evidence_base_note": "70 primary reports; literature cutoff 2026-10-13; source examination UTC date 2026-10-13; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez, separately logged public original-body retrieval, and Consensus Pro browser searches. Provider output retained as observed browser text with citation-link mappings, or as previously exported connector documents where present. AI synthesis is not primary full-text verification. Consensus retrieved/included counts are not examined-primary counts. Scite monthly limit was reached earlier in this session; no new Scite query or incoming citation-context audit is claimed for these cases. Tool receipts record actual use. Supplementary discovery outputs do not earn primary-count credit. No independent blinded review.", "skill_version": "5.3", "validator_run": "PASS: exact archived HSEF v5.3 validator rerun after final sealing.", "validator_warnings_addressed": "No warnings.", "limits": "Bounded source-based critical review; no complete-paper/supplement audit, independent scientific peer review or blinded calibration. Revision cases retain original prose outside the three framework output blocks and have explicit correction logs." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "These topic families were selected from an editorial traffic-priority list. Selection was visible; no blind calibration or predetermined clinical verdict was preregistered." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "NMN/placebo assignment makes a clinical first crossing possible. Higher dose/exposure or blood-NAD gradients do not establish functional dose-response in the registered older population, and other molecules cannot substitute as independent same-node clinical evidence. Human genetics and lifelong natural experiments on the exact supplement/mediator were considered but no qualifying set was examined. Reliable prespecified replicated function, target-tissue mechanism and durable trajectory are needed for higher rungs." }, { "kind": "natural_experiment", "available": false, "why_not_sufficient": "NMN/placebo assignment makes a clinical first crossing possible. Higher dose/exposure or blood-NAD gradients do not establish functional dose-response in the registered older population, and other molecules cannot substitute as independent same-node clinical evidence. Human genetics and lifelong natural experiments on the exact supplement/mediator were considered but no qualifying set was examined. Reliable prespecified replicated function, target-tissue mechanism and durable trajectory are needed for higher rungs." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "NMN/placebo assignment makes a clinical first crossing possible. Higher dose/exposure or blood-NAD gradients do not establish functional dose-response in the registered older population, and other molecules cannot substitute as independent same-node clinical evidence. Human genetics and lifelong natural experiments on the exact supplement/mediator were considered but no qualifying set was examined. Reliable prespecified replicated function, target-tissue mechanism and durable trajectory are needed for higher rungs." }, { "kind": "withdrawal_rechallenge", "available": true, "why_not_sufficient": "NMN/placebo assignment makes a clinical first crossing possible. Higher dose/exposure or blood-NAD gradients do not establish functional dose-response in the registered older population, and other molecules cannot substitute as independent same-node clinical evidence. Human genetics and lifelong natural experiments on the exact supplement/mediator were considered but no qualifying set was examined. Reliable prespecified replicated function, target-tissue mechanism and durable trajectory are needed for higher rungs." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "NMN/placebo assignment makes a clinical first crossing possible. Higher dose/exposure or blood-NAD gradients do not establish functional dose-response in the registered older population, and other molecules cannot substitute as independent same-node clinical evidence. Human genetics and lifelong natural experiments on the exact supplement/mediator were considered but no qualifying set was examined. Reliable prespecified replicated function, target-tissue mechanism and durable trajectory are needed for higher rungs." } ], "convergence_present": false, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 70, "claims_total": 75, "claims_verified": 75, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 70, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Actual original PDF Methods/Results confirm age65–75, twelve-week assigned NMN, null stepping/grip/SPPB scores and a baseline-adjusted positive secondary four-metre time. Multiple endpoint testing and selective four-week follow-up limit certainty; two placebo twelve-week observations were missing, and NAD correlation is not mediator necessity or lifespan.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: Original PDF Methods page3/table1; web lines136-174, Original PDF Methods/Results pages6-7; web lines403-445, Original PDF Results figure2 page11; web lines670-674. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C2", "text": "Actual Methods/Results confirm ≥65, twelve-week four-arm timing assignment, secondary physical outcomes and a nominal sit-to-stand interaction. Bonferroni posthoc reports improvement within every group rather than demonstrated NMN-placebo pair superiority; largest within-group effect is not treatment efficacy, and primary sleep interaction was null.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:2. Materials and Methods:paragraph0, 1:2. Materials and Methods:paragraph1, 1:2. Materials and Methods:paragraph2, 1:2. Materials and Methods:paragraph3, 1:2. Materials and Methods:paragraph7, 1:2. Materials and Methods:paragraph8, 2:3. Results:paragraph0, 2:3. Results:paragraph1, 2:3. Results:paragraph2, 2:3. Results:paragraph3. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C3", "text": "Twenty-eight-day MIB-626 in 30 overweight adults raised NAD and improved selected weight/lipid/BP measures but not strength, fatigability, aerobic capacity or stair power. Under-eight-week mixed-age physiological trial is outside registered functional scope; markers and cardiometabolic changes cannot replace older-adult function.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C4", "text": "Fourteen-day microcrystalline NMN dose assignment increased blood NMN/NAD and metabolome measures in 32 adults aged 55–80. Pharmacodynamic exposure and short observed tolerability do not establish older-adult eight-week function, formulation interchangeability or lifespan.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C5", "text": "Fourteen older diabetic men with impaired baseline function had no between-group grip or walking benefit after 24 weeks of 250 mg NMN. Small sample limits precision; borderline exploratory frailty/retinal measures do not rescue primary nulls, and healthy versus diabetic baseline context remains distinct.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C6", "text": "NICE randomized 90 PAD adults and found a six-month NR six-minute-walk benefit, while resveratrol added no benefit. NR differs from NMN; one-sided 90% interval and adherence-selected analyses require clear labeling, and an indexed erratum remains linked without detailed correction audit.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C7", "text": "Six-week NR crossover in middle-aged/older adults increased NAD metabolism and reported selected vascular physiology leads. Different molecule, mixed age and short follow-up do not establish registered NMN physical function or human aging/lifespan.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C8", "text": "Ten-week NR in 20 MCI adults increased NAD and selected clocks while cognition remained stable. Uncorrected CBF signals and exploratory clock movement do not establish function or slower aging; drug and disease differ from NMN scope.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C9", "text": "Eight-week NR dose assignment increased blood NAD with no observed dose-related adverse-event differences. Tolerability and pharmacodynamics are not equivalence to NMN, physical benefit or lifetime healthy-aging safety.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C10", "text": "NR crossover changed selected muscle metabolites/body composition but not insulin sensitivity, mitochondrial function or most metabolic endpoints. Minor fat-free-mass change is not measured strength; six-week obese mixed-age NR exposure cannot replace older NMN function.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C11", "text": "NR plus exercise did not improve daytime BP more than placebo plus exercise despite higher NAD catabolites. Short hypertensive trial and posthoc medication-free nighttime trends are distinct from verified physical function or a confirmed baseline subgroup.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C12", "text": "A 12-week NR MCI pilot doubled NAD without improved cognitive primary, total CBF or BP. Exploratory regional-CBF hypotheses do not overturn the primary null or establish NMN function and human longevity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C13", "text": "Two-day NR/pterostilbene escalation in hospitalized AKI patients increased selected NAD measures with variable response and short safety observations. Combination exposure, acute disease and biomarker endpoint do not establish older-adult function, recovery efficacy or healthy-aging equivalence.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C14", "text": "Local mitochondria-targeted NMN hydrogel reduced dexamethasone muscle-cell senescence/mitochondrial abnormalities in preclinical experiments. Delivery includes SS-31/liposome/scaffold coeffects and induced disease; markers and local injections cannot establish oral human functional efficacy or lifespan.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C15", "text": "Seven-month NMN in aging high-fat-diet mice improved selected grip/locomotor and metabolic/organ measures. High dose, diet, species and autophagy correlations differ from human trials; physiological benefit is not examined human or necessarily mouse lifespan extension.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C16", "text": "PERMET found no six-month metformin six-minute-walk or secondary functional advantage in 202 PAD adults without diabetes. Metformin and PAD are distinct from NMN; gastrointestinal events and follow-up attrition matter, and nulls do not negate metformin's established other indications.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C17", "text": "MET-PREVENT found no four-month metformin gait benefit in 72 frail/sarcopenic older adults, with poor tolerability and more admissions. Exact older frailty context is bounded; admissions are observed harms requiring attribution rather than proof of every metformin risk, and this is not NMN.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C18", "text": "Long-term DPPOS original-group analysis found no sustained walking-endurance differences about 20 years after randomization. Later shared interventions and survival/completer selection differ from maintained blinded treatment; one DPP parent is not new clinical longevity proof.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C19", "text": "Small older HIV/diabetes cohort found no metformin association with measured cognition, frailty or physical function. Observational prescribing, restricted disease and low precision do not establish causal absence or equivalence to NMN.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C20", "text": "Posthoc metformin/weight-loss factorial trial in breast-cancer survivors found no significant epigenetic-age assignment effects at six months. Clock null does not by itself establish absent clinical benefit; disease and exposure differ from NMN and human life extension remains unmeasured.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C21", "text": "DPPOS long-term original assignments were not associated with spirometry or respiratory-symptom differences. Shared DPP cohort with later open-label/cointervention exposure is not independent continuous-dose or NMN evidence.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C22", "text": "Two-week metformin in 16 older adults increased muscle H2O2 measures without altering maximal mitochondrial respiration. ROS/biopsy markers and short exposure are not organismal aging or physical benefit; correlations do not establish free-radical causal primacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C23", "text": "HOME posthoc analysis found less weight gain with metformin but no reported dietary-energy explanation over 4.3 years. Selected completed diet histories and self-reported intake cannot prove mediator absence; diabetic weight effect is not NMN function or nondiabetic longevity.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C24", "text": "Metformin pretreatment during brief bedrest altered older-adult muscle atrophy/fibrosis and senescence measures in recovery. Short induced disuse and histology markers do not establish long-term gait, general healthy aging or NMN efficacy; candidate SASP mediation is not isolated.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C25", "text": "EMPOWIR diet plus metformin improved selected weight/fat measures in midlife hyperinsulinemic women with completed follow-up. Mixed treatment/rerandomization and body composition are not older physical function or life extension; marker and outcome-specific positives remain bounded.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C26", "text": "MASTERS metformin blunted resistance-training muscle growth, with a nonsignificant trend in strength gains. Lean-mass/hypertrophy and strength are distinct; the adverse exercise interaction does not quantify NMN efficacy, and an erratum remains attached.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C27", "text": "Large matched metformin AMD cohorts found comparable development/progression under their clinical-significance criterion. Some confidence intervals exclude unity despite authors' equivalence-style criterion; do not conflate statistical and meaningful significance or infer NMN equivalence.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C28", "text": "Longitudinal diabetic metformin cohorts showed no significant individual-cohort clonal-growth effect but a small pooled association. Small molecular clone-rate association is not clinically established protection or NMN longevity; two cohorts remain components of one reported analysis.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C29", "text": "Danish singleton/twin analyses did not reproduce superior survival of metformin-treated diabetes relative to nondiabetic controls. Diabetes status and prescribing confounding prevent inference that metformin causes excess mortality; comparator choice does not establish healthy-person longevity efficacy.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C30", "text": "Diabetic metformin exposure was associated with lower open-angle-glaucoma incidence in a retrospective cohort. Exposure-dose association and model projections are not randomized prevention, human lifespan or equivalence to NAD precursors.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C31", "text": "Older diabetic-veteran metformin use associated with selected lower age-related comorbidity patterns. Latent classes partly defined by outcomes and residual prescribing confounding cannot establish causal baseline subtypes or nondiabetic geroprotection.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C32", "text": "MASTERS secondary analysis linked muscle density with performance and selected metformin exercise-response patterns. Shared parent and baseline/subgroup associations are not independent causal lines or proof that mass or lipid density is the necessary mediator.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C33", "text": "Older diabetic veterans had a metformin-versus-sulfonylurea survival association differing by frailty context. Active-drug selection and diabetes indication do not establish healthy-person life extension or NMN equivalence; frailty association is not randomized prevention.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C34", "text": "An 80-person 60-day NMN dose trial increased NAD and six-minute-walk response in adults aged 40–65, with no HOMA-IR difference. Mixed middle age is outside the full registered at-least-60 population; algorithmic biological-age score and PP analysis do not establish lifespan or isolated NAD mediation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C35", "text": "Ten-week NMN in overweight prediabetic postmenopausal women improved clamp muscle-insulin sensitivity and selected remodeling signals. Clamp/metabolic physiology is not measured strength/gait/exercise capacity or human aging; population and mediators remain distinct.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C36", "text": "NADPARK NR increased variable brain NAD and molecular measures, with clinical changes among NAD responders. Responder-defined clinical association, one-month disease exposure and another precursor do not establish the NMN older-function gate or confirmed neuroprotection.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C37", "text": "Early human NR dosing and mouse studies demonstrated NAD-related pharmacokinetics and sensitive NAAD readouts. Single-person lead and short pharmacodynamics are not function/healthspan or proof that intact NR and NMN share identical tissue routes.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C38", "text": "RYR1-myopathy patients had heterogeneous blood NAD dysregulation, and patient-cell NR changed selected energetic measures. Disease deficiency and cultured myotube responses are not clinical treatment or age-related oral NMN benefit; mouse redox findings did not reproduce all human patterns.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C39", "text": "One-day combined-activator precursor comparisons changed metabolomic NAD products with precursor-specific effects and niacin flushing. Mixture, acute dosing and plasma products do not establish function or interchangeability; direct NMN uptake and health benefit cannot be inferred from ranks.", "carries_number": false, "load_bearing_for": [ "SC1", "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C40", "text": "Six-week NMN plus training improved selected ventilatory-threshold measures in younger/middle-aged runners, while VO2max and peak power did not differ. Outside registered age/duration, training cointervention and outcome multiplicity; ventilatory threshold is not equivalent to peak aerobic capacity or slower aging.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C41", "text": "NR in stable COPD lowered sputum IL8 and increased NAD, with selected persistent marker effects. Inflammation and exploratory clock signatures do not establish pulmonary function, generalized aging or NMN efficacy; drug/disease/time differ.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C42", "text": "Twenty-one-day NR in aged men increased muscle NAD metabolites and lowered selected inflammatory signatures without altered bioenergetics. Target engagement is not physical-function efficacy; short other-precursor exposure cannot cross the registered NMN eight-week gate.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C43", "text": "Actual Methods/Results report nominal gait/left-grip signals, NAD augmentation and no mass effect; a supplier switched supplements in22of42 at week6, leaving ten per arm at week12. Randomized balance was disrupted; every analysis was exploratory without P correction, and six-week left-grip/mixed-duration results cannot alone satisfy the registered ≥eight-week gate.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph10, 1:Results:paragraph11, 1:Results:paragraph133, 1:Results:paragraph214, 2:Discussion:paragraph9, 3:Methods:paragraph1, 3:Methods:paragraph2, 3:Methods:paragraph3, 3:Methods:paragraph4, 3:Methods:paragraph22, 3:Methods:paragraph23, 3:Methods:paragraph24. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C44", "text": "NMN/Sirt3 manipulations changed cultured MSC mitochondrial and senescence measures. Replicative-cell senescence, overexpression and inhibitor effects are not organismal aging or physical function in human recipients; pharmacological specificity remains bounded.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C45", "text": "NR-trial secondary neuronal-enriched-vesicle analysis changed NAD and selected pathology-associated markers. Shared six-week precursor trial and vesicle enrichment do not establish actual brain function, neuron-specific origin certainty or prevented neurodegeneration.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C46", "text": "Thirty healthy subjects receiving 12-week NMN had higher blood NAD/NAMN and no observed major laboratory abnormalities. Pharmacodynamics and limited safety do not establish older-adult physical improvement, intact NMN uptake or lifetime healthy aging.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C47", "text": "Long-term open-label NR in ataxia-telangiectasia showed selected coordination/eye-movement changes relative to historical expectations. No concurrent randomized control, all-age rare disease and different molecule; historical trajectories and practice effects constrain causal transfer to NMN older adults.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C48", "text": "Twelve-week NMN increased serum nicotinamide in middle-aged adults, but arterial-stiffness between-group difference was nonsignificant. Metabolite and trend are not proven function or age slowing; middle age and vascular outcome differ from the physical gate.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C49", "text": "Single-dose NMN in ten men changed pharmacokinetic metabolites with no major short-term examined clinical effects. Uncontrolled hours-long dosing does not establish eight-week function, durable safety or longevity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C50", "text": "Five-month NR twin study altered NAD, mitochondrial and stem-cell measures without improved adiposity/metabolic health. Both twins received NR without placebo, and cellular mitochondrial function differs from measured physical performance; distinct precursor cannot establish NMN efficacy.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C51", "text": "NR-SAFE four-week high-dose NR increased NAD with no observed major safety problem and a clinical PD score signal. Clinical change also tracked shorter levodopa-dose interval; short pharmacological timing confounding prevents unique NR or broader healthy-aging attribution.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C52", "text": "CKD crossover NR/CoQ10 altered metabolic/lipid measures without greater VO2peak, work or work efficiency. Submaximal oxygen changes do not overturn primary exercise nulls; six-week disease-specific other-molecule results are not NMN efficacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C53", "text": "An AD combined-metabolic-activator trial reported within-group cognition change and a selected higher-baseline treatment contrast. NR is one of four ingredients; subgroup and within-arm analyses do not establish component necessity or general healthy-aging benefit.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C54", "text": "NR stimulated cultured human BAT uncoupling but did not increase in vivo human BAT activity/thermogenesis. Actual cell-to-human dissociation bounds translation; another precursor and brown-fat endpoint do not establish older NMN physical function.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C55", "text": "NMN pretreatment increased NAD and reduced angiotensin-II smooth-muscle-cell senescence in a mechanically stimulated organ-on-chip. A microphysiological induced-cell model is not prevented clinical aneurysm, human physical function or lifespan extension.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C56", "text": "Four-week high-dose NMN in 31 adults aged 20–65 had no major examined safety abnormality. Short mixed-age tolerability does not establish older function, long-term tumor risk or a universal safe dose.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C57", "text": "Shared 80-person NMN posthoc analysis associated NAD change with walk/SF36 response and modeled marker doses. Achieved marker associations and selected response models do not randomize the NAD mediator, validate personalised dosing or add a causal trial.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2", "SC3" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C58", "text": "NR psoriasis trial and cellular genetic/pharmacological work linked marker immune suppression to SLIT2/ROBO1 signaling. Four-week immune pathway endpoints are not older physical healthspan; mechanism in psoriasis cannot supply NMN aging necessity or equivalence.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C59", "text": "NR/pterostilbene in an older induced-muscle-injury trial did not improve stem-cell recruitment or muscle-recovery measures. Combination and injury model differ from chronic older NMN use; tissue changes and short follow-up need separate clinical interpretation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC4" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C60", "text": "Triple-isotope mouse tracing indicated NMN-induced NAD largely arises through nicotinamide/NR salvage with little intact uptake. Route/tissue mouse pharmacodynamics cannot establish identical human delivery or function and prevents assuming oral NMN directly enters every target cell.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C61", "text": "Metformin cohorts and pilot samples associated microbiome/metabolite patterns with cognition mainly in a sex-stratified analysis. Whole-cohort microbial ratio association was null; exploratory sex stratification and mixed designs do not isolate a necessary gut mediator or NMN equivalence.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 61 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C62", "text": "Metformin added to celecoxib improved WOMAC pain/function and selected markers in obese knee-OA patients over twelve weeks. A genuine disease-specific adjunct positive is retained, with retrospective registration; it is not equivalent to NMN physical-aging or life-extension evidence.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 62 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C63", "text": "In younger men, testosterone changed IgG glycan measures while metformin did not significantly alter glycosylation. GlycanAge and another age/molecule are not physical efficacy or human healthspan; null marker response does not prove all clinical effects absent.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 63 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C64", "text": "Metformin attenuated exercise VO2max/insulin-sensitivity and mitochondrial adaptations in older adults despite training benefits. Variable individual response is not a responder-defined efficacy scope; this exercise interaction does not negate established diabetic indications or determine NMN efficacy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 64 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C65", "text": "Six-week metformin in about-70-year-old adults changed tissue gene pathways and selected postprandial metabolic responses. Omics and physiology do not establish physical performance, slower aging or necessary mTOR/MYC mediation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 65 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C66", "text": "DEMFOS found lifestyle-related performance benefit but no added six-month metformin effect over matched intensive lifestyle. The correct randomized additive-drug contrast is null; benefit versus weaker lifestyle cannot be attributed to metformin or equivalent NMN action.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 66 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C67", "text": "MASTERS statin secondary analysis found an apparent growth-response modification but no significant strength benefit. Shared parent and nonrandom baseline statin use cannot establish randomized drug synergy; hypertrophy does not equal strength or longevity.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 67 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C68", "text": "DPPOS follow-up found lower frailty odds after original lifestyle assignment but not metformin assignment. Shared long-term parent and later cointerventions limit isolated maintenance effects; a genuine lifestyle signal does not prove metformin or NMN geroprotection.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3", "SC4" ], "source_ns": [ 68 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C69", "text": "METFORAGING found no significant 96-week primary PhenoAge difference in a small older-HIV metformin trial. Under-recruited PP analysis, biomarkers and disease-specific population do not establish lifespan or equivalent healthy-aging benefit.", "carries_number": true, "load_bearing_for": [ "SC1", "SC3", "SC4" ], "source_ns": [ 69 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "C70", "text": "MASTERS transcriptomic secondary analysis found altered exercise/aging-signature pathways alongside the parent's blunted hypertrophy. Youthful expression alongside adverse growth response illustrates marker/function separation; shared biopsies do not add an independent trial or unique mediator proof.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2", "SC3", "SC4" ], "source_ns": [ 70 ], "verification": "verified", "verified_against": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-13", "note": "" }, { "id": "CSC1", "text": "NMN reliably changes blood NAD-related exposure measures across several controlled formulations. These are genuine pharmacodynamic effects, not proof that muscle NAD was functionally limiting or that NAD itself is the necessary mediator. Different salvage routes and compartments prevent direct uptake and functional-aging inference; marker-only support retains Γ.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 22, 23, 24, 25, 28, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 63, 65, 69, 70 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-13", "note": "" }, { "id": "CSC2", "text": "A twelve-week placebo-controlled trial in baseline age65–75 reports a baseline-adjusted secondary four-metre gait-time difference, and the smaller older-men trial has nominal gait signals with substantial allocation errors and uncorrected exploratory testing. Our registered gate permits gait outcomes and does not secretly require a study-primary endpoint. The direct functional contrast therefore supports a tentative first clinical crossing, Δ, with Low confidence. Stepping, grip, SPPB, chair-stand and older-diabetic primary nulls remain explicit. This is not established broad functional improvement or mechanistic proof; multiplicity and disrupted balance leave the tentative crossing vulnerable.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 10, 11, 14, 15, 16, 17, 18, 19, 21, 24, 26, 32, 34, 35, 38, 40, 42, 43, 44, 47, 48, 50, 52, 54, 57, 59, 62, 64, 66, 67, 68, 70 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-13", "note": "" }, { "id": "CSC3", "text": "A true short-term gait effect does not itself establish slower biological aging, disease prevention or longer human lifespan. No qualifying NMN clinical aging-trajectory/survival set was examined. Animal physiology, NAD markers and algorithmic biological-age scores are separate outcomes and systems; cap 4 blocks their promotion to the broad longevity inference.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 8, 9, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 40, 41, 43, 44, 45, 46, 47, 48, 49, 51, 53, 55, 56, 57, 58, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-13", "note": "" }, { "id": "CSC4", "text": "NR and metformin are distinct exposures with different disease-specific successes and nulls, not clinically established equivalent healthy-aging interventions. NR has a genuine PAD walking trial positive, while metformin frailty, PAD and lifestyle-additive function trials have context-specific nulls and some exercise interactions. A knee-OA adjunct metformin positive is also retained. No direct equivalence or common healthy-aging efficacy experiment establishes the proposed equality; this unsupported generalization is Α rather than a declaration that either molecule is universally ineffective.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 6, 7, 8, 9, 10, 11, 12, 13, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 36, 37, 38, 39, 41, 42, 45, 47, 50, 51, 52, 53, 54, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-13", "note": "" }, { "id": "CH", "text": "NMN raises blood NAD; older-adult gait signals are tentative and inconsistent, with no established broader physical or longevity benefit.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 43, 2, 5, 3, 6 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-13", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Morifuji M, Higashi S, Ebihara S et al. Ingestion of β-nicotinamide mononucleotide increased blood NAD levels, maintained walking speed, and improved sleep quality in older adults in a double-blind randomized, placebo-controlled study. GeroScience. 2024.", "tier": "A", "kind": "rct", "pmid": "38789831", "doi": "10.1007/s11357-024-01204-1", "url": "https://pubmed.ncbi.nlm.nih.gov/38789831/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NMN-UMIN000047871", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: Original PDF Methods page3/table1; web lines136-174, Original PDF Methods/Results pages6-7; web lines403-445, Original PDF Results figure2 page11; web lines670-674. No complete-paper or supplement audit claimed.", "carries_claims": [ "C1", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 2, "citation": "Kim M, Seol J, Sato T et al. Effect of 12-Week Intake of Nicotinamide Mononucleotide on Sleep Quality, Fatigue, and Physical Performance in Older Japanese Adults: A Randomized, Double-Blind Placebo-Controlled Study. Nutrients. 2022.", "tier": "A", "kind": "rct", "pmid": "35215405", "doi": "10.3390/nu14040755", "url": "https://pubmed.ncbi.nlm.nih.gov/35215405/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NMN-UMIN000038097", "access_depth": "full_text_partial", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:2. Materials and Methods:paragraph0, 1:2. Materials and Methods:paragraph1, 1:2. Materials and Methods:paragraph2, 1:2. Materials and Methods:paragraph3, 1:2. Materials and Methods:paragraph7, 1:2. Materials and Methods:paragraph8, 2:3. Results:paragraph0, 2:3. Results:paragraph1, 2:3. Results:paragraph2, 2:3. Results:paragraph3. No complete-paper or supplement audit claimed.", "carries_claims": [ "C2", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 3, "citation": "Pencina KM, Valderrabano R, Wipper B et al. Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study. The Journal of clinical endocrinology and metabolism. 2023.", "tier": "A", "kind": "rct", "pmid": "36740954", "doi": "10.1210/clinem/dgad027", "url": "https://pubmed.ncbi.nlm.nih.gov/36740954/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36740954", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C3", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 4, "citation": "Pencina KM, Lavu S, Dos Santos M et al. MIB-626, an Oral Formulation of a Microcrystalline Unique Polymorph of β-Nicotinamide Mononucleotide, Increases Circulating Nicotinamide Adenine Dinucleotide and its Metabolome in Middle-Aged and Older Adults. The journals of gerontology. Series A, Biological sciences and medical sciences. 2023.", "tier": "A", "kind": "rct", "pmid": "35182418", "doi": "10.1093/gerona/glac049", "url": "https://pubmed.ncbi.nlm.nih.gov/35182418/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID35182418", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C4", "CSC1", "CSC2", "CSC3" ] }, { "n": 5, "citation": "Akasaka H, Nakagami H, Sugimoto K et al. Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study. Geriatrics & gerontology international. 2023.", "tier": "A", "kind": "rct", "pmid": "36443648", "doi": "10.1111/ggi.14513", "url": "https://pubmed.ncbi.nlm.nih.gov/36443648/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID36443648", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C5", "CSC1", "CSC2", "CSC3", "CH" ] }, { "n": 6, "citation": "McDermott MM, Martens CR, Domanchuk KJ et al. Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial. Nature communications. 2024.", "tier": "A", "kind": "rct", "pmid": "38871717", "doi": "10.1038/s41467-024-49092-5", "url": "https://pubmed.ncbi.nlm.nih.gov/38871717/", "status_flags": [ "ErratumIn: PMID39134546" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID38871717", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C6", "CSC1", "CSC2", "CSC3", "CSC4", "CH" ] }, { "n": 7, "citation": "Martens CR, Denman BA, Mazzo MR et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature communications. 2018.", "tier": "A", "kind": "rct", "pmid": "29599478", "doi": "10.1038/s41467-018-03421-7", "url": "https://pubmed.ncbi.nlm.nih.gov/29599478/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NR-NCT02921659", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC1", "CSC2", "CSC4" ] }, { "n": 8, "citation": "Orr ME, Kotkowski E, Ramirez P et al. A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. GeroScience. 2024.", "tier": "A", "kind": "rct", "pmid": "37994989", "doi": "10.1007/s11357-023-00999-9", "url": "https://pubmed.ncbi.nlm.nih.gov/37994989/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID37994989", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C8", "CSC1", "CSC3", "CSC4" ] }, { "n": 9, "citation": "Conze D, Brenner C, Kruger CL. Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Scientific reports. 2019.", "tier": "A", "kind": "rct", "pmid": "31278280", "doi": "10.1038/s41598-019-46120-z", "url": "https://pubmed.ncbi.nlm.nih.gov/31278280/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID31278280", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1", "CSC3", "CSC4" ] }, { "n": 10, "citation": "Remie CME, Roumans KHM, Moonen MPB et al. Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans. The American journal of clinical nutrition. 2020.", "tier": "A", "kind": "rct", "pmid": "32320006", "doi": "10.1093/ajcn/nqaa072", "url": "https://pubmed.ncbi.nlm.nih.gov/32320006/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "NR-NCT02835664", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C10", "CSC1", "CSC2", "CSC4" ] }, { "n": 11, "citation": "Lin Y, Zeidan RS, Lapierre-Nguyen S et al. Nicotinamide riboside combined with exercise to treat hypertension in middle-aged and older adults: a pilot randomized clinical trial. 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EClinicalMedicine. 2026.", "tier": "A", "kind": "primary", "pmid": "42023167", "doi": "10.1016/j.eclinm.2026.103874", "url": "https://pubmed.ncbi.nlm.nih.gov/42023167/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "PMID42023167", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C69", "CSC1", "CSC3", "CSC4" ] }, { "n": 70, "citation": "Kulkarni AS, Peck BD, Walton RG et al. Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults. Aging. 2020.", "tier": "A", "kind": "rct", "pmid": "33071237", "doi": "10.18632/aging.104096", "url": "https://pubmed.ncbi.nlm.nih.gov/33071237/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-13", "status_checked_on": "2026-10-13", "study_id": "MASTERS-NCT02308228", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed.", "carries_claims": [ "C70", "CSC1", "CSC2", "CSC3", "CSC4" ] } ], "independence_basis": { "required": false, "lines": [], "shared_failure_mode_checked": true, "note": "No claim reachesΖ. The nominal gait line remains vulnerable to multiplicity and small-study conduct; NMN posthoc response modeling shares its original parent. NR and metformin have different exposures and baseline diseases and do not make independent NMN aging lines. 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Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale." } ], "supplementary_source_checks": [ { "title": "Igarashi et al.,2026: Sustained NAD augmentation by high-dose nicotinamide mononucleotide supplementation in older adults", "url": "https://www.nature.com/articles/s41514-026-00482-7", "status": "Peer-reviewed accepted original published25September2026; DOI10.1038/s41514-026-00482-7; exact PubMed DOI query returned0; no invented PMID. Separately counted outside70PMID-based originals.", "access": "Publisher original abstract actually read; attempted PDF redirected to HTML and did not yield body or supplement reading.", "what_it_shows": "In adults≥65,1250mgNMN daily24weeks raises NAD; auditory primary and physical-performance endpoints show no significant improvement; exploratory changes fail multiple-testing correction.", "what_it_does_not_show": "No universal proof that every dose lacks benefit, no confirmed physical efficacy or human lifespan extension; complete Methods/Results/participant counts were not examined." }, { "title": "UMIN000047871 Morifuji trial registry", "url": "https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000054201", "status": "Public protocol registry, not an additional primary paper; same trial as38789831.", "access": "Original age, design, primary/secondary and exclusion fields actually read.", "what_it_shows": "Ages65–75; randomized double-blind placebo; stepping primary and SPPB/grip secondary, excluding baseline motor dysfunction/serious disease.", "what_it_does_not_show": "No additional trial outcome; stale unpublished field cannot erase the existing2024publisher original." }, { "title": "UMIN000054187 NMN-plus-strength-training registry", "url": "https://center6.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000061872", "status": "Public registered function experiment; fields conflict on publication status. No verified pending or published result inferred.", "access": "Original design, eligibility, primary strength outcomes and status/results fields actually read.", "what_it_shows": "Randomized double-blind NMN/placebo on matched24-week training in≥65reduced-muscle adults;65enrolled. Status says main results published while publication says unpublished, without result URL.", "what_it_does_not_show": "No outcome or reliable pending-readout date; planned future final follow-up and inconsistent status are not evidence of efficacy." } ], "consensus_validation": { "completed": true, "status": "completed_original_source_reconciliation", "provider_mode": "Consensus Pro signed-in browser; observed output and citation link mappings", "queries": [ "https://consensus.app/search/oral-nmn-effects-physical-function/1g0i68mCRJ29oX0Yk-WdQA/" ], "query_record_note": "Exact provider question/response retained privately in its retrieval receipt.", "primary_comparison_count": 12, "primary_comparisons": [ { "pmid": "35215405", "doi": "10.3390/nu14040755", "source_type": "primary study report", "study_group": "NMN-UMIN000038097", "access_depth": "full_text_partial", "consensus_aspect": "Within-group effect versus NMN/placebo efficacy", "result_comparison": "Observed Consensus appropriately notes the weak between-group interpretation. Actual original M/R identify physical outcomes as secondary, a nominal sit-to-stand interaction, Bonferroni posthoc within-arm improvement in every group, and largest pre/post Cohen d for NMN-afternoon. 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This supports registered age/duration eligibility but does not establish no attrition bias or all older disease populations. Provider subgroup/general-function wording remains bounded to this experiment.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/35215405/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\examinations\\original-0-8-10000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\body-presentation-receipts\\35215405-s1-p0-1-2-3-7-8.json", "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\body-presentation-receipts\\35215405-s2-p0-1-2-3.json" ] }, { "pmid": "35927255", "doi": "10.1038/s41514-022-00084-z", "source_type": "primary study report", "study_group": "NMN-UMIN000036321", "access_depth": "full_text_partial", "consensus_aspect": "Only twenty completed versus allocation-related data exclusion", "result_comparison": "Provider describes twenty completed with a post-week-six deviation. Original M/R identify42randomized and a supplier cross-switch in eleven participants per arm, excluding their week-twelve data and leaving10per arm. This is not ordinary20of42follow-up completion; compromised assigned exposure and baseline balance must be explicit.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/35927255/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\examinations\\original-40-48-10000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\body-presentation-receipts\\35927255-s1-p0-2-3-10-11-133-214.json", "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\body-presentation-receipts\\35927255-s2-p9.json", "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\body-presentation-receipts\\35927255-s3-p1-2-3-4-22-23-24.json" ] }, { "pmid": "35927255", "doi": "10.1038/s41514-022-00084-z", "source_type": "primary study report", "study_group": "NMN-UMIN000036321", "access_depth": "full_text_partial", "consensus_aspect": "Nominal physical effects and ≥eight-week gate", "result_comparison": "Original Methods make NAD/body composition primary and function secondary, and explicitly apply no multiple-comparison correction. Gait and left-grip mixed-model signals are exploratory; six-week left-grip/chair-stand findings cannot alone satisfy ≥eight-week registration. Twelve-week gait remains a tentative signal with the small valid sample, rather than certain replicated strength benefit.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/35927255/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\examinations\\original-40-48-10000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\body-presentation-receipts\\35927255-s1-p0-2-3-10-11-133-214.json", "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\body-presentation-receipts\\35927255-s2-p9.json", "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\body-presentation-receipts\\35927255-s3-p1-2-3-4-22-23-24.json" ] }, { "pmid": "38789831", "doi": "10.1007/s11357-024-01204-1", "source_type": "primary study report", "study_group": "NMN-UMIN000047871", "access_depth": "full_text_partial", "consensus_aspect": "Null stepping primary and actual controlled secondary gait", "result_comparison": "Provider accurately separates the null primary and gait secondary. DOI-matched original PDF M/R actually confirm ages65–75 and baseline-adjusted ANCOVA; stepping, grip and total SPPB scores are null, while four-metre time is positive. The registered review allows gait, so secondary status constrains certainty rather than silently adding a primary-only gate.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/38789831/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\examinations\\original-0-8-10000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\body-presentation-receipts\\38789831-web-original-pdf-selected-pages.json" ] }, { "pmid": "38789831", "doi": "10.1007/s11357-024-01204-1", "source_type": "primary study report", "study_group": "NMN-UMIN000047871", "access_depth": "full_text_partial", "consensus_aspect": "Missing observations and multiplicity", "result_comparison": "Original Results designate all60as efficacy set but report unavailable measurements, including two placebo participants at week12. Original statistics analyze baseline-adjusted timepoints and only twelve-week-positive variables at four weeks; no familywise correction is stated in the examined passage. Provider robust-benefit caution is appropriate, but no unexamined complete-data or correction analysis is claimed.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/38789831/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\examinations\\original-0-8-10000.json" ], "body_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\body-presentation-receipts\\38789831-web-original-pdf-selected-pages.json" ] }, { "pmid": "36443648", "doi": "10.1111/ggi.14513", "source_type": "primary study report", "study_group": "PMID36443648", "access_depth": "abstract_metadata", "consensus_aspect": "Direct older-diabetic function null", "result_comparison": "Provider correctly describes the24-week250mgolder-diabetes impaired-function trial. Examined original abstract retains primary grip/walk nulls, fourteen participants and borderline exploratory observations. Small power limits precise exclusion, but frailty/retinal trends cannot be promoted into a positive primary or erase healthy-context signals. No body access is claimed.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/36443648/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\examinations\\original-0-8-10000.json" ], "body_receipts": [] }, { "pmid": "33888596", "doi": "10.1126/science.abe9985", "source_type": "primary study report", "study_group": "PMID33888596", "access_depth": "abstract_metadata", "consensus_aspect": "Clamp physiology versus physical function", "result_comparison": "Provider correctly distinguishes prediabetic insulin-sensitivity physiology from older physical efficacy. Original abstract reports clamp/signaling/remodeling benefits, rather than a strength/gait/capacity result. Any additional claim of measured grip/fatigability nulls needs the corresponding original passages; absence from our examined abstract is not a measured null.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/33888596/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\examinations\\original-32-40-10000.json" ], "body_receipts": [] }, { "pmid": "34238308", "doi": "10.1186/s12970-021-00442-4", "source_type": "primary study report", "study_group": "PMID34238308", "access_depth": "abstract_metadata", "consensus_aspect": "Ventilatory threshold versus VO2max", "result_comparison": "Original younger/middle-aged six-week runner abstract supports selected ventilatory-threshold improvements while VO2max, O2-pulse and peak power do not differ. Provider aerobic-capacity wording must preserve exact readouts, training and out-of-scope duration/age rather than treating every fitness endpoint as positive.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/34238308/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\examinations\\original-32-40-10000.json" ], "body_receipts": [] }, { "pmid": "38871717", "doi": "10.1038/s41467-024-49092-5", "source_type": "primary study report", "study_group": "PMID38871717", "access_depth": "abstract_metadata", "consensus_aspect": "Provider broad NR-null summary versus genuine PAD benefit", "result_comparison": "Provider warns correctly against merging NMN and NR, but its adjacent summary broadly emphasizes NR functional nulls. The actual NICE original abstract reports a six-month NR-PAD walking benefit, with a one-sided90%interval and distinct adherent-subgroup analysis. This specific positive is retained, with its indexed erratum attached and no transfer to NMN or human longevity.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/38871717/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\examinations\\original-0-8-10000.json" ], "body_receipts": [] }, { "pmid": "42532077", "doi": "10.1016/j.lanhl.2026.100883", "source_type": "primary study report", "study_group": "PMID42532077", "access_depth": "abstract_metadata", "consensus_aspect": "Metformin add-on versus lifestyle contrast", "result_comparison": "Provider correctly cites metformin older-function nulls. Actual DEMFOS abstract shows intensive-lifestyle-plus-metformin superiority over less intensive lifestyle, but no advantage over matched intensive-lifestyle-plus-placebo. The useful lifestyle effect cannot be assigned to metformin.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/42532077/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\examinations\\original-64-70-10000.json" ], "body_receipts": [] }, { "pmid": "40147475", "doi": "10.1016/j.lanhl.2025.100695", "source_type": "primary study report", "study_group": "PMID40147475", "access_depth": "abstract_metadata", "consensus_aspect": "Clinical null and tolerability boundary", "result_comparison": "Provider retains the frail-older metformin null and poor tolerability. Original abstract gives a near-zero gait contrast, more observed admissions and an unrelated adjudicated death. These disease-specific findings are relevant harms/function boundaries, not proof of harm or inefficacy for every diabetic use or NMN.", "original_source": "https://pubmed.ncbi.nlm.nih.gov/40147475/", "source_examination_receipts": [ "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\examinations\\original-16-24-10000.json" ], "body_receipts": [] } ], "grade_changed": false, "grade_change_note": "Source-based adjudication; no independent blinded regrade claimed.", "raw_receipts": [ { "path": "deliverables\\hsef_v53_traffic_ranks_21_22_2026-10-13\\nad-boosters-human-function\\consensus-browser-2026-10-13.json", "sha256": "2f08e3bd729ee01d220e4c83b04f26225df132be69b110cad240e7c2b12b7f29" } ], "independent_blinded_audit": false, "cutoff": "2026-10-13", "completed_utc": "2026-10-13T17:35:01.384779+00:00", "conclusion": "Endpoint hierarchy, experimental scope and original-source limits determine the evidence cards; provider wording does not override them." } }