{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "NAD+/Sirtuin Aging Hypothesis", "entry_form": "phenomenon", "gradeable_restatement": "Age-related NAD+ decline limits sirtuin activity and is a causal driver of organismal aging, so NAD+ precursor repletion restores youthful function and improves human healthspan or lifespan.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Species, genotype, baseline disease, diet, dose and timing", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "NAD+/Sirtuin Aging Hypothesis", "central_claim": "Age-related NAD+ decline limits sirtuin activity and is a causal driver of organismal aging, so NAD+ precursor repletion restores youthful function and improves human healthspan or lifespan.", "proposed_mechanism": "Age-related NAD+ decline limits sirtuin activity and is a causal driver of organismal aging, so NAD+ precursor repletion restores youthful function and improves human healthspan or lifespan.", "claimed_scope": "animal and human organismal aging; tissue and disease contexts retained", "claimed_level": [ "progression" ], "is_conjunctive": true, "conjunctive_note": "The precursor-reversal framing is conjunctive; weakest-link applies to SC1–SC4. Neither blood NAD engagement nor a disease-specific functional result alone establishes general aging reversal." }, "rubric_routing": { "primary_rubric": "06-metabolism-aging.md", "secondary_rubrics": [], "index_notes_applied": [ "The precursor-reversal framing is conjunctive; weakest-link applies to SC1–SC4. Neither blood NAD engagement nor a disease-specific functional result alone establishes general aging reversal." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "NAD+ levels decline with age in multiple tissues.", "subclaim_type": "existence", "scope": "specified human and experimental tissues", "claimed_scope": "specified human and experimental tissues", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Quantitative age comparison with composition and assay controls", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC1 is an existence/age-association subclaim. Human skin and brain age comparisons and animal NAD measurements support a decline in specified tissues, but do not causally identify that decline as an aging initiator [29–32,34,35,50]. Β is the associative evidence level, not a statement that the observed decline is false." }, { "id": "SC2", "statement": "NAD+ decline causally contributes to age-related dysfunction through sirtuin-dependent mechanisms.", "subclaim_type": "mechanism", "scope": "specified adult animal tissues and aging phenotypes", "claimed_scope": "specified adult animal tissues and aging phenotypes", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Selective depletion/repletion, sirtuin epistasis and functional rescue", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC2 reaches Ε for defined functional contributions. SIRT3 co-deletion removes aged CD38-knockout glucose benefit despite elevated NAD, worm sir-2.1 is required for tested NAD-dependent longevity, and other adult interventions improve specified function [32,36,50,52,53]. Developmental genetics, compartment and alternative pathways limit general initiation or exclusive mediation." }, { "id": "SC3", "statement": "NR or NMN repletion improves human clinical healthspan or lifespan.", "subclaim_type": "generalization", "scope": "human populations identified at baseline", "claimed_scope": "human populations identified at baseline", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Randomized functional/clinical endpoints separated from blood NAD levels", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC3 reaches Ε only for measured human functional outcomes in baseline-defined settings. NICE walking meets its liberal prespecified one-sided phase II criterion; small NMN trials report secondary walking/ventilatory signals [7,14,15,19]. Null functional and primary outcomes map limits [1,6,16,21,25–28]. No human lifespan extension, general disability reduction or youthful restoration is demonstrated." }, { "id": "SC4", "statement": "Sirtuins act as general longevity regulators rather than context-specific metabolic response proteins.", "subclaim_type": "primacy", "scope": "adult organismal aging across species and human scope", "claimed_scope": "adult organismal aging across species and human scope", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Orthogonal loss/gain/rescue and lifespan/healthspan outcomes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC4 remains Γ for general endogenous longevity primacy. SIRT6 construct sufficiency and fly gain/loss support bounded biology, but constitutive development, background/sex variation and controlled Sir2 failures prevent a general adult-human necessity inference [39–45,51,58]." } ], "aggregation_rule": "weakest-link", "aggregation_preregistered": true, "aggregation_rationale": "The precursor-reversal framing is conjunctive; weakest-link applies to SC1–SC4. Neither blood NAD engagement nor a disease-specific functional result alone establishes general aging reversal.", "primary_subclaim_id": "SC3", "aggregation_derivation": "Preregistered weakest-link returns Β because SC1 is scored at association/existence level; SC2 and bounded functional SC3 reach Ε, and general primacy SC4 is Γ. This conservative aggregation is preserved even though it can understate the strength of narrower causal contributions. The named primary subclaim SC3 returns Ε for the measured human functional scope. Scope-matched returns Γ: only SC4 carries the central claim's general organismal-aging scope, while SC3 is restricted to baseline-defined trial populations and is reported separately. Neither sensitivity establishes human lifespan or general aging reversal.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Ε", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Nutrient-sensing network primacy", "core_claim": "NAD interventions participate in multiple metabolic and repair pathways.", "explains_what_nominal_does_not": "NAD interventions participate in multiple metabolic and repair pathways.", "strongest_supporting_evidence": [ "AMPK, vATPase/mTOR and compartment contrasts accompany or replace proposed exclusive sirtuin routes [36,56,58,59]." ], "strongest_contradictory_evidence": [ "No one network is fully identified as the primary human aging cause." ], "hsef_level_for_this_model": "Ε", "rationale": "AMPK, vATPase/mTOR and compartment contrasts accompany or replace proposed exclusive sirtuin routes [36,56,58,59]. No one network is fully identified as the primary human aging cause." }, { "rank_in_tournament": 2, "model_id": "M4", "is_nominal": false, "name": "Senescence/CD38 degradation sink", "core_claim": "Inflammatory senescence drives a modifiable NAD sink.", "explains_what_nominal_does_not": "Inflammatory senescence drives a modifiable NAD sink.", "strongest_supporting_evidence": [ "Senescence/CD38 perturbations map degradation and functional feedback [32,34–36,47,48]." ], "strongest_contradictory_evidence": [ "CD38 pleiotropy, lifelong knockouts and tissue differences prevent universal initiation claims." ], "hsef_level_for_this_model": "Ε", "rationale": "Senescence/CD38 perturbations map degradation and functional feedback [32,34–36,47,48]. CD38 pleiotropy, lifelong knockouts and tissue differences prevent universal initiation claims." }, { "rank_in_tournament": 3, "model_id": "M3", "is_nominal": false, "name": "Sirtuins as bounded stress sensors", "core_claim": "Particular sirtuins protect particular contexts.", "explains_what_nominal_does_not": "Particular sirtuins protect particular contexts.", "strongest_supporting_evidence": [ "SIRT3 epistasis, aged HSC function and worm requirement support constrained roles [32,44,50]." ], "strongest_contradictory_evidence": [ "Sirtuin isoforms and tissues differ; general endogenous longevity primacy is not isolated." ], "hsef_level_for_this_model": "Ε", "rationale": "SIRT3 epistasis, aged HSC function and worm requirement support constrained roles [32,44,50]. Sirtuin isoforms and tissues differ; general endogenous longevity primacy is not isolated." }, { "rank_in_tournament": 4, "model_id": "M5", "is_nominal": false, "name": "Permissive redox-cofactor availability", "core_claim": "NAD pools enable several necessary cellular reactions.", "explains_what_nominal_does_not": "NAD pools enable several necessary cellular reactions.", "strongest_supporting_evidence": [ "Human engagement, organ compartment and depletion experiments show availability/turnover rather than one universal aging clock [13,23,59,60]." ], "strongest_contradictory_evidence": [ "Cell buffering and variable clinical function mean a restored pool is not sufficient for youthful organismal function." ], "hsef_level_for_this_model": "Γ", "rationale": "Human engagement, organ compartment and depletion experiments show availability/turnover rather than one universal aging clock [13,23,59,60]. Cell buffering and variable clinical function mean a restored pool is not sufficient for youthful organismal function." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "NAD decline/sirtuin primacy", "core_claim": "Age-associated NAD loss initiates general aging through limited sirtuin activity.", "explains_what_nominal_does_not": "Age-associated NAD loss initiates general aging through limited sirtuin activity.", "strongest_supporting_evidence": [ "Age-associated decline plus defined NAD/sirtuin functional rescues make a coherent hypothesis [29–32,50]." ], "strongest_contradictory_evidence": [ "The registered conjunction includes association, general primacy and human aging reversal; no result identifies all those clauses." ], "hsef_level_for_this_model": "Β", "rationale": "Age-associated decline plus defined NAD/sirtuin functional rescues make a coherent hypothesis [29–32,50]. The registered conjunction includes association, general primacy and human aging reversal; no result identifies all those clauses." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Adult, tissue-specific NAD depletion/repletion with sirtuin loss/rescue and clinical function, keeping precursor exposure and non-sirtuin cofactor routes intact, distinguishes exclusive primacy from feedback and parallel pathways.", "study_separating_rank1_from_rank2": "Adult, tissue-specific NAD depletion/repletion with sirtuin loss/rescue and clinical function, keeping precursor exposure and non-sirtuin cofactor routes intact, distinguishes exclusive primacy from feedback and parallel pathways.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT02942888", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "NR increased blood NAD in a randomized MCI pilot without improving cognition; the CBF signal did not withstand multiplicity correction.", "what_it_does_not_show": "Safety and exploratory methylation changes do not demonstrate clinical cognitive or aging reversal.", "confounders_present": [ "Safety and exploratory methylation changes do not demonstrate clinical cognitive or aging reversal." ], "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": [] } }, { "n": 2, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID35235774", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "NADPARK demonstrated variable brain NAD engagement after NR in a small randomized untreated-PD trial.", "what_it_does_not_show": "Mild clinical changes in post-treatment NAD responders cannot define an unbiased aging-efficacy population.", "confounders_present": [ "Mild clinical changes in post-treatment NAD responders cannot define an unbiased aging-efficacy population." ], "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": [] } }, { "n": 3, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39548320", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "NR reduced the prespecified sputum IL8 inflammatory endpoint in a COPD randomized trial.", "what_it_does_not_show": "Inflammatory improvement is not a demonstrated functional healthspan or mortality effect.", "confounders_present": [ "Inflammatory improvement is not a demonstrated functional healthspan or mortality effect." ], "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": [] } }, { "n": 4, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29599478", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "A randomized older-adult crossover established NR blood target engagement and tolerability with suggestive vascular changes.", "what_it_does_not_show": "Potential blood-pressure and arterial signals require confirmatory outcome separation; no longevity result.", "confounders_present": [ "Potential blood-pressure and arterial signals require confirmatory outcome separation; no longevity result." ], "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": [] } }, { "n": 5, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID31412242", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "NR changed the muscle NAD metabolome and inflammatory markers in older men but did not change measured mitochondrial bioenergetics.", "what_it_does_not_show": "Metabolite engagement and lower inflammation are distinct from clinical aging reversal.", "confounders_present": [ "Metabolite engagement and lower inflammation are distinct from clinical aging reversal." ], "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": [] } }, { "n": 6, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37159264", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "The CKD randomized crossover found no NR benefit on peak oxygen consumption, work or efficiency despite metabolic changes.", "what_it_does_not_show": "This constrains the measured disease and short exposure; it does not prove all NR regimens ineffective.", "confounders_present": [ "This constrains the measured disease and short exposure; it does not prove all NR regimens ineffective." ], "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": [] } }, { "n": 7, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03743636", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec3, Sec33, Sec34. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "NICE reported a 17.6-m NR-placebo walking contrast, one-sided P=.08, satisfying its prespecified phase II alpha .10; NR plus resveratrol was null.", "what_it_does_not_show": "This is not a conventional two-sided .05 confirmatory result; contrasts lacked multiplicity adjustment and adherence subsets were post hoc. The examined correction restores only the omitted trial registration.", "confounders_present": [ "This is not a conventional two-sided .05 confirmatory result; contrasts lacked multiplicity adjustment and adherence subsets were post hoc. The examined correction restores only the omitted trial registration." ], "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": [] } }, { "n": 8, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT02921659", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "NR altered NAD and AD-associated signaling measures in neuron-enriched extracellular-vesicle preparations.", "what_it_does_not_show": "Enrichment is not direct brain sampling, and these changes do not demonstrate clinical cognition or healthspan improvement.", "confounders_present": [ "Enrichment is not direct brain sampling, and these changes do not demonstrate clinical cognition or healthspan improvement." ], "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": [] } }, { "n": 9, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37899683", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "An open-label ataxia-telangiectasia programme reported motor improvement relative to historical expectations.", "what_it_does_not_show": "No randomized counterfactual; a rare syndromic disorder is not ordinary aging.", "confounders_present": [ "No randomized counterfactual; a rare syndromic disorder is not ordinary 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": [] } }, { "n": 10, "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 et al. 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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID31278280", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized NR dose groups increased blood NAD with short-term safety assessment.", "what_it_does_not_show": "Dose target engagement is not a clinical aging outcome.", "confounders_present": [ "Dose target engagement is not a clinical aging outcome." ], "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": [] } }, { "n": 11, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT05344404", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "NR-SAFE established short high-dose tolerability; UPDRS improvement coincided with a shorter interval since levodopa.", "what_it_does_not_show": "Medication timing limits attribution of the clinical change; no human sirtuin mediation or general aging result.", "confounders_present": [ "Medication timing limits attribution of the clinical change; no human sirtuin mediation or general aging result." ], "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": [] } }, { "n": 12, "pmid": "32790648", "title": "Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure.", "citation": "Zhou B, Wang DD, Qiu Y et al. Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure. The Journal of clinical investigation. 2020.", "doi": "10.1172/JCI138538", "pmcid": "PMC7598081", "url": "https://pubmed.ncbi.nlm.nih.gov/32790648/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32790648/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID32790648", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "HF patient PBMC assays and a four-patient NR pilot showed cellular respiratory and inflammatory changes.", "what_it_does_not_show": "Cellular readouts and an uncontrolled pilot do not demonstrate clinical heart-failure efficacy or human healthspan.", "confounders_present": [ "Cellular readouts and an uncontrolled pilot do not demonstrate clinical heart-failure efficacy or human healthspan." ], "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": [] } }, { "n": 13, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID33888596", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: BODY. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "NMN improved muscle insulin sensitivity in randomized prediabetic postmenopausal women; muscle steady-state NAD did not increase although turnover metabolites did.", "what_it_does_not_show": "Hepatic and adipose insulin sensitivity did not improve; selective human sirtuin or PDGFR mediation was not tested, and metabolic sensitivity is not lifespan.", "confounders_present": [ "Hepatic and adipose insulin sensitivity did not improve; selective human sirtuin or PDGFR mediation was not tested, and metabolic sensitivity is not 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": [] } }, { "n": 14, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36482258", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "A randomized NMN dose trial reported secondary six-minute-walk and quality-of-life benefits alongside blood NAD increases.", "what_it_does_not_show": "Small dose groups, multiple endpoints, short duration and unvalidated blood-age algorithms prevent a general lifespan or aging-reversal claim.", "confounders_present": [ "Small dose groups, multiple endpoints, short duration and unvalidated blood-age algorithms prevent a general lifespan or aging-reversal claim." ], "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": [] } }, { "n": 15, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34238308", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "NMN plus exercise improved ventilatory-threshold measures in recreational runners while VO2max did not improve.", "what_it_does_not_show": "Young/middle-aged trained context, small dose groups and co-exercise do not establish general anti-aging efficacy.", "confounders_present": [ "Young/middle-aged trained context, small dose groups and co-exercise do not establish general anti-aging 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": [] } }, { "n": 16, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36740954", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "MIB626 changed blood NAD, weight and selected vascular/metabolic measures but not measured strength, fatigue, aerobic capacity, stair power or insulin sensitivity.", "what_it_does_not_show": "Molecular engagement is dissociated from these short-term functional endpoints.", "confounders_present": [ "Molecular engagement is dissociated from these short-term functional endpoints." ], "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": [] } }, { "n": 17, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36797393", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "NMN increased serum nicotinamide without a significant between-group arterial-stiffness benefit.", "what_it_does_not_show": "Blood engagement and an exploratory subgroup cannot replace the null primary contrast.", "confounders_present": [ "Blood engagement and an exploratory subgroup cannot replace the null primary contrast." ], "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": [] } }, { "n": 18, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID31685720", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "An acute single-arm NMN dose study established short-term pharmacokinetic and safety observations.", "what_it_does_not_show": "Ten participants and acute exposure do not assess healthspan or efficacy.", "confounders_present": [ "Ten participants and acute exposure do not assess healthspan or 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": [] } }, { "n": 19, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID38789831", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "A randomized NMN trial missed its primary stepping endpoint while showing secondary walking and sleep signals.", "what_it_does_not_show": "Secondary outcomes support bounded investigation but do not convert the primary endpoint into a positive confirmatory trial.", "confounders_present": [ "Secondary outcomes support bounded investigation but do not convert the primary endpoint into a positive confirmatory 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": [] } }, { "n": 20, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID35215405", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "The four-group older-adult NMN study found timing-related interactions; all groups improved sit-to-stand performance and placebo-PM also improved drowsiness.", "what_it_does_not_show": "The largest within-group effect is not itself an isolated NMN-placebo efficacy contrast.", "confounders_present": [ "The largest within-group effect is not itself an isolated NMN-placebo efficacy contrast." ], "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": [] } }, { "n": 21, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36443648", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "A small 24-week trial in older diabetic men found no grip-strength or walking benefit; the frailty difference did not meet conventional significance.", "what_it_does_not_show": "The small trial does not establish equivalence or lack of effect in all baseline contexts.", "confounders_present": [ "The small trial does not establish equivalence or lack of effect in all baseline contexts." ], "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": [] } }, { "n": 22, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID36002548", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Four-week high-dose NMN testing assessed tolerability and safety.", "what_it_does_not_show": "Short safety follow-up does not test clinical aging benefit.", "confounders_present": [ "Short safety follow-up does not test clinical 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": [] } }, { "n": 23, "pmid": "41540253", "title": "The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans.", "citation": "Christen S, Redeuil K, Goulet L et al. The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans. Nature metabolism. 2026.", "doi": "10.1038/s42255-025-01421-8", "pmcid": "PMC12855009", "url": "https://pubmed.ncbi.nlm.nih.gov/41540253/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/41540253/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT05517122", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "A 2026 randomized open-label comparison found sustained blood NAD rises with NR/NMN and different acute nicotinamide behavior; ex vivo fermentation suggested a deamidation route.", "what_it_does_not_show": "Exposure routing and ex vivo microbial metabolism do not demonstrate in-vivo human necessity, sirtuin mediation or clinical aging efficacy.", "confounders_present": [ "Exposure routing and ex vivo microbial metabolism do not demonstrate in-vivo human necessity, sirtuin mediation or clinical aging 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": [] } }, { "n": 24, "pmid": "38191197", "title": "Safety and efficacy of long-term nicotinamide mononucleotide supplementation on metabolism, sleep, and nicotinamide adenine dinucleotide biosynthesis in healthy, middle-aged Japanese men.", "citation": "Yamaguchi S, Irie J, Mitsuishi M et al. Safety and efficacy of long-term nicotinamide mononucleotide supplementation on metabolism, sleep, and nicotinamide adenine dinucleotide biosynthesis in healthy, middle-aged Japanese men. Endocrine journal. 2024.", "doi": "10.1507/endocrj.EJ23-0431", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/38191197/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38191197/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID38191197", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "A small single-arm NMN study reported PBMC NAD and exploratory metabolic changes, including a tiny hyperinsulinemic subgroup.", "what_it_does_not_show": "No randomized counterfactual or validated human aging trajectory.", "confounders_present": [ "No randomized counterfactual or validated human aging trajectory." ], "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": [] } }, { "n": 25, "pmid": "29992272", "title": "A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects.", "citation": "Dollerup OL, Christensen B, Svart M et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. The American journal of clinical nutrition. 2018.", "doi": "10.1093/ajcn/nqy132", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/29992272/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29992272/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT02303483", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Randomized NR in obese men did not improve insulin sensitivity, metabolism or body composition.", "what_it_does_not_show": "Dose, sex and baseline disease constrain the negative result; blood exposure does not prove muscle compartment engagement.", "confounders_present": [ "Dose, sex and baseline disease constrain the negative result; blood exposure does not prove muscle compartment engagement." ], "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": [] } }, { "n": 26, "pmid": "31710095", "title": "Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin-resistant men.", "citation": "Dollerup OL, Chubanava S, Agerholm M et al. Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin-resistant men. The Journal of physiology. 2020.", "doi": "10.1113/JP278752", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31710095/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31710095/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT02303483", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "The same obese-men NR trial found no muscle NAD, respiration or mitochondrial morphology improvement, with lower NAMPT expression.", "what_it_does_not_show": "This is a shared-cohort mechanistic follow-up, not an independent efficacy trial.", "confounders_present": [ "This is a shared-cohort mechanistic follow-up, not an independent efficacy 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": [] } }, { "n": 27, "pmid": "31390002", "title": "Effects of Nicotinamide Riboside on Endocrine Pancreatic Function and Incretin Hormones in Nondiabetic Men With Obesity.", "citation": "Dollerup OL, Trammell SAJ, Hartmann B et al. Effects of Nicotinamide Riboside on Endocrine Pancreatic Function and Incretin Hormones in Nondiabetic Men With Obesity. The Journal of clinical endocrinology and metabolism. 2019.", "doi": "10.1210/jc.2019-01081", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31390002/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31390002/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT02303483", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "The same randomized obese-men NR cohort showed no pancreatic/incretin response benefit.", "what_it_does_not_show": "Shared participants do not add an independent causal replication.", "confounders_present": [ "Shared participants do not add an independent causal replication." ], "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": [] } }, { "n": 28, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT03754842", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "contradicts", "what_it_shows": "Randomized NR-pterostilbene did not improve muscle-injury regeneration, strength or muscle-stem-cell outcomes in older adults.", "what_it_does_not_show": "A bundled preparation and injury protocol cannot isolate NR alone or all aging outcomes.", "confounders_present": [ "A bundled preparation and injury protocol cannot isolate NR alone or all aging outcomes." ], "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": [] } }, { "n": 29, "pmid": "22848760", "title": "Age-associated changes in oxidative stress and NAD+ metabolism in human tissue.", "citation": "Massudi H, Grant R, Braidy N et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PloS one. 2012.", "doi": "10.1371/journal.pone.0042357", "pmcid": "PMC3407129", "url": "https://pubmed.ncbi.nlm.nih.gov/22848760/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22848760/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID22848760", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Cross-sectional human skin measurements linked age to NAD depletion and sex-dependent enzyme/activity differences.", "what_it_does_not_show": "Surgical sampling, tissue composition and age association do not establish an initiating aging mechanism.", "confounders_present": [ "Surgical sampling, tissue composition and age association do not establish an initiating aging mechanism." ], "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": [] } }, { "n": 30, "pmid": "25730862", "title": "In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences.", "citation": "Zhu XH, Lu M, Lee BY et al. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proceedings of the National Academy of Sciences of the United States of America. 2015.", "doi": "10.1073/pnas.1417921112", "pmcid": "PMC4352772", "url": "https://pubmed.ncbi.nlm.nih.gov/25730862/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25730862/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID25730862", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Human brain magnetic-resonance measurements associated older age with lower NAD and altered NAD redox balance.", "what_it_does_not_show": "Cross-sectional assay-derived measures do not identify causal direction or general whole-body NAD depletion.", "confounders_present": [ "Cross-sectional assay-derived measures do not identify causal direction or general whole-body NAD depletion." ], "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": [] } }, { "n": 31, "pmid": "24360282", "title": "Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.", "citation": "Gomes AP, Price NL, Ling AJ et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013.", "doi": "10.1016/j.cell.2013.11.037", "pmcid": "PMC4076149", "url": "https://pubmed.ncbi.nlm.nih.gov/24360282/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24360282/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID24360282", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Mouse NAD decline and repletion were linked to a SIRT1-dependent pseudohypoxic mitochondrial response.", "what_it_does_not_show": "Mitochondrial molecular rescue alone does not prove organismal aging reversal; this paper remains abstract-level in this review.", "confounders_present": [ "Mitochondrial molecular rescue alone does not prove organismal aging reversal; this paper remains abstract-level in this review." ], "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": [] } }, { "n": 32, "pmid": "27304511", "title": "CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism.", "citation": "Camacho-Pereira J, Tarragó MG, Chini CCS et al. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell metabolism. 2016.", "doi": "10.1016/j.cmet.2016.05.006", "pmcid": "PMC4911708", "url": "https://pubmed.ncbi.nlm.nih.gov/27304511/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27304511/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID27304511", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: S7. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M3", "M4" ], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "In aged mice, CD38 loss elevated NAD and improved glucose tolerance; SIRT3 co-deletion removed functional and mitochondrial benefits despite elevated NAD.", "what_it_does_not_show": "Lifelong double knockout, mixed genetic background and CD38 pleiotropy limit adult-onset and general-human inference.", "confounders_present": [ "Lifelong double knockout, mixed genetic background and CD38 pleiotropy limit adult-onset and general-human inference." ], "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": [] } }, { "n": 33, "pmid": "28068222", "title": "Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice.", "citation": "Mills KF, Yoshida S, Stein LR et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell metabolism. 2016.", "doi": "10.1016/j.cmet.2016.09.013", "pmcid": "PMC5668137", "url": "https://pubmed.ncbi.nlm.nih.gov/28068222/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28068222/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID28068222", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Long-term NMN improved several age-associated activity, metabolic and ocular functions in mice.", "what_it_does_not_show": "Not a mortality-extension trial and not isolated proof of one required sirtuin across species.", "confounders_present": [ "Not a mortality-extension trial and not isolated proof of one required sirtuin across species." ], "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": [] } }, { "n": 34, "pmid": "33199924", "title": "Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages.", "citation": "Covarrubias AJ, Kale A, Perrone R et al. Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nature metabolism. 2020.", "doi": "10.1038/s42255-020-00305-3", "pmcid": "PMC7908681", "url": "https://pubmed.ncbi.nlm.nih.gov/33199924/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33199924/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID33303985" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID33199924", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M4" ], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Senescent-cell inflammatory signals promoted CD38-positive macrophages and age-associated NAD loss.", "what_it_does_not_show": "This places senescence/inflammation upstream of a NAD sink; it does not identify NAD decline as the universal initiator. Linked erratum detail was not examined.", "confounders_present": [ "This places senescence/inflammation upstream of a NAD sink; it does not identify NAD decline as the universal initiator. Linked erratum detail was not examined." ], "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": [] } }, { "n": 35, "pmid": "33199925", "title": "CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels.", "citation": "Chini CCS, Peclat TR, Warner GM et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nature metabolism. 2020.", "doi": "10.1038/s42255-020-00298-z", "pmcid": "PMC8752031", "url": "https://pubmed.ncbi.nlm.nih.gov/33199925/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33199925/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID33199925", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M4" ], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Senescence ablation and ecto-CD38 experiments linked inflammatory tissue context to NAD degradation and precursor availability.", "what_it_does_not_show": "Functional CD38 feedback does not by itself establish general sirtuin-mediated longevity primacy.", "confounders_present": [ "Functional CD38 feedback does not by itself establish general sirtuin-mediated longevity 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": [] } }, { "n": 36, "pmid": "29719225", "title": "A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline.", "citation": "Tarragó MG, Chini CCS, Kanamori KS et al. A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline. Cell metabolism. 2018.", "doi": "10.1016/j.cmet.2018.03.016", "pmcid": "PMC5935140", "url": "https://pubmed.ncbi.nlm.nih.gov/29719225/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29719225/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29719225", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "The CD38 inhibitor 78c improved age-associated glucose, exercise/muscle and cardiac measures; NAD-synthesis inhibition reversed benefit.", "what_it_does_not_show": "Several NAD-dependent and non-sirtuin signaling pathways change; this is not exclusive sirtuin mediation or human aging efficacy.", "confounders_present": [ "Several NAD-dependent and non-sirtuin signaling pathways change; this is not exclusive sirtuin mediation or human aging 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": [] } }, { "n": 37, "pmid": "27127236", "title": "NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice.", "citation": "Zhang H, Ryu D, Wu Y et al. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science (New York, N.Y.). 2016.", "doi": "10.1126/science.aaf2693", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/27127236/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27127236/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID27127236", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "NR improved mouse muscle-stem-cell regeneration and other stem-cell measures, with a reported lifespan effect.", "what_it_does_not_show": "Single-model rescue does not prove a general human aging driver or one required endogenous sirtuin.", "confounders_present": [ "Single-model rescue does not prove a general human aging driver or one required endogenous sirtuin." ], "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": [] } }, { "n": 38, "pmid": "29514072", "title": "Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice.", "citation": "Mitchell SJ, Bernier M, Aon MA et al. Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice. Cell metabolism. 2018.", "doi": "10.1016/j.cmet.2018.02.001", "pmcid": "PMC5854409", "url": "https://pubmed.ncbi.nlm.nih.gov/29514072/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29514072/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29514072", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Nicotinamide improved selected high-fat-diet health measures without extending mouse lifespan.", "what_it_does_not_show": "Different precursor, diet and tissue NAD response limit direct falsification of all NR/NMN protocols.", "confounders_present": [ "Different precursor, diet and tissue NAD response limit direct falsification of all NR/NMN protocols." ], "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": [] } }, { "n": 39, "pmid": "34050173", "title": "Restoration of energy homeostasis by SIRT6 extends healthy lifespan.", "citation": "Roichman A, Elhanati S, Aon MA et al. Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nature communications. 2021.", "doi": "10.1038/s41467-021-23545-7", "pmcid": "PMC8163764", "url": "https://pubmed.ncbi.nlm.nih.gov/34050173/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34050173/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34050173", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec3, Sec16. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Constitutive SIRT6 overexpression extended median survival in both sexes on B6; SIRT1 overexpression did not add median-survival benefit.", "what_it_does_not_show": "Developmental transgene sufficiency is not adult endogenous necessity or human aging primacy.", "confounders_present": [ "Developmental transgene sufficiency is not adult endogenous necessity or human aging 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": [] } }, { "n": 40, "pmid": "22367546", "title": "The sirtuin SIRT6 regulates lifespan in male mice.", "citation": "Kanfi Y, Naiman S, Amir G et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature. 2012.", "doi": "10.1038/nature10815", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/22367546/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22367546/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID22367546", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "SIRT6-transgenic mice showed male-specific lifespan extension in the earlier background.", "what_it_does_not_show": "Sex/background differences and constitutive overexpression constrain generalization and endogenous necessity.", "confounders_present": [ "Sex/background differences and constitutive overexpression constrain generalization and endogenous necessity." ], "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": [] } }, { "n": 41, "pmid": "35091469", "title": "Sirt6 regulates lifespan in Drosophila melanogaster.", "citation": "Taylor JR, Wood JG, Mizerak E et al. Sirt6 regulates lifespan in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the United States of America. 2022.", "doi": "10.1073/pnas.2111176119", "pmcid": "PMC8812521", "url": "https://pubmed.ncbi.nlm.nih.gov/35091469/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35091469/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID35091469", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Fly Sirt6 gain/loss and Myc-linked contrasts affected lifespan and physiology.", "what_it_does_not_show": "Developmental expression and species scope do not establish adult human longevity regulation.", "confounders_present": [ "Developmental expression and species scope do not establish adult human longevity regulation." ], "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": [] } }, { "n": 42, "pmid": "21938067", "title": "Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila.", "citation": "Burnett C, Valentini S, Cabreiro F et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature. 2011.", "doi": "10.1038/nature10296", "pmcid": "PMC3188402", "url": "https://pubmed.ncbi.nlm.nih.gov/21938067/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21938067/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID21938067", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: BODY. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Strong", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "contradicts", "what_it_shows": "Genetic-background and matched-transgenic controls removed previously attributed worm/fly Sir2-overexpression longevity; elevated expression persisted.", "what_it_does_not_show": "This challenges those paradigms and proposed DR necessity, not every sirtuin protein or all later SIRT6 results.", "confounders_present": [ "This challenges those paradigms and proposed DR necessity, not every sirtuin protein or all later SIRT6 results." ], "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": [] } }, { "n": 43, "pmid": "31002797", "title": "SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species.", "citation": "Tian X, Firsanov D, Zhang Z et al. SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species. Cell. 2019.", "doi": "10.1016/j.cell.2019.03.043", "pmcid": "PMC6499390", "url": "https://pubmed.ncbi.nlm.nih.gov/31002797/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31002797/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID31002797", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "comparative observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Across rodent species, SIRT6 sequence/activity tracked DNA-repair performance and longevity.", "what_it_does_not_show": "Evolutionary correlation and ex vivo sequence effects do not prove lifespan extension by editing an adult organism.", "confounders_present": [ "Evolutionary correlation and ex vivo sequence effects do not prove lifespan extension by editing an adult organism." ], "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": [] } }, { "n": 44, "pmid": "23375372", "title": "SIRT3 reverses aging-associated degeneration.", "citation": "Brown K, Xie S, Qiu X et al. SIRT3 reverses aging-associated degeneration. Cell reports. 2013.", "doi": "10.1016/j.celrep.2013.01.005", "pmcid": "PMC3582834", "url": "https://pubmed.ncbi.nlm.nih.gov/23375372/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23375372/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID23375372", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "SIRT3 affected aged or stressed hematopoietic-stem-cell regeneration while being dispensable for tested young homeostasis.", "what_it_does_not_show": "A transplantation/stress function is not universal organismal aging necessity.", "confounders_present": [ "A transplantation/stress function is not universal organismal aging necessity." ], "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": [] } }, { "n": 45, "pmid": "30853213", "title": "LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation.", "citation": "Simon M, Van Meter M, Ablaeva J et al. LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation. Cell metabolism. 2019.", "doi": "10.1016/j.cmet.2019.02.014", "pmcid": "PMC6449196", "url": "https://pubmed.ncbi.nlm.nih.gov/30853213/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30853213/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID30853213", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "LINE1/NRTI contrasts improved severe Sirt6-deficient growth and survival phenotypes.", "what_it_does_not_show": "Constitutive deficiency and progeroid development are distinct from reversing normal adult aging.", "confounders_present": [ "Constitutive deficiency and progeroid development are distinct from reversing normal adult 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": [] } }, { "n": 46, "pmid": "37683629", "title": "NAD+ rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis.", "citation": "Zhan R, Meng X, Tian D et al. NAD+ rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis. Neuron. 2023.", "doi": "10.1016/j.neuron.2023.08.010", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/37683629/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37683629/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID40250429" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37683629", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Endothelial CX43/PARP1/NMN/SIRT3 experiments affected aged blood-brain-barrier dysfunction.", "what_it_does_not_show": "A specific vascular endpoint and linked correction not fully examined do not establish human organismal longevity.", "confounders_present": [ "A specific vascular endpoint and linked correction not fully examined do not establish human organismal 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": [] } }, { "n": 47, "pmid": "38129670", "title": "NADase CD38 is a key determinant of ovarian aging.", "citation": "Yang Q, Chen W, Cong L et al. NADase CD38 is a key determinant of ovarian aging. Nature aging. 2024.", "doi": "10.1038/s43587-023-00532-9", "pmcid": "PMC10798903", "url": "https://pubmed.ncbi.nlm.nih.gov/38129670/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38129670/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID38129670", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CD38 genetic/pharmacological contrasts preserved age-associated ovarian function and fertility.", "what_it_does_not_show": "Reproductive function is a bounded health phenotype, not overall lifespan or human fertility efficacy.", "confounders_present": [ "Reproductive function is a bounded health phenotype, not overall lifespan or human fertility 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": [] } }, { "n": 48, "pmid": "39044033", "title": "An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.", "citation": "Song Z, Park SH, Mu WC et al. An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging. Nature aging. 2024.", "doi": "10.1038/s43587-024-00670-8", "pmcid": "PMC11565225", "url": "https://pubmed.ncbi.nlm.nih.gov/39044033/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39044033/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39044033", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "CD38/MCU contrasts rescued aged hematopoietic function but showed different CD38 roles in young proliferation.", "what_it_does_not_show": "Age and lineage dependence argue against universal inhibition independent of tissue state.", "confounders_present": [ "Age and lineage dependence argue against universal inhibition independent of tissue state." ], "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": [] } }, { "n": 49, "pmid": "32755581", "title": "Nicotinamide Mononucleotide Supplementation Reverses the Declining Quality of Maternally Aged Oocytes.", "citation": "Miao Y, Cui Z, Gao Q et al. Nicotinamide Mononucleotide Supplementation Reverses the Declining Quality of Maternally Aged Oocytes. Cell reports. 2020.", "doi": "10.1016/j.celrep.2020.107987", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32755581/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32755581/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID32755581", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "NMN improved meiotic, fertilization and ovulatory functions in aged mouse oocytes.", "what_it_does_not_show": "Not a trial of efficacy in older women or direct survival extension.", "confounders_present": [ "Not a trial of efficacy in older women or direct survival 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": [] } }, { "n": 50, "pmid": "23870130", "title": "The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling.", "citation": "Mouchiroud L, Houtkooper RH, Moullan N et al. The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. Cell. 2013.", "doi": "10.1016/j.cell.2013.06.016", "pmcid": "PMC3753670", "url": "https://pubmed.ncbi.nlm.nih.gov/23870130/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23870130/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID23870130", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "NAD repletion extended worm lifespan through sir-2.1-dependent and mitochondrial-stress/FOXO pathways.", "what_it_does_not_show": "Worm genetic specificity does not establish a universally limiting human NAD-sirtuin aging mechanism.", "confounders_present": [ "Worm genetic specificity does not establish a universally limiting human NAD-sirtuin aging mechanism." ], "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": [] } }, { "n": 51, "pmid": "17086191", "title": "Resveratrol improves health and survival of mice on a high-calorie diet.", "citation": "Baur JA, Pearson KJ, Price NL et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006.", "doi": "10.1038/nature05354", "pmcid": "PMC4990206", "url": "https://pubmed.ncbi.nlm.nih.gov/17086191/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17086191/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID17086191", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Resveratrol improved health and survival of high-calorie-fed middle-aged mice.", "what_it_does_not_show": "Diet rescue and a pleiotropic compound are not unique endogenous-sirtuin proof or an NR/NMN trial.", "confounders_present": [ "Diet rescue and a pleiotropic compound are not unique endogenous-sirtuin proof or an NR/NMN 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": [] } }, { "n": 52, "pmid": "38504132", "title": "Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.", "citation": "Membrez M, Migliavacca E, Christen S et al. Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nature metabolism. 2024.", "doi": "10.1038/s42255-024-00997-x", "pmcid": "PMC10963276", "url": "https://pubmed.ncbi.nlm.nih.gov/38504132/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38504132/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID38504132", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Trigonelline tracer and perturbation work linked NAD/sirtuin-dependent worm function/lifespan and improved aged-mouse muscle performance.", "what_it_does_not_show": "Human sarcopenia association is not randomized human efficacy; precursor routing does not identify all aging mediation.", "confounders_present": [ "Human sarcopenia association is not randomized human efficacy; precursor routing does not identify all aging 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": [] } }, { "n": 53, "pmid": "21982712", "title": "Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice.", "citation": "Yoshino J, Mills KF, Yoon MJ et al. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell metabolism. 2011.", "doi": "10.1016/j.cmet.2011.08.014", "pmcid": "PMC3204926", "url": "https://pubmed.ncbi.nlm.nih.gov/21982712/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21982712/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID21982712", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "NMN improved diet/age-associated mouse glucose dysfunction with partially SIRT1-linked mechanisms.", "what_it_does_not_show": "Disease, diet and sex context constrain inference to a general aging initiator.", "confounders_present": [ "Disease, diet and sex context constrain inference to a general aging initiator." ], "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": [] } }, { "n": 54, "pmid": "25921090", "title": "SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice.", "citation": "Yoon MJ, Yoshida M, Johnson S et al. SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice. Cell metabolism. 2015.", "doi": "10.1016/j.cmet.2015.04.002", "pmcid": "PMC4426056", "url": "https://pubmed.ncbi.nlm.nih.gov/25921090/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25921090/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID25921090", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Adipose NAMPT manipulation, NMN rescue and antibody contrasts linked an endocrine NAD/sirtuin circuit to hypothalamic activity and function.", "what_it_does_not_show": "Specified tissue communication does not prove general organismal longevity primacy.", "confounders_present": [ "Specified tissue communication does not prove general organismal longevity 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": [] } }, { "n": 55, "pmid": "31131364", "title": "Slc12a8 is a nicotinamide mononucleotide transporter.", "citation": "Grozio A, Mills KF, Yoshino J et al. Slc12a8 is a nicotinamide mononucleotide transporter. Nature metabolism. 2019.", "doi": "10.1038/s42255-018-0009-4", "pmcid": "PMC6530925", "url": "https://pubmed.ncbi.nlm.nih.gov/31131364/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31131364/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID32694647" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID31131364", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Weak", "system": "animal interventional", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "The paper reported Slc12a8-dependent NMN transport using cellular and mouse tracer/genetic experiments.", "what_it_does_not_show": "The delivery interpretation is contested in linked comments and correction; not a load-bearing human uptake or aging-efficacy result.", "confounders_present": [ "The delivery interpretation is contested in linked comments and correction; not a load-bearing human uptake or aging-efficacy result." ], "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": [] } }, { "n": 56, "pmid": "38422177", "title": "Glycolysis-Mediated Activation of v-ATPase by Nicotinamide Mononucleotide Ameliorates Lipid-Induced Cardiomyopathy by Repressing the CD36-TLR4 Axis.", "citation": "Wang S, Han Y, Liu R et al. Glycolysis-Mediated Activation of v-ATPase by Nicotinamide Mononucleotide Ameliorates Lipid-Induced Cardiomyopathy by Repressing the CD36-TLR4 Axis. Circulation research. 2024.", "doi": "10.1161/CIRCRESAHA.123.322910", "pmcid": "PMC10906217", "url": "https://pubmed.ncbi.nlm.nih.gov/38422177/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38422177/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID38422177", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [ "M2" ], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "NMN improved diet-associated cardiac function through vATPase/mTOR and metabolic contrasts.", "what_it_does_not_show": "An experimentally narrowed alternative route argues against exclusive sirtuin mediation; not general human aging reversal.", "confounders_present": [ "An experimentally narrowed alternative route argues against exclusive sirtuin mediation; not general human aging reversal." ], "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": [] } }, { "n": 57, "pmid": "34497121", "title": "NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING.", "citation": "Hou Y, Wei Y, Lautrup S et al. NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING. Proceedings of the National Academy of Sciences of the United States of America. 2021.", "doi": "10.1073/pnas.2011226118", "pmcid": "PMC8449423", "url": "https://pubmed.ncbi.nlm.nih.gov/34497121/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34497121/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34497121", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "NR improved cognition/synapse and inflammatory phenotypes in APP/PS1 mice, with cGAS-STING involvement.", "what_it_does_not_show": "Disease-model/cell mechanism does not establish human AD efficacy or a general sirtuin aging driver.", "confounders_present": [ "Disease-model/cell mechanism does not establish human AD efficacy or a general sirtuin aging driver." ], "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": [] } }, { "n": 58, "pmid": "39695235", "title": "Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing.", "citation": "Qu Q, Chen Y, Wang Y et al. Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing. Nature. 2025.", "doi": "10.1038/s41586-024-08348-2", "pmcid": "PMC12222023", "url": "https://pubmed.ncbi.nlm.nih.gov/39695235/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39695235/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39695235", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "LCA/TULP3/sirtuin-vATPase-AMPK contrasts altered worm/fly lifespan and aged-mouse muscle performance.", "what_it_does_not_show": "Allosteric activation and overexpression are not proof that age-related NAD decline initiates aging.", "confounders_present": [ "Allosteric activation and overexpression are not proof that age-related NAD decline initiates 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": [] } }, { "n": 59, "pmid": "39702414", "title": "Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.", "citation": "Høyland LE, VanLinden MR, Niere M et al. Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD. Nature metabolism. 2024.", "doi": "10.1038/s42255-024-01174-w", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39702414/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39702414/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39702414", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [ "M5" ], "evidence_class": "Weak", "system": "cell experimental", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Engineered compartmental NAD depletion showed buffering and differential vulnerability when mitochondria were targeted.", "what_it_does_not_show": "Cultured-cell tolerance or failure is not an organismal aging or clinical healthspan endpoint.", "confounders_present": [ "Cultured-cell tolerance or failure is not an organismal aging or clinical healthspan endpoint." ], "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": [] } }, { "n": 60, "pmid": "40117359", "title": "Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD+ synthesis via enterohepatic circulation.", "citation": "Yaku K, Palikhe S, Iqbal T et al. Nicotinamide riboside and nicotinamide mononucleotide facilitate NAD+ synthesis via enterohepatic circulation. Science advances. 2025.", "doi": "10.1126/sciadv.adr1538", "pmcid": "PMC11927621", "url": "https://pubmed.ncbi.nlm.nih.gov/40117359/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/40117359/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID40117359", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal interventional", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "NMN/NR tracer experiments identified enterohepatic and microbial deamidation routes in mice.", "what_it_does_not_show": "Delivery routing does not establish functional aging efficacy or in-vivo human mediation.", "confounders_present": [ "Delivery routing does not establish functional aging efficacy or in-vivo human 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": [] } } ], "verification_summary": { "load_bearing_claims_checked": 65, "verified": 65, "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": "Β", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Pure association evidence — however large, however replicated — cannot exceed Β.", "specific_trigger": "SC1 is an existence/age-association subclaim. Human skin and brain age comparisons and animal NAD measurements support a decline in specified tissues, but do not causally identify that decline as an aging initiator [29–32,34,35,50]. Β is the associative evidence level, not a statement that the observed decline is false.", "resulting_ceiling": "Β" }, { "subclaim_id": "SC4", "cap": "Γ", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Overexpression in model systems caps at Γ", "specific_trigger": "SC4 remains Γ for general endogenous longevity primacy. SIRT6 construct sufficiency and fly gain/loss support bounded biology, but constitutive development, background/sex variation and controlled Sir2 failures prevent a general adult-human necessity inference [39–45,51,58].", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Age-related NAD+ decline limits sirtuin activity and is a causal driver of organismal aging, so NAD+ precursor repletion restores youthful function and improves human healthspan or lifespan.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Narrow functional intervention and genetic epistasis can reach Ε in their actual scope. An isolated marker or transgene leg is not re-capped over a convergent set. Here the general endogenous-primacy clause is still construct-heavy and unisolated. SC1 is separately preregistered as existence/association; its Β does not demote the SC2/SC3 causal contributions. The resulting weakest-link score is an aggregation sensitivity, not a blanket dismissal.", "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": "unclear", "qualifying_evidence_citation": "PMID24360282, PMID27304511, PMID33199924, PMID33199925, PMID23870130", "gamma_hard_rules_triggered": [ "NAD level change measurements alone, mitochondrial metrics alone and senescence marker changes alone cap isolated surrogate inferences.", "SC2 includes functional worm and aged-mouse contrasts, and SC3 includes actual walking/ventilatory outcomes: neither assembled set is honestly described as biomarkers only.", "Single-species/strain legs constrain generalization, not the whole cross-system set. Constitutive transgene sufficiency cannot identify endogenous general longevity necessity." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "SC1 is an existence/age-association subclaim. Human skin and brain age comparisons and animal NAD measurements support a decline in specified tissues, but do not causally identify that decline as an aging initiator [29–32,34,35,50]. Β is the associative evidence level, not a statement that the observed decline is false.", "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": "PMID33888596, PMID31710095, PMID24360282, PMID27304511, PMID28068222, PMID33199924, PMID33199925, PMID29719225, PMID27127236, PMID29514072, PMID23375372, PMID37683629, PMID38129670, PMID39044033, PMID32755581, PMID23870130, PMID38504132, PMID21982712, PMID25921090, PMID38422177, PMID34497121, PMID39702414, PMID40117359", "gamma_hard_rules_triggered": [ "NAD level change measurements alone, mitochondrial metrics alone and senescence marker changes alone cap isolated surrogate inferences.", "SC2 includes functional worm and aged-mouse contrasts, and SC3 includes actual walking/ventilatory outcomes: neither assembled set is honestly described as biomarkers only.", "Single-species/strain legs constrain generalization, not the whole cross-system set. Constitutive transgene sufficiency cannot identify endogenous general longevity necessity." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "SC2 reaches Ε for defined functional contributions. SIRT3 co-deletion removes aged CD38-knockout glucose benefit despite elevated NAD, worm sir-2.1 is required for tested NAD-dependent longevity, and other adult interventions improve specified function [32,36,50,52,53]. Developmental genetics, compartment and alternative pathways limit general initiation or exclusive mediation.", "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": "yes", "qualifying_evidence_citation": "PMID37994989, PMID31412242, PMID37159264, PMID38871717, PMID33888596, PMID36482258, PMID34238308, PMID36740954, PMID36797393, PMID38789831, PMID36443648, PMID29992272, PMID31710095, PMID31390002, PMID35998039", "gamma_hard_rules_triggered": [ "NAD level change measurements alone, mitochondrial metrics alone and senescence marker changes alone cap isolated surrogate inferences.", "SC2 includes functional worm and aged-mouse contrasts, and SC3 includes actual walking/ventilatory outcomes: neither assembled set is honestly described as biomarkers only.", "Single-species/strain legs constrain generalization, not the whole cross-system set. Constitutive transgene sufficiency cannot identify endogenous general longevity necessity." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "SC3 reaches Ε only for measured human functional outcomes in baseline-defined settings. NICE walking meets its liberal prespecified one-sided phase II criterion; small NMN trials report secondary walking/ventilatory signals [7,14,15,19]. Null functional and primary outcomes map limits [1,6,16,21,25–28]. No human lifespan extension, general disability reduction or youthful restoration is demonstrated.", "ceiling_from_boundary_check": "Δ or higher" }, { "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": "unclear", "qualifying_evidence_citation": "PMID34050173, PMID22367546, PMID35091469, PMID21938067, PMID23375372, PMID30853213, PMID17086191, PMID39695235", "gamma_hard_rules_triggered": [ "NAD level change measurements alone, mitochondrial metrics alone and senescence marker changes alone cap isolated surrogate inferences.", "SC2 includes functional worm and aged-mouse contrasts, and SC3 includes actual walking/ventilatory outcomes: neither assembled set is honestly described as biomarkers only.", "Single-species/strain legs constrain generalization, not the whole cross-system set. Constitutive transgene sufficiency cannot identify endogenous general longevity necessity." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "SC4 remains Γ for general endogenous longevity primacy. SIRT6 construct sufficiency and fly gain/loss support bounded biology, but constitutive development, background/sex variation and controlled Sir2 failures prevent a general adult-human necessity inference [39–45,51,58].", "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": [ "[31] Mouse NAD decline and repletion were linked to a SIRT1-dependent pseudohypoxic mitochondrial response.", "[32] In aged mice, CD38 loss elevated NAD and improved glucose tolerance; SIRT3 co-deletion removed functional and mitochondrial benefits despite elevated NAD.", "[34] Senescent-cell inflammatory signals promoted CD38-positive macrophages and age-associated NAD loss.", "[35] Senescence ablation and ecto-CD38 experiments linked inflammatory tissue context to NAD degradation and precursor availability.", "[50] NAD repletion extended worm lifespan through sir-2.1-dependent and mitochondrial-stress/FOXO pathways." ], "what_would_cross_it": "For Δ in the broad driver interpretation, selective adult depletion and rescue must change an aging trajectory with composition/assay control; descriptive decline itself remains a different question." }, { "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": [ "[13] NMN improved muscle insulin sensitivity in randomized prediabetic postmenopausal women; muscle steady-state NAD did not increase although turnover metabolites did.", "[26] The same obese-men NR trial found no muscle NAD, respiration or mitochondrial morphology improvement, with lower NAMPT expression.", "[31] Mouse NAD decline and repletion were linked to a SIRT1-dependent pseudohypoxic mitochondrial response.", "[32] In aged mice, CD38 loss elevated NAD and improved glucose tolerance; SIRT3 co-deletion removed functional and mitochondrial benefits despite elevated NAD.", "[33] Long-term NMN improved several age-associated activity, metabolic and ocular functions in mice.", "[34] Senescent-cell inflammatory signals promoted CD38-positive macrophages and age-associated NAD loss.", "[35] Senescence ablation and ecto-CD38 experiments linked inflammatory tissue context to NAD degradation and precursor availability.", "[36] The CD38 inhibitor 78c improved age-associated glucose, exercise/muscle and cardiac measures; NAD-synthesis inhibition reversed benefit.", "[37] NR improved mouse muscle-stem-cell regeneration and other stem-cell measures, with a reported lifespan effect.", "[38] Nicotinamide improved selected high-fat-diet health measures without extending mouse lifespan.", "[44] SIRT3 affected aged or stressed hematopoietic-stem-cell regeneration while being dispensable for tested young homeostasis.", "[46] Endothelial CX43/PARP1/NMN/SIRT3 experiments affected aged blood-brain-barrier dysfunction.", "[47] CD38 genetic/pharmacological contrasts preserved age-associated ovarian function and fertility.", "[48] CD38/MCU contrasts rescued aged hematopoietic function but showed different CD38 roles in young proliferation.", "[49] NMN improved meiotic, fertilization and ovulatory functions in aged mouse oocytes.", "[50] NAD repletion extended worm lifespan through sir-2.1-dependent and mitochondrial-stress/FOXO pathways.", "[52] Trigonelline tracer and perturbation work linked NAD/sirtuin-dependent worm function/lifespan and improved aged-mouse muscle performance.", "[53] NMN improved diet/age-associated mouse glucose dysfunction with partially SIRT1-linked mechanisms.", "[54] Adipose NAMPT manipulation, NMN rescue and antibody contrasts linked an endocrine NAD/sirtuin circuit to hypothalamic activity and function.", "[56] NMN improved diet-associated cardiac function through vATPase/mTOR and metabolic contrasts.", "[57] NR improved cognition/synapse and inflammatory phenotypes in APP/PS1 mice, with cGAS-STING involvement.", "[59] Engineered compartmental NAD depletion showed buffering and differential vulnerability when mitochondria were targeted.", "[60] NMN/NR tracer experiments identified enterohepatic and microbial deamidation routes in mice." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires causal effect in constrained contexts, backgrounds, or species.", "satisfied": "yes", "supporting_evidence": [ "[13] NMN improved muscle insulin sensitivity in randomized prediabetic postmenopausal women; muscle steady-state NAD did not increase although turnover metabolites did.", "[26] The same obese-men NR trial found no muscle NAD, respiration or mitochondrial morphology improvement, with lower NAMPT expression.", "[31] Mouse NAD decline and repletion were linked to a SIRT1-dependent pseudohypoxic mitochondrial response.", "[32] In aged mice, CD38 loss elevated NAD and improved glucose tolerance; SIRT3 co-deletion removed functional and mitochondrial benefits despite elevated NAD.", "[33] Long-term NMN improved several age-associated activity, metabolic and ocular functions in mice.", "[34] Senescent-cell inflammatory signals promoted CD38-positive macrophages and age-associated NAD loss.", "[35] Senescence ablation and ecto-CD38 experiments linked inflammatory tissue context to NAD degradation and precursor availability.", "[36] The CD38 inhibitor 78c improved age-associated glucose, exercise/muscle and cardiac measures; NAD-synthesis inhibition reversed benefit.", "[37] NR improved mouse muscle-stem-cell regeneration and other stem-cell measures, with a reported lifespan effect.", "[38] Nicotinamide improved selected high-fat-diet health measures without extending mouse lifespan.", "[44] SIRT3 affected aged or stressed hematopoietic-stem-cell regeneration while being dispensable for tested young homeostasis.", "[46] Endothelial CX43/PARP1/NMN/SIRT3 experiments affected aged blood-brain-barrier dysfunction.", "[47] CD38 genetic/pharmacological contrasts preserved age-associated ovarian function and fertility.", "[48] CD38/MCU contrasts rescued aged hematopoietic function but showed different CD38 roles in young proliferation.", "[49] NMN improved meiotic, fertilization and ovulatory functions in aged mouse oocytes.", "[50] NAD repletion extended worm lifespan through sir-2.1-dependent and mitochondrial-stress/FOXO pathways.", "[52] Trigonelline tracer and perturbation work linked NAD/sirtuin-dependent worm function/lifespan and improved aged-mouse muscle performance.", "[53] NMN improved diet/age-associated mouse glucose dysfunction with partially SIRT1-linked mechanisms.", "[54] Adipose NAMPT manipulation, NMN rescue and antibody contrasts linked an endocrine NAD/sirtuin circuit to hypothalamic activity and function.", "[56] NMN improved diet-associated cardiac function through vATPase/mTOR and metabolic contrasts.", "[57] NR improved cognition/synapse and inflammatory phenotypes in APP/PS1 mice, with cGAS-STING involvement.", "[59] Engineered compartmental NAD depletion showed buffering and differential vulnerability when mitochondria were targeted.", "[60] NMN/NR tracer experiments identified enterohepatic and microbial deamidation routes in mice." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Reproducible intervention effects\n- Mechanistic narrowing\n- Evidence not reducible to general sickness, caloric reduction, or developmental artifacts", "satisfied": "no", "supporting_evidence": [ "[13] NMN improved muscle insulin sensitivity in randomized prediabetic postmenopausal women; muscle steady-state NAD did not increase although turnover metabolites did.", "[26] The same obese-men NR trial found no muscle NAD, respiration or mitochondrial morphology improvement, with lower NAMPT expression.", "[31] Mouse NAD decline and repletion were linked to a SIRT1-dependent pseudohypoxic mitochondrial response.", "[32] In aged mice, CD38 loss elevated NAD and improved glucose tolerance; SIRT3 co-deletion removed functional and mitochondrial benefits despite elevated NAD.", "[33] Long-term NMN improved several age-associated activity, metabolic and ocular functions in mice.", "[34] Senescent-cell inflammatory signals promoted CD38-positive macrophages and age-associated NAD loss.", "[35] Senescence ablation and ecto-CD38 experiments linked inflammatory tissue context to NAD degradation and precursor availability.", "[36] The CD38 inhibitor 78c improved age-associated glucose, exercise/muscle and cardiac measures; NAD-synthesis inhibition reversed benefit.", "[37] NR improved mouse muscle-stem-cell regeneration and other stem-cell measures, with a reported lifespan effect.", "[38] Nicotinamide improved selected high-fat-diet health measures without extending mouse lifespan.", "[44] SIRT3 affected aged or stressed hematopoietic-stem-cell regeneration while being dispensable for tested young homeostasis.", "[46] Endothelial CX43/PARP1/NMN/SIRT3 experiments affected aged blood-brain-barrier dysfunction.", "[47] CD38 genetic/pharmacological contrasts preserved age-associated ovarian function and fertility.", "[48] CD38/MCU contrasts rescued aged hematopoietic function but showed different CD38 roles in young proliferation.", "[49] NMN improved meiotic, fertilization and ovulatory functions in aged mouse oocytes.", "[50] NAD repletion extended worm lifespan through sir-2.1-dependent and mitochondrial-stress/FOXO pathways.", "[52] Trigonelline tracer and perturbation work linked NAD/sirtuin-dependent worm function/lifespan and improved aged-mouse muscle performance.", "[53] NMN improved diet/age-associated mouse glucose dysfunction with partially SIRT1-linked mechanisms.", "[54] Adipose NAMPT manipulation, NMN rescue and antibody contrasts linked an endocrine NAD/sirtuin circuit to hypothalamic activity and function.", "[56] NMN improved diet-associated cardiac function through vATPase/mTOR and metabolic contrasts.", "[57] NR improved cognition/synapse and inflammatory phenotypes in APP/PS1 mice, with cGAS-STING involvement.", "[59] Engineered compartmental NAD depletion showed buffering and differential vulnerability when mitochondria were targeted.", "[60] NMN/NR tracer experiments identified enterohepatic and microbial deamidation routes in mice." ], "what_would_cross_it": "For Ζ, independently narrow adult-onset endogenous NAD-to-sirtuin mediation across backgrounds/species while excluding intake, developmental, redox and CD38-pleiotropy alternatives." }, { "subclaim_id": "SC3", "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] NR increased blood NAD in a randomized MCI pilot without improving cognition; the CBF signal did not withstand multiplicity correction.", "[5] NR changed the muscle NAD metabolome and inflammatory markers in older men but did not change measured mitochondrial bioenergetics.", "[6] The CKD randomized crossover found no NR benefit on peak oxygen consumption, work or efficiency despite metabolic changes.", "[7] NICE reported a 17.6-m NR-placebo walking contrast, one-sided P=.08, satisfying its prespecified phase II alpha .10; NR plus resveratrol was null.", "[13] NMN improved muscle insulin sensitivity in randomized prediabetic postmenopausal women; muscle steady-state NAD did not increase although turnover metabolites did.", "[14] A randomized NMN dose trial reported secondary six-minute-walk and quality-of-life benefits alongside blood NAD increases.", "[15] NMN plus exercise improved ventilatory-threshold measures in recreational runners while VO2max did not improve.", "[16] MIB626 changed blood NAD, weight and selected vascular/metabolic measures but not measured strength, fatigue, aerobic capacity, stair power or insulin sensitivity.", "[17] NMN increased serum nicotinamide without a significant between-group arterial-stiffness benefit.", "[19] A randomized NMN trial missed its primary stepping endpoint while showing secondary walking and sleep signals.", "[21] A small 24-week trial in older diabetic men found no grip-strength or walking benefit; the frailty difference did not meet conventional significance.", "[25] Randomized NR in obese men did not improve insulin sensitivity, metabolism or body composition.", "[26] The same obese-men NR trial found no muscle NAD, respiration or mitochondrial morphology improvement, with lower NAMPT expression.", "[27] The same randomized obese-men NR cohort showed no pancreatic/incretin response benefit.", "[28] Randomized NR-pterostilbene did not improve muscle-injury regeneration, strength or muscle-stem-cell outcomes in older adults." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ε", "requirement_quoted": "Requires causal effect in constrained contexts, backgrounds, or species.", "satisfied": "yes", "supporting_evidence": [ "[1] NR increased blood NAD in a randomized MCI pilot without improving cognition; the CBF signal did not withstand multiplicity correction.", "[5] NR changed the muscle NAD metabolome and inflammatory markers in older men but did not change measured mitochondrial bioenergetics.", "[6] The CKD randomized crossover found no NR benefit on peak oxygen consumption, work or efficiency despite metabolic changes.", "[7] NICE reported a 17.6-m NR-placebo walking contrast, one-sided P=.08, satisfying its prespecified phase II alpha .10; NR plus resveratrol was null.", "[13] NMN improved muscle insulin sensitivity in randomized prediabetic postmenopausal women; muscle steady-state NAD did not increase although turnover metabolites did.", "[14] A randomized NMN dose trial reported secondary six-minute-walk and quality-of-life benefits alongside blood NAD increases.", "[15] NMN plus exercise improved ventilatory-threshold measures in recreational runners while VO2max did not improve.", "[16] MIB626 changed blood NAD, weight and selected vascular/metabolic measures but not measured strength, fatigue, aerobic capacity, stair power or insulin sensitivity.", "[17] NMN increased serum nicotinamide without a significant between-group arterial-stiffness benefit.", "[19] A randomized NMN trial missed its primary stepping endpoint while showing secondary walking and sleep signals.", "[21] A small 24-week trial in older diabetic men found no grip-strength or walking benefit; the frailty difference did not meet conventional significance.", "[25] Randomized NR in obese men did not improve insulin sensitivity, metabolism or body composition.", "[26] The same obese-men NR trial found no muscle NAD, respiration or mitochondrial morphology improvement, with lower NAMPT expression.", "[27] The same randomized obese-men NR cohort showed no pancreatic/incretin response benefit.", "[28] Randomized NR-pterostilbene did not improve muscle-injury regeneration, strength or muscle-stem-cell outcomes in older adults." ], "what_would_cross_it": "" }, { "subclaim_id": "SC3", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Reproducible intervention effects\n- Mechanistic narrowing\n- Evidence not reducible to general sickness, caloric reduction, or developmental artifacts", "satisfied": "no", "supporting_evidence": [ "[1] NR increased blood NAD in a randomized MCI pilot without improving cognition; the CBF signal did not withstand multiplicity correction.", "[5] NR changed the muscle NAD metabolome and inflammatory markers in older men but did not change measured mitochondrial bioenergetics.", "[6] The CKD randomized crossover found no NR benefit on peak oxygen consumption, work or efficiency despite metabolic changes.", "[7] NICE reported a 17.6-m NR-placebo walking contrast, one-sided P=.08, satisfying its prespecified phase II alpha .10; NR plus resveratrol was null.", "[13] NMN improved muscle insulin sensitivity in randomized prediabetic postmenopausal women; muscle steady-state NAD did not increase although turnover metabolites did.", "[14] A randomized NMN dose trial reported secondary six-minute-walk and quality-of-life benefits alongside blood NAD increases.", "[15] NMN plus exercise improved ventilatory-threshold measures in recreational runners while VO2max did not improve.", "[16] MIB626 changed blood NAD, weight and selected vascular/metabolic measures but not measured strength, fatigue, aerobic capacity, stair power or insulin sensitivity.", "[17] NMN increased serum nicotinamide without a significant between-group arterial-stiffness benefit.", "[19] A randomized NMN trial missed its primary stepping endpoint while showing secondary walking and sleep signals.", "[21] A small 24-week trial in older diabetic men found no grip-strength or walking benefit; the frailty difference did not meet conventional significance.", "[25] Randomized NR in obese men did not improve insulin sensitivity, metabolism or body composition.", "[26] The same obese-men NR trial found no muscle NAD, respiration or mitochondrial morphology improvement, with lower NAMPT expression.", "[27] The same randomized obese-men NR cohort showed no pancreatic/incretin response benefit.", "[28] Randomized NR-pterostilbene did not improve muscle-injury regeneration, strength or muscle-stem-cell outcomes in older adults." ], "what_would_cross_it": "For Ζ, independently replicate prespecified clinical function with stronger confirmatory inference and dose/tissue engagement; lifelong clinical aging or survival must be tested separately from short disease-specific walking." }, { "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": [ "[39] Constitutive SIRT6 overexpression extended median survival in both sexes on B6; SIRT1 overexpression did not add median-survival benefit.", "[40] SIRT6-transgenic mice showed male-specific lifespan extension in the earlier background.", "[41] Fly Sirt6 gain/loss and Myc-linked contrasts affected lifespan and physiology.", "[42] Genetic-background and matched-transgenic controls removed previously attributed worm/fly Sir2-overexpression longevity; elevated expression persisted.", "[44] SIRT3 affected aged or stressed hematopoietic-stem-cell regeneration while being dispensable for tested young homeostasis.", "[45] LINE1/NRTI contrasts improved severe Sirt6-deficient growth and survival phenotypes.", "[51] Resveratrol improved health and survival of high-calorie-fed middle-aged mice.", "[58] LCA/TULP3/sirtuin-vATPase-AMPK contrasts altered worm/fly lifespan and aged-mouse muscle performance." ], "what_would_cross_it": "For Δ, selectively perturb adult endogenous sirtuin activity and demonstrate corresponding aging trajectory, with rescue and non-sirtuin pathways held intact rather than developmental construct sufficiency." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "NAD-engaged MCI cognition remained unchanged [1].", "CKD exercise outcomes were null [6].", "Obese-men NR metabolic and muscle follow-ups share a null trial [25–27].", "The NMN stepping primary endpoint was null despite secondary walking signals [19].", "Controlled worm/fly Sir2 overexpression lost previously reported longevity [42]." ], "note": "Baseline diagnosis, age, sex, species, genotype, compartment, dose and follow-up are pre-outcome contexts. Post-treatment NAD responders, adherence-selected subsets and exploratory hyperinsulinemic groups do not define successful scope." }, "falsification_patterns_met": [ { "subclaim_id": "SC3", "pattern": "Pathway manipulation changes biomarkers but not lifespan/healthspan", "evidence": "Several human trials dissociate molecular engagement from measured function [1,5,6,16,25–28]. Missing survival data are not a demonstrated negative survival result.", "downgrade_applied": false }, { "subclaim_id": "SC4", "pattern": "Effects disappear across strains or species", "evidence": "Background-controlled worm/fly Sir2 longevity disappears, while distinct SIRT6 experiments remain positive [39–42]. This contradicts uniformity, not every isoform.", "downgrade_applied": false }, { "subclaim_id": "SC2", "pattern": "Necessity fails when the proposed pathway is removed", "evidence": "Alternative vATPase/mTOR pathways undermine exclusive sirtuin mediation [56]; SIRT3 deletion abolishing one benefit is positive narrow epistasis, not a failed necessity test [32].", "downgrade_applied": false } ], "pitfalls_flagged": [ { "subclaim_id": "SC3", "pitfall": "13. Therapeutic effect misread as mechanistic proof", "where": "Walking benefit does not identify sirtuin mediation or general human aging reversal." }, { "subclaim_id": "SC4", "pitfall": "16. Untested generalization confused with mapped boundaries", "where": "Sex, strain, isoform and developmental exposure constrain endogenous adult scope." }, { "subclaim_id": "SC2", "pitfall": "21. A universal cap re-applied to a convergent evidence set", "where": "The worm and mouse functional contribution set retains Ε; single marker legs do not erase it." }, { "subclaim_id": "SC3", "pitfall": "22. Scope fitted to the result", "where": "Post-treatment NAD or adherence responders are not prespecified efficacy populations." } ], "causal_tally_audit": { "tally_claimed_by_document": 43, "tally_after_audit": 43, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Discriminating positive and null contrasts are not all successful aging-reversal tests.", "Reports from one NR obesity cohort are a single intervention family; rare-disease and young-runner results do not prove healthy-aging efficacy." ] }, "steelman": { "case_one_rung_higher": "The strongest Γ case for the full proposition combines aging association with functional interventions and coherent sirtuin epistasis. That is scientifically more informative than correlation alone. Under the locked weakest-link decomposition, however, SC1 is the age-association existence item and remains Β; changing the aggregation retrospectively would hide this methodological limitation.", "case_one_rung_lower": "An Α characterization would reduce the programme to an aging narrative. Direct age measurements, molecular engagement, functional interventions and genetic epistasis refute that characterization. The broader aging-reversal claim remains unproved without making the entire evidence base anecdotal.", "which_rejected": "Retain Β under the registered aggregation, while exposing the Ε primary-subclaim sensitivity. Reject Α because observed decline and causal contributions are empirical. Do not retrospectively change the claim or rule to obtain Γ.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: In baseline-defined older adults, randomize adequate NR/NMN exposure and test prespecified clinical function/disability over meaningful follow-up. Pair this with an adult-selective mechanistic contrast that blocks the proposed sirtuin mediator while preserving NAD repletion and other NAD-dependent routes, with selective rescue and masked outcome assessment. Human exposure instruments or lifelong natural experiments can complement the mediator experiment." }, "final_score": { "hsef_level": "Β", "hsef_descriptor": "Associational", "confidence": "Moderate", "confidence_rationale": "60 primary reports with 5 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "Preregistered weakest-link returns Β because SC1 is scored at association/existence level; SC2 and bounded functional SC3 reach Ε, and general primacy SC4 is Γ. This conservative aggregation is preserved even though it can understate the strength of narrower causal contributions. The named primary subclaim SC3 returns Ε for the measured human functional scope. Scope-matched returns Γ: only SC4 carries the central claim's general organismal-aging scope, while SC3 is restricted to baseline-defined trial populations and is reported separately. Neither sensitivity establishes human lifespan or general aging reversal." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": "5", "derivation": "Direction is mixed feedback rather than solely downstream: senescence/CD38 inflammation produces NAD loss, but NAD/CD38 manipulation also changes functional outcomes (step 1 no sole consequence; step 2 causal dependency present). General initiation, prevention and rate limitation are not jointly established (step 3). Essential cofactor availability does not prove that age-related depletion is required for aging (step 4). Defined deficits amplify or maintain dysfunction initiated by tissue, inflammatory and metabolic changes, matching step 5.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Completed 2024–2026 compartment, trigonelline, precursor-routing and endocrine/vascular programmes [46,48,52,56,59,60,23] test specific mechanisms. No currently pending boundary-crossing clinical aging trial was verified.", "justification": "Completed 2024–2026 compartment, trigonelline, precursor-routing and endocrine/vascular programmes [46,48,52,56,59,60,23] test specific mechanisms. No currently pending boundary-crossing clinical aging trial was verified." }, "stability": { "value": "Stable", "trigger": "No specifically verified pending general-aging clinical trajectory or selective human sirtuin-mediation result identified in this bounded search. Completed reports are not pending triggers.", "justification": "No specifically verified pending general-aging clinical trajectory or selective human sirtuin-mediation result identified in this bounded search. Completed reports are not pending triggers." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Β", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Β", "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": "In baseline-defined older adults, randomize adequate NR/NMN exposure and test prespecified clinical function/disability over meaningful follow-up. Pair this with an adult-selective mechanistic contrast that blocks the proposed sirtuin mediator while preserving NAD repletion and other NAD-dependent routes, with selective rescue and masked outcome assessment. Human exposure instruments or lifelong natural experiments can complement the mediator experiment.", "readout": "Clinical function, disability, incident age-related disease and survival, separately from blood/tissue NAD and sirtuin activity", "critical_control": "Tissue engagement, age/sex/disease context, intake, co-interventions, multiplicity and mediation specificity; no responder-selected inference", "supporting_result": "Replicated clinical aging benefit lost specifically with sirtuin blockade and restored by mediator rescue", "falsifying_result": "Adequate engagement without clinical benefit, or preserved benefit when the nominal sirtuin mediator is removed" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Which tissue compartments decline with age and why?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Which NAD functions require which sirtuin isoforms in adults?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Can narrow walking signals survive independent confirmatory testing?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Do clinical benefits change disability or survival rather than short physiology?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "How do inflammation, precursor routing and non-sirtuin cofactors alter causality?", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-04", "reviewer": "Codex", "evidence_base_note": "60 primary reports; cutoff 2026-10-04; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/PMC; SciSpace and authenticated Consensus discovery; primary-source verification. No API credential handled.", "skill_version": "5.3", "validator_run": "Archived validator run; receipt and logs accompany this pair.", "validator_warnings_addressed": "Claim-form warning is justified: the popularity-list topic is explicitly restated as a causal proposition. The steelman specifies the missing experiment.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "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": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Exposure instruments, adult-specific genetic rescue, independent drug classes, lifelong natural experiments and dose-response clinical function are eligible equivalents. Current blood dose-response does not identify aging mediation; worms and mice supply narrow causality without a human causal aging instrument. No independent human necessity/sufficiency chain carries the full claim to Ζ." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Exposure instruments, adult-specific genetic rescue, independent drug classes, lifelong natural experiments and dose-response clinical function are eligible equivalents. Current blood dose-response does not identify aging mediation; worms and mice supply narrow causality without a human causal aging instrument. No independent human necessity/sufficiency chain carries the full claim to Ζ." }, { "kind": "dose_response_across_populations", "available": true, "why_not_sufficient": "Exposure instruments, adult-specific genetic rescue, independent drug classes, lifelong natural experiments and dose-response clinical function are eligible equivalents. Current blood dose-response does not identify aging mediation; worms and mice supply narrow causality without a human causal aging instrument. No independent human necessity/sufficiency chain carries the full claim to Ζ." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Exposure instruments, adult-specific genetic rescue, independent drug classes, lifelong natural experiments and dose-response clinical function are eligible equivalents. Current blood dose-response does not identify aging mediation; worms and mice supply narrow causality without a human causal aging instrument. No independent human necessity/sufficiency chain carries the full claim to Ζ." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Exposure instruments, adult-specific genetic rescue, independent drug classes, lifelong natural experiments and dose-response clinical function are eligible equivalents. Current blood dose-response does not identify aging mediation; worms and mice supply narrow causality without a human causal aging instrument. No independent human necessity/sufficiency chain carries the full claim to Ζ." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 60, "claims_total": 65, "claims_verified": 65, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 60, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "NR increased blood NAD in a randomized MCI pilot without improving cognition; the CBF signal did not withstand multiplicity correction. Safety and exploratory methylation changes do not demonstrate clinical cognitive or aging reversal.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C2", "text": "NADPARK demonstrated variable brain NAD engagement after NR in a small randomized untreated-PD trial. Mild clinical changes in post-treatment NAD responders cannot define an unbiased aging-efficacy population.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C3", "text": "NR reduced the prespecified sputum IL8 inflammatory endpoint in a COPD randomized trial. Inflammatory improvement is not a demonstrated functional healthspan or mortality effect.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C4", "text": "A randomized older-adult crossover established NR blood target engagement and tolerability with suggestive vascular changes. Potential blood-pressure and arterial signals require confirmatory outcome separation; no longevity result.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C5", "text": "NR changed the muscle NAD metabolome and inflammatory markers in older men but did not change measured mitochondrial bioenergetics. Metabolite engagement and lower inflammation are distinct from clinical aging reversal.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C6", "text": "The CKD randomized crossover found no NR benefit on peak oxygen consumption, work or efficiency despite metabolic changes. This constrains the measured disease and short exposure; it does not prove all NR regimens ineffective.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C7", "text": "NICE reported a 17.6-m NR-placebo walking contrast, one-sided P=.08, satisfying its prespecified phase II alpha .10; NR plus resveratrol was null. This is not a conventional two-sided .05 confirmatory result; contrasts lacked multiplicity adjustment and adherence subsets were post hoc. The examined correction restores only the omitted trial registration.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec3, Sec33, Sec34. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C8", "text": "NR altered NAD and AD-associated signaling measures in neuron-enriched extracellular-vesicle preparations. Enrichment is not direct brain sampling, and these changes do not demonstrate clinical cognition or healthspan improvement.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C9", "text": "An open-label ataxia-telangiectasia programme reported motor improvement relative to historical expectations. No randomized counterfactual; a rare syndromic disorder is not ordinary aging.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C10", "text": "Randomized NR dose groups increased blood NAD with short-term safety assessment. Dose target engagement is not a clinical aging outcome.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C11", "text": "NR-SAFE established short high-dose tolerability; UPDRS improvement coincided with a shorter interval since levodopa. Medication timing limits attribution of the clinical change; no human sirtuin mediation or general aging result.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C12", "text": "HF patient PBMC assays and a four-patient NR pilot showed cellular respiratory and inflammatory changes. Cellular readouts and an uncontrolled pilot do not demonstrate clinical heart-failure efficacy or human healthspan.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C13", "text": "NMN improved muscle insulin sensitivity in randomized prediabetic postmenopausal women; muscle steady-state NAD did not increase although turnover metabolites did. Hepatic and adipose insulin sensitivity did not improve; selective human sirtuin or PDGFR mediation was not tested, and metabolic sensitivity is not lifespan.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: BODY. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C14", "text": "A randomized NMN dose trial reported secondary six-minute-walk and quality-of-life benefits alongside blood NAD increases. Small dose groups, multiple endpoints, short duration and unvalidated blood-age algorithms prevent a general lifespan or aging-reversal claim.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C15", "text": "NMN plus exercise improved ventilatory-threshold measures in recreational runners while VO2max did not improve. Young/middle-aged trained context, small dose groups and co-exercise do not establish general anti-aging efficacy.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C16", "text": "MIB626 changed blood NAD, weight and selected vascular/metabolic measures but not measured strength, fatigue, aerobic capacity, stair power or insulin sensitivity. Molecular engagement is dissociated from these short-term functional endpoints.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C17", "text": "NMN increased serum nicotinamide without a significant between-group arterial-stiffness benefit. Blood engagement and an exploratory subgroup cannot replace the null primary contrast.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C18", "text": "An acute single-arm NMN dose study established short-term pharmacokinetic and safety observations. Ten participants and acute exposure do not assess healthspan or efficacy.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C19", "text": "A randomized NMN trial missed its primary stepping endpoint while showing secondary walking and sleep signals. Secondary outcomes support bounded investigation but do not convert the primary endpoint into a positive confirmatory trial.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C20", "text": "The four-group older-adult NMN study found timing-related interactions; all groups improved sit-to-stand performance and placebo-PM also improved drowsiness. The largest within-group effect is not itself an isolated NMN-placebo efficacy contrast.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C21", "text": "A small 24-week trial in older diabetic men found no grip-strength or walking benefit; the frailty difference did not meet conventional significance. The small trial does not establish equivalence or lack of effect in all baseline contexts.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C22", "text": "Four-week high-dose NMN testing assessed tolerability and safety. Short safety follow-up does not test clinical aging benefit.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C23", "text": "A 2026 randomized open-label comparison found sustained blood NAD rises with NR/NMN and different acute nicotinamide behavior; ex vivo fermentation suggested a deamidation route. Exposure routing and ex vivo microbial metabolism do not demonstrate in-vivo human necessity, sirtuin mediation or clinical aging efficacy.", "carries_number": true, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C24", "text": "A small single-arm NMN study reported PBMC NAD and exploratory metabolic changes, including a tiny hyperinsulinemic subgroup. No randomized counterfactual or validated human aging trajectory.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C25", "text": "Randomized NR in obese men did not improve insulin sensitivity, metabolism or body composition. Dose, sex and baseline disease constrain the negative result; blood exposure does not prove muscle compartment engagement.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C26", "text": "The same obese-men NR trial found no muscle NAD, respiration or mitochondrial morphology improvement, with lower NAMPT expression. This is a shared-cohort mechanistic follow-up, not an independent efficacy trial.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C27", "text": "The same randomized obese-men NR cohort showed no pancreatic/incretin response benefit. Shared participants do not add an independent causal replication.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C28", "text": "Randomized NR-pterostilbene did not improve muscle-injury regeneration, strength or muscle-stem-cell outcomes in older adults. A bundled preparation and injury protocol cannot isolate NR alone or all aging outcomes.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C29", "text": "Cross-sectional human skin measurements linked age to NAD depletion and sex-dependent enzyme/activity differences. Surgical sampling, tissue composition and age association do not establish an initiating aging mechanism.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C30", "text": "Human brain magnetic-resonance measurements associated older age with lower NAD and altered NAD redox balance. Cross-sectional assay-derived measures do not identify causal direction or general whole-body NAD depletion.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C31", "text": "Mouse NAD decline and repletion were linked to a SIRT1-dependent pseudohypoxic mitochondrial response. Mitochondrial molecular rescue alone does not prove organismal aging reversal; this paper remains abstract-level in this review.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C32", "text": "In aged mice, CD38 loss elevated NAD and improved glucose tolerance; SIRT3 co-deletion removed functional and mitochondrial benefits despite elevated NAD. Lifelong double knockout, mixed genetic background and CD38 pleiotropy limit adult-onset and general-human inference.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: S7. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C33", "text": "Long-term NMN improved several age-associated activity, metabolic and ocular functions in mice. Not a mortality-extension trial and not isolated proof of one required sirtuin across species.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C34", "text": "Senescent-cell inflammatory signals promoted CD38-positive macrophages and age-associated NAD loss. This places senescence/inflammation upstream of a NAD sink; it does not identify NAD decline as the universal initiator. Linked erratum detail was not examined.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C35", "text": "Senescence ablation and ecto-CD38 experiments linked inflammatory tissue context to NAD degradation and precursor availability. Functional CD38 feedback does not by itself establish general sirtuin-mediated longevity primacy.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C36", "text": "The CD38 inhibitor 78c improved age-associated glucose, exercise/muscle and cardiac measures; NAD-synthesis inhibition reversed benefit. Several NAD-dependent and non-sirtuin signaling pathways change; this is not exclusive sirtuin mediation or human aging efficacy.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C37", "text": "NR improved mouse muscle-stem-cell regeneration and other stem-cell measures, with a reported lifespan effect. Single-model rescue does not prove a general human aging driver or one required endogenous sirtuin.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C38", "text": "Nicotinamide improved selected high-fat-diet health measures without extending mouse lifespan. Different precursor, diet and tissue NAD response limit direct falsification of all NR/NMN protocols.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C39", "text": "Constitutive SIRT6 overexpression extended median survival in both sexes on B6; SIRT1 overexpression did not add median-survival benefit. Developmental transgene sufficiency is not adult endogenous necessity or human aging primacy.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec3, Sec16. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C40", "text": "SIRT6-transgenic mice showed male-specific lifespan extension in the earlier background. Sex/background differences and constitutive overexpression constrain generalization and endogenous necessity.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C41", "text": "Fly Sirt6 gain/loss and Myc-linked contrasts affected lifespan and physiology. Developmental expression and species scope do not establish adult human longevity regulation.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C42", "text": "Genetic-background and matched-transgenic controls removed previously attributed worm/fly Sir2-overexpression longevity; elevated expression persisted. This challenges those paradigms and proposed DR necessity, not every sirtuin protein or all later SIRT6 results.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: BODY. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C43", "text": "Across rodent species, SIRT6 sequence/activity tracked DNA-repair performance and longevity. Evolutionary correlation and ex vivo sequence effects do not prove lifespan extension by editing an adult organism.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C44", "text": "SIRT3 affected aged or stressed hematopoietic-stem-cell regeneration while being dispensable for tested young homeostasis. A transplantation/stress function is not universal organismal aging necessity.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C45", "text": "LINE1/NRTI contrasts improved severe Sirt6-deficient growth and survival phenotypes. Constitutive deficiency and progeroid development are distinct from reversing normal adult aging.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C46", "text": "Endothelial CX43/PARP1/NMN/SIRT3 experiments affected aged blood-brain-barrier dysfunction. A specific vascular endpoint and linked correction not fully examined do not establish human organismal longevity.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C47", "text": "CD38 genetic/pharmacological contrasts preserved age-associated ovarian function and fertility. Reproductive function is a bounded health phenotype, not overall lifespan or human fertility efficacy.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C48", "text": "CD38/MCU contrasts rescued aged hematopoietic function but showed different CD38 roles in young proliferation. Age and lineage dependence argue against universal inhibition independent of tissue state.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C49", "text": "NMN improved meiotic, fertilization and ovulatory functions in aged mouse oocytes. Not a trial of efficacy in older women or direct survival extension.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C50", "text": "NAD repletion extended worm lifespan through sir-2.1-dependent and mitochondrial-stress/FOXO pathways. Worm genetic specificity does not establish a universally limiting human NAD-sirtuin aging mechanism.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C51", "text": "Resveratrol improved health and survival of high-calorie-fed middle-aged mice. Diet rescue and a pleiotropic compound are not unique endogenous-sirtuin proof or an NR/NMN trial.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C52", "text": "Trigonelline tracer and perturbation work linked NAD/sirtuin-dependent worm function/lifespan and improved aged-mouse muscle performance. Human sarcopenia association is not randomized human efficacy; precursor routing does not identify all aging mediation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C53", "text": "NMN improved diet/age-associated mouse glucose dysfunction with partially SIRT1-linked mechanisms. Disease, diet and sex context constrain inference to a general aging initiator.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C54", "text": "Adipose NAMPT manipulation, NMN rescue and antibody contrasts linked an endocrine NAD/sirtuin circuit to hypothalamic activity and function. Specified tissue communication does not prove general organismal longevity primacy.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C55", "text": "The paper reported Slc12a8-dependent NMN transport using cellular and mouse tracer/genetic experiments. The delivery interpretation is contested in linked comments and correction; not a load-bearing human uptake or aging-efficacy result.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C56", "text": "NMN improved diet-associated cardiac function through vATPase/mTOR and metabolic contrasts. An experimentally narrowed alternative route argues against exclusive sirtuin mediation; not general human aging reversal.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C57", "text": "NR improved cognition/synapse and inflammatory phenotypes in APP/PS1 mice, with cGAS-STING involvement. Disease-model/cell mechanism does not establish human AD efficacy or a general sirtuin aging driver.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C58", "text": "LCA/TULP3/sirtuin-vATPase-AMPK contrasts altered worm/fly lifespan and aged-mouse muscle performance. Allosteric activation and overexpression are not proof that age-related NAD decline initiates aging.", "carries_number": true, "load_bearing_for": [ "SC4" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C59", "text": "Engineered compartmental NAD depletion showed buffering and differential vulnerability when mitochondria were targeted. Cultured-cell tolerance or failure is not an organismal aging or clinical healthspan endpoint.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C60", "text": "NMN/NR tracer experiments identified enterohepatic and microbial deamidation routes in mice. Delivery routing does not establish functional aging efficacy or in-vivo human mediation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC1", "text": "SC1 is an existence/age-association subclaim. Human skin and brain age comparisons and animal NAD measurements support a decline in specified tissues, but do not causally identify that decline as an aging initiator [29–32,34,35,50]. Β is the associative evidence level, not a statement that the observed decline is false.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 29, 30, 31, 32, 34, 35, 50 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC2", "text": "SC2 reaches Ε for defined functional contributions. SIRT3 co-deletion removes aged CD38-knockout glucose benefit despite elevated NAD, worm sir-2.1 is required for tested NAD-dependent longevity, and other adult interventions improve specified function [32,36,50,52,53]. Developmental genetics, compartment and alternative pathways limit general initiation or exclusive mediation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 13, 23, 26, 31, 32, 33, 34, 35, 36, 37, 38, 44, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC3", "text": "SC3 reaches Ε only for measured human functional outcomes in baseline-defined settings. NICE walking meets its liberal prespecified one-sided phase II criterion; small NMN trials report secondary walking/ventilatory signals [7,14,15,19]. Null functional and primary outcomes map limits [1,6,16,21,25–28]. No human lifespan extension, general disability reduction or youthful restoration is demonstrated.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC4", "text": "SC4 remains Γ for general endogenous longevity primacy. SIRT6 construct sufficiency and fly gain/loss support bounded biology, but constitutive development, background/sex variation and controlled Sir2 failures prevent a general adult-human necessity inference [39–45,51,58].", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 39, 40, 41, 42, 43, 44, 45, 51, 58 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CH", "text": "NAD decline and bounded NAD/sirtuin functional effects are real evidence; general human aging reversal is unproved. Locked weakest-link scoring returns Β, with Ε for defined animal contributions and human functional endpoints.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 29, 30, 32, 7, 14, 42 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-04", "note": "" } ], "citation_ledger": [ { "n": 1, "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": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT02942888", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. 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