In plain terms

The claim being assessed: Nicotinamide mononucleotide supplementation improves physical function in older adults.

Where the evidence stands: Δ — First real causal test passed. At least one proper experiment has shown the mechanism can change the outcome.

What this mechanism does: This makes the process worse or keeps it going, but something else starts it.

Strongest evidence for it: Primary SC2 tentatively crosses Δ, with Low confidence, because the registered physical-function gate includes a genuine assigned secondary gait contrast. The quality concerns—multiple endpoints, incomplete twelve-week observations, an older trial allocation error and exploratory testing—are not hidden or converted into an unstated primary-endpoint requirement. Functional benefit is inconsistent across measures and contexts, and a separate emerging longer-dose trial adds a null boundary. Evidence does not establish broad strength/exercise efficacy, isolated NAD necessity or human longevity. SC1/SC3 marker-to-clinical inference and SC4 molecule equivalence remain separately bounded.

What decisive evidence would look like

In plain terms, researchers would change the proposed cause, confirm it changed as intended, and measure a meaningful health outcome while checking other explanations. The result should be able to support or count against the claim.

Relative explanatory fit: Alternative ranked ahead

What this review means

NMN raises blood NAD; older-adult gait signals are tentative and inconsistent, with no established broader physical or longevity benefit.

Implications for health and treatment: Primary SC2 tentatively crosses Δ, with Low confidence, because the registered physical-function gate includes a genuine assigned secondary gait contrast. The quality concerns—multiple endpoints, incomplete twelve-week observations, an older trial allocation error and exploratory testing—are not hidden or converted into an unstated primary-endpoint requirement. Functional benefit is inconsistent across measures and contexts, and a separate emerging longer-dose trial adds a null boundary. Evidence does not establish broad strength/exercise efficacy, isolated NAD necessity or human longevity. SC1/SC3 marker-to-clinical inference and SC4 molecule equivalence remain separately bounded.

Limits for individual care: 70 primary reports with 3 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness. The grade applies to the exact registered claim; stronger findings for narrower subclaims remain separate. No complete-paper audit or blinded calibration is claimed. This educational review does not establish an individual treatment recommendation.

Medical information notice: This review provides general health information, not medical advice. It cannot diagnose a condition or replace an individual discussion with a qualified clinician.

Source checking used bounded original primary abstract passages/status records and selected original partial-body passages. No complete-abstract or complete-paper audit, or independent scientific peer review, is claimed. Detailed access counts and limitations appear in the review.

A low grade is not an accusation. It means the causal work has not been done yet, which is the ordinary state of most actively studied mechanisms in biology.

At a glance

Sub-claims assessed separately

Full assessment

From here the review is written for a technical reader: caps and thresholds, competing models, the independence basis, and the citation ledger.

Sources: 70 primary reports; claims: 75; verified: 75; unverified: 0. Verification is bounded attribution. Access: 3 partial-body and 67 bounded abstract/status examinations. Literature cutoff: 2026-10-13; source examination UTC date: 2026-10-13. No complete-paper audit or blinded calibration claimed. Adversarial review: Generated by Sol 6.1; adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-14. 7 corrections applied (see ADVERSARIAL REVIEW AND APPROVAL). Status: Approved as revised.

AT A GLANCE

NMN raises blood NAD; older-adult gait signals are tentative and inconsistent, with no established broader physical or longevity benefit.

Deciding experiment: Randomize baseline-defined ≥60 adults to exact NMN formulation and matched placebo for 24 weeks, with gait/strength/capacity prespecified as primary or multiplicity-controlled co-primary, meaningful effect size and complete assignment-based analysis. Include prospectively defined healthy and impaired-function/diabetes strata with interaction testing, independent blinded assessors and proper allocation auditing. Measure muscle NAD and pathway controls separately, and extend functional/disease follow-up.

Belief versus evidence: Primary SC2 tentatively crosses Δ, with Low confidence, because the registered physical-function gate includes a genuine assigned secondary gait contrast. The quality concerns—multiple endpoints, incomplete twelve-week observations, an older trial allocation error and exploratory testing—are not hidden or converted into an unstated primary-endpoint requirement. Functional benefit is inconsistent across measures and contexts, and a separate emerging longer-dose trial adds a null boundary. Evidence does not establish broad strength/exercise efficacy, isolated NAD necessity or human longevity. SC1/SC3 marker-to-clinical inference and SC4 molecule equivalence remain separately bounded.

Best-supported rival: Exposure and functional response are partly dissociated (Δ) — the highest-ranked model that is not the nominal. NMN raises NAD while clinical effects vary by measure, baseline physiology and trial context: controlled NAD rise coexists with stepping, strength, aerobic and disease-specific nulls, and direct gait positives remain bounded. The nominal model, NMN restoring a functionally limiting NAD pathway, ranks second. PMID38789831 original M/R gives a genuine secondary baseline-adjusted gait-time contrast alongside null stepping/grip/SPPB, while PMID35215405 shows within-group sit-to-stand improvement in every arm. These separate a specific tentative clinical signal from a blanket function claim or a largest-within-arm effect interpretation.

COMPETING MECHANISTIC MODELS

Rank 2: NMN restores a functionally limiting NAD pathway (Δ). NMN exposure can improve selected older-adult performance by restoring a limiting pathway. A genuine secondary gait contrast and nominal older-men gait signals provide tentative clinical support. Blood markers do not prove tissue limitation or mediator necessity; many physical measures and clinical contexts remain null.

Rank 1: Exposure and functional response are partly dissociated (Δ). NMN raises NAD while clinical effects vary by measure, baseline physiology and trial context. Controlled NAD rise coexists with stepping, strength, aerobic and disease-specific nulls; direct gait positives remain bounded. Dissociation does not demonstrate which pathway causes every genuine positive or that all supplementation is ineffective.

Rank 3: Secondary testing and study conduct contribute to apparent benefit (Γ). Practice, multiple outcomes, incomplete data and disrupted allocation can generate nominal signals. All-group within improvements, uncorrected exploratory outcomes and the 22-person supplier cross-switch are concrete concerns. A baseline-adjusted controlled gait contrast is not merely within-arm improvement and cannot be dismissed solely because it is secondary.

Rank 4: Distinct molecules and disease states have distinct effects (Γ). NR, NMN and metformin act through overlapping but non-equivalent pathways and patient settings. NR-PAD walking benefit, metformin-PAD/frailty nulls and specific adjunct successes distinguish outcomes. Cross-trial comparisons do not constitute randomized drug equivalence or prove every molecular mediator.

The tournament does not alter the nominal level. Compatible pathways and flexible alternatives are not automatically proved by explaining observations.

FULL REVIEW

Registered claim and scope

Nicotinamide mononucleotide supplementation improves physical function in older adults.

The precise lead clinical proposition is SC2. Mechanism, competing-cause, generalization and safety companions remain separately reported; they do not replace the primary clinical endpoint.

Selection: position 21 in the registered editorial traffic-priority list; registration timestamp 2026-10-13T16:06:25.734540+00:00. Ranked editorial traffic priority rather than measured global popularity or a preset verdict. Registered claim assessed against original sources; no independent blinded calibration is claimed.

Evidence and causal interpretation

Rubric fit: Rubric06 separates NAD/mitochondrial markers, function, healthspan and lifespan. The explicit clinical adaptation treats measured gait/strength/capacity as the registered physical phenotype rather than demanding a lifespan result for a non-lifespan claim. A randomized genuine secondary function endpoint may cross the first threshold with appropriate confidence and multiplicity limits; a null study primary does not automatically erase every secondary clinical signal. Human function is not inferred from animal/cell markers, and molecule-specific treatment benefit is not mediator necessity.

The strongest consistent NMN result is exposure: blood NAD and metabolites rise. That does not by itself establish physical benefit, muscle delivery or slower aging. Older-function results must be assessed as actual performance contrasts.

Morifuji randomizes baseline age 65–75 adults for twelve weeks. Original Methods/Results show baseline-adjusted ANCOVA, a null stepping primary, null grip and total SPPB, and a positive secondary four-metre time. Two placebo week-twelve observations were absent despite all 60 being designated the efficacy set. No familywise correction was stated. This is a real controlled functional signal with low certainty, not proof of broad performance gains or NAD mediation.

The Kim four-arm trial has physical outcomes secondary to sleep/fatigue and applies Bonferroni posthoc analyses after interactions. Actual Results show improved sit-to-stand within all four groups and the largest within-arm NMN-afternoon effect. That alone is not a demonstrated NMN-placebo efficacy contrast. Igarashi has nominal gait/left-grip signals, but a supplier cross-switch at week 6 removes 22 of 42 twelve-week observations and disrupts balance; analyses were explicitly exploratory without correction. Six-week or pooled-duration signals do not alone answer an eight-week gate.

A small 24-week older-diabetic impaired-function trial has primary walking/grip nulls. A shorter mixed-age MIB-626 trial has NAD positives but physical nulls. The younger-runner trial changes ventilatory-threshold measures without VO2max or peak-power differences and lies outside our age/duration scope. Middle-aged six-minute-walk positives and prediabetic clamp physiology remain genuine adjacent findings rather than older-function or longevity proof.

Consensus discovery added a timely original outside the initial indexed pool. The independently read Igarashi 2026 publisher abstract reports 1250 mg NMN for 24 weeks in adults ≥65, with NAD augmentation but auditory and physical-performance nulls. This accepted peer-reviewed primary is identified by its actual DOI, separately displayed outside the 70 PMID-based reports. No body or invented PMID is claimed, and a higher-dose null does not automatically erase a genuine lower-dose secondary gait signal.

The family contains different drugs. NICE reports a genuine six-month NR-PAD walking benefit, with a one-sided 90% interval and separate adherence analyses, whereas other NR disease trials have markers without primary function. Metformin fails to add function in PERMET, MET-PREVENT and DEMFOS contexts and can blunt exercise adaptations, while a knee-OA adjunct trial has genuine pain/function benefit. These results do not justify a generic equivalence claim or dismissal of every disease-specific treatment.

Additional original-source checks outside the primary-report count

Igarashi et al., 2026: Sustained NAD augmentation by high-dose nicotinamide mononucleotide supplementation in older adults. Status: Peer-reviewed accepted original published 25 September 2026; DOI 10.1038/s41514-026-00482-7; exact PubMed DOI query returned 0; no invented PMID. Separately counted outside 70 PMID-based originals. Access: Publisher original abstract actually read; attempted PDF redirected to HTML and did not yield body or supplement reading. In adults ≥65, 1250 mg NMN daily 24 weeks raises NAD; auditory primary and physical-performance endpoints show no significant improvement; exploratory changes fail multiple-testing correction. No universal proof that every dose lacks benefit, no confirmed physical efficacy or human lifespan extension; complete Methods/Results/participant counts were not examined. This source is not included in the primary-report target or treated as a complete-paper audit.

UMIN000047871 Morifuji trial registry. Status: Public protocol registry, not an additional primary paper; same trial as 38789831. Access: Original age, design, primary/secondary and exclusion fields actually read. Ages 65–75; randomized double-blind placebo; stepping primary and SPPB/grip secondary, excluding baseline motor dysfunction/serious disease. No additional trial outcome; stale unpublished field cannot erase the existing 2024 publisher original. This source is not included in the primary-report target or treated as a complete-paper audit.

UMIN000054187 NMN-plus-strength-training registry. Status: Public registered function experiment; fields conflict on publication status. No verified pending or published result inferred. Access: Original design, eligibility, primary strength outcomes and status/results fields actually read. Randomized double-blind NMN/placebo on matched 24-week training in ≥65 reduced-muscle adults; 65 enrolled. Status says main results published while publication says unpublished, without result URL. No outcome or reliable pending-readout date; planned future final follow-up and inconsistent status are not evidence of efficacy. This source is not included in the primary-report target or treated as a complete-paper audit.

HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3)

Subclaim matrix and aggregation

Preregistered aggregation: primary-subclaim. Primary SC2 tentatively crosses Δ, with Low confidence, because the registered physical-function gate includes a genuine assigned secondary gait contrast. The quality concerns—multiple endpoints, incomplete twelve-week observations, an older trial allocation error and exploratory testing—are not hidden or converted into an unstated primary-endpoint requirement. Functional benefit is inconsistent across measures and contexts, and a separate emerging longer-dose trial adds a null boundary. Evidence does not establish broad strength/exercise efficacy, isolated NAD necessity or human longevity. SC1/SC3 marker-to-clinical inference and SC4 molecule equivalence remain separately bounded. Sensitivities: weakest-link Α; primary-subclaim Δ; scope-matched Δ.

Decisive-perturbation inventory and causal tally

[1] Actual original PDF Methods/Results confirm age 65–75, twelve-week assigned NMN, null stepping/grip/SPPB scores and a baseline-adjusted positive secondary four-metre time. Multiple endpoint testing and selective four-week follow-up limit certainty; two placebo twelve-week observations were missing, and NAD correlation is not mediator necessity or lifespan.

[2] Actual Methods/Results confirm ≥65, twelve-week four-arm timing assignment, secondary physical outcomes and a nominal sit-to-stand interaction. Bonferroni posthoc reports improvement within every group rather than demonstrated NMN-placebo pair superiority; largest within-group effect is not treatment efficacy, and primary sleep interaction was null.

[3] Twenty-eight-day MIB-626 in 30 overweight adults raised NAD and improved selected weight/lipid/BP measures but not strength, fatigability, aerobic capacity or stair power. Under-eight-week mixed-age physiological trial is outside registered functional scope; markers and cardiometabolic changes cannot replace older-adult function.

[5] Fourteen older diabetic men with impaired baseline function had no between-group grip or walking benefit after 24 weeks of 250 mg NMN. Small sample limits precision; borderline exploratory frailty/retinal measures do not rescue primary nulls, and healthy versus diabetic baseline context remains distinct.

[6] NICE randomized 90 PAD adults and found a six-month NR six-minute-walk benefit, while resveratrol added no benefit. NR differs from NMN; one-sided 90% interval and adherence-selected analyses require clear labeling, and an indexed erratum remains linked without detailed correction audit.

[16] PERMET found no six-month metformin six-minute-walk or secondary functional advantage in 202 PAD adults without diabetes. Metformin and PAD are distinct from NMN; gastrointestinal events and follow-up attrition matter, and nulls do not negate metformin's established other indications.

[17] MET-PREVENT found no four-month metformin gait benefit in 72 frail/sarcopenic older adults, with poor tolerability and more admissions. Exact older frailty context is bounded; admissions are observed harms requiring attribution rather than proof of every metformin risk, and this is not NMN.

[26] MASTERS metformin blunted resistance-training muscle growth, with a nonsignificant trend in strength gains. Lean-mass/hypertrophy and strength are distinct; the adverse exercise interaction does not quantify NMN efficacy, and an erratum remains attached.

[35] Ten-week NMN in overweight prediabetic postmenopausal women improved clamp muscle-insulin sensitivity and selected remodeling signals. Clamp/metabolic physiology is not measured strength/gait/exercise capacity or human aging; population and mediators remain distinct.

[40] Six-week NMN plus training improved selected ventilatory-threshold measures in younger/middle-aged runners, while VO2max and peak power did not differ. Outside registered age/duration, training cointervention and outcome multiplicity; ventilatory threshold is not equivalent to peak aerobic capacity or slower aging.

[43] Actual Methods/Results report nominal gait/left-grip signals, NAD augmentation and no mass effect; a supplier switched supplements in 22 of 42 at week 6, leaving ten per arm at week 12. Randomized balance was disrupted; every analysis was exploratory without P correction, and six-week left-grip/mixed-duration results cannot alone satisfy the registered ≥eight-week gate.

[64] Metformin attenuated exercise VO2max/insulin-sensitivity and mitochondrial adaptations in older adults despite training benefits. Variable individual response is not a responder-defined efficacy scope; this exercise interaction does not negate established diabetic indications or determine NMN efficacy.

[66] DEMFOS found lifestyle-related performance benefit but no added six-month metformin effect over matched intensive lifestyle. The correct randomized additive-drug contrast is null; benefit versus weaker lifestyle cannot be attributed to metformin or equivalent NMN action.

Tally: 1 positive qualifying study unit across scoped subclaims (the twelve-week randomized gait-time contrast supporting SC2); 54 screened discriminating contrast units. These are not independent causal lines or proof of full-claim necessity/sufficiency. Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines. One positive qualifying source is counted for the tentative ≥eight-week primary gate; nominal six-week/pooled signals and marker trials are not added as strong independent crossings. NAD responder correlations, shared trials, other molecules and nonregistered age/duration do not add independent NMN functional causal units. Genuine other-molecule disease-specific positives and all measured nulls retain their scope without being loaned into NMN aging proof.

Outside the primary SC2 functional gate, no positive field-valid crossing was verified for the SC1 exposure-marker, SC3 longevity or SC4 equivalence scopes in this bounded audit. Pivotal null or negative tests remain informative; their implications depend on comparator quality, target engagement, power and the registered scope.

Cap audit, precedence and Β/Γ/Δ boundary

Universal marker cap 4 binds NAD/clock-to-physical or physical-to-longevity inference, not measured gait itself. Association cap 2 binds NAD-gait correlations and diabetic survival cohorts, not the randomized function contrast. Rubric06 clinical adaptation scores this non-lifespan physical claim on its declared phenotype. Full-body trial-conduct concerns lower confidence and constrain higher thresholds; they are not hidden changes to registration. No weakest clinical-null or biomarker leg is re-capped over an independently complementary same-scope set; no high-ladder convergent mediator set exists.

Universal six-cap audit: Six caps audited: cell senescence and one animal context cannot establish human function; prognostic/survival associations are not causal NMN proof; ectopic or pharmacological pathway manipulations do not establish endogenous mediator necessity; cap 4 binds marker/function/longevity inference steps, not directly measured gait; no endogenous propagation claim is supported by forced transfer; baseline eligibility remains before outcome. No cap is re-applied to erase a complementary exact phenotype set, and no outcome-defined responder rescue is admitted.

Gamma hard-rule audit: All ROS/NAD/mitochondrial/senescence-marker-only rules audited. They constrain SC1/SC3 and mechanistic classes, but do not erase an actually measured placebo-controlled gait phenotype. Single-species/strain rules bind animal-to-human extrapolation; clinical physical-treatment adaptation is explicit. No convergent human mechanism/trajectory set was built by borrowing another precursor or diabetes indication.

SC1 cap: “Biomarker change without functional/phenotypic change caps at Γ.” NMN reliably changes blood NAD-related exposure measures across several controlled formulations. These are genuine pharmacodynamic effects, not proof that muscle NAD was functionally limiting or that NAD itself is the necessary mediator. Different salvage routes and compartments prevent direct uptake and functional-aging inference; marker-only support retains Γ.

SC3 cap: “Biomarker change without functional/phenotypic change caps at Γ.” A true short-term gait effect does not itself establish slower biological aging, disease prevention or longer human lifespan. No qualifying NMN clinical aging-trajectory/survival set was examined. Animal physiology, NAD markers and algorithmic biological-age scores are separate outcomes and systems; cap 4 blocks their promotion to the broad longevity inference.

SC1 field-valid definition: “ - Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension - Must separate developmental effects from true aging effects - Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: no. NMN reliably changes blood NAD-related exposure measures across several controlled formulations. These are genuine pharmacodynamic effects, not proof that muscle NAD was functionally limiting or that NAD itself is the necessary mediator. Different salvage routes and compartments prevent direct uptake and functional-aging inference; marker-only support retains Γ.

SC2 field-valid definition: “ - Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension - Must separate developmental effects from true aging effects - Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: yes. A twelve-week placebo-controlled trial in baseline age 65–75 reports a baseline-adjusted secondary four-metre gait-time difference, and the smaller older-men trial has nominal gait signals with substantial allocation errors and uncorrected exploratory testing. Our registered gate permits gait outcomes and does not secretly require a study-primary endpoint. The direct functional contrast therefore supports a tentative first clinical crossing, Δ, with Low confidence. Stepping, grip, SPPB, chair-stand and older-diabetic primary nulls remain explicit. This is not established broad functional improvement or mechanistic proof; multiplicity and disrupted balance leave the tentative crossing vulnerable.

SC3 field-valid definition: “ - Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension - Must separate developmental effects from true aging effects - Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: no. A true short-term gait effect does not itself establish slower biological aging, disease prevention or longer human lifespan. No qualifying NMN clinical aging-trajectory/survival set was examined. Animal physiology, NAD markers and algorithmic biological-age scores are separate outcomes and systems; cap 4 blocks their promotion to the broad longevity inference.

SC4 field-valid definition: “ - Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension - Must separate developmental effects from true aging effects - Biomarker change alone does NOT satisfy this threshold” Positive full-scope result: no. NR and metformin are distinct exposures with different disease-specific successes and nulls, not clinically established equivalent healthy-aging interventions. NR has a genuine PAD walking trial positive, while metformin frailty, PAD and lifestyle-additive function trials have context-specific nulls and some exercise interactions. A knee-OA adjunct metformin positive is also retained. No direct equivalence or common healthy-aging efficacy experiment establishes the proposed equality; this unsupported generalization is Α rather than a declaration that either molecule is universally ineffective.

SC1 applied rubric adaptation (distinct from the unchanged literal criterion): Target-marker rise is real but remains physiological support rather than function or isolated mediator proof.

SC2 applied rubric adaptation (distinct from the unchanged literal criterion): Assess actual placebo-controlled function in the fixed ≥60, ≥eight-week gate; retain exact endpoint hierarchy and correct between-group contrasts, and avoid an added posthoc requirement that every endpoint be positive.

SC3 applied rubric adaptation (distinct from the unchanged literal criterion): Require separately measured human disease trajectory or survival rather than translate gait, NAD or trained-age scores into longevity.

SC4 applied rubric adaptation (distinct from the unchanged literal criterion): Require molecule-specific clinical comparisons or a valid equivalence design; class analogies and shared aging language do not establish equal effects.

SC1 literal Γ hard rule: “ROS change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “NAD level change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Mitochondrial metrics alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Senescence marker changes alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Single-species or single-strain evidence” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC1 literal Γ hard rule: “Biomarker-only improvement without organismal benefit” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “ROS change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “NAD level change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Mitochondrial metrics alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Senescence marker changes alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Single-species or single-strain evidence” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC2 literal Γ hard rule: “Biomarker-only improvement without organismal benefit” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “ROS change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “NAD level change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Mitochondrial metrics alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Senescence marker changes alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Single-species or single-strain evidence” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC3 literal Γ hard rule: “Biomarker-only improvement without organismal benefit” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “ROS change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “NAD level change measurements alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Mitochondrial metrics alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Senescence marker changes alone” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Single-species or single-strain evidence” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

SC4 literal Γ hard rule: “Biomarker-only improvement without organismal benefit” Not triggered literally for this assembled scoped case. Any adapted clinical, proxy or system-inference restriction is stated separately in the subclaim rationale.

Upward threshold ladder

SC1 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied: no. Demonstrate target-tissue NAD restoration and function with mechanism-specific perturbation/rescue, rather than peripheral exposure alone.

SC2 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied: yes.

SC2 Ε: “Requires causal effect in constrained contexts, backgrounds, or species.” Satisfied: no. Independently replicate a prespecified functional estimand in a sufficiently powered exact-formulation trial with familywise control, proper allocation, complete follow-up and meaningful effect sizes. Map baseline disease/function and dose without selecting outcomes afterward.

SC3 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied: no. Measure clinical disease-free/function trajectory or survival in long prospective human NMN work and isolate mediation, rather than infer longevity from a surrogate.

SC4 Δ: “Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.” Satisfied: no. Directly compare exact molecules or undertake separate adequately powered clinical trials with justified equivalence margins and matched population/outcomes.

Upper ladder: NMN/placebo assignment makes a clinical first crossing possible. Higher dose/exposure or blood-NAD gradients do not establish functional dose-response in the registered older population, and other molecules cannot substitute as independent same-node clinical evidence. Human genetics and lifelong natural experiments on the exact supplement/mediator were considered but no qualifying set was examined. Reliable prespecified replicated function, target-tissue mechanism and durable trajectory are needed for higher rungs.

Independence: No claim reaches Ζ. The nominal gait line remains vulnerable to multiplicity and small-study conduct; NMN posthoc response modeling shares its original parent. NR and metformin have different exposures and baseline diseases and do not make independent NMN aging lines. MASTERS/DPPOS secondary reports are one parent each.

Falsification and pitfalls

Marker engagement does not uniformly improve function. Multiple controlled NMN/NR studies have exposure positives and physical/cognitive nulls. The cap bounds marker inference without cancelling the separately measured gait contrast. Additional downgrade: False.

Dose/class generalization is not established. Exact disease/duration/molecule contrasts differ, with metformin nulls and NR-PAD positives. A class-wide or lifespan claim cannot borrow a narrow functional result. Additional downgrade: False.

Within-group change treated as randomized benefit. Kim all-arm sit-to-stand improvements and large NMN-PM Cohen d do not establish NMN-placebo superiority.

Biomarker confirmation. NAD, mitochondrial and trained-age readouts do not establish physical benefit or life extension.

Posthoc primary-endpoint gate. Our preregistered gate allows actual gait; absence of a trial-primary success is not automatic rejection of every controlled secondary signal.

Multiplicity and allocation ignored. Nominal P values, extensive exploratory testing and 22-person supplier error lower certainty.

Mechanism and molecule conflation. NR, NMN, mixtures and metformin are not interchangeable trials; target engagement is not necessary mediation.

Study reports counted as independent lines. MASTERS, DPPOS and NMN dose-trial posthoc papers retain parent IDs.

Adversarial steelman: above, then below

Ε could be defended from two older-adult gait signals and null strength/disease boundaries. Its strongest version needs reproducible clinically credible positive context attribution. Supplier errors, uncorrected testing, a secondary endpoint and incomplete observations leave the present causality/context map too fragile for established context-specific efficacy.

Γ could be defended by treating the evidence as NAD markers plus exploratory functional leads. The strongest concern is real multiplicity/conduct uncertainty. However, actual Morifuji M/R give a randomized baseline-adjusted gait outcome under the registered age/duration gate; requiring a study-primary endpoint would add a new rule after seeing results. Δ with Low confidence preserves that tentative measured functional crossing while making fragility explicit.

Tentatively retain Δ Low. Reject a confident Ε context claim because independent prespecified functional confirmation and clear context interactions are missing. Reject a blanket Γ marker-only account because one controlled actual gait phenotype meets our declared endpoint gate. A correction or failed credible replication could change the first-crossing assessment; source attribution and final clinical certainty remain distinct.

Final score, causal direction and M/S/D

Primary SC2 tentatively crosses Δ, with Low confidence, because the registered physical-function gate includes a genuine assigned secondary gait contrast. The quality concerns—multiple endpoints, incomplete twelve-week observations, an older trial allocation error and exploratory testing—are not hidden or converted into an unstated primary-endpoint requirement. Functional benefit is inconsistent across measures and contexts, and a separate emerging longer-dose trial adds a null boundary. Evidence does not establish broad strength/exercise efficacy, isolated NAD necessity or human longevity. SC1/SC3 marker-to-clinical inference and SC4 molecule equivalence remain separately bounded.

Assigned NMN precedes target-marker and tentative functional changes. Necessity, initiation and rate limitation for human age-related functional decline are unproven. Other interventions modify function and several exposures change markers without benefit, so the role describes a possible trajectory modifier rather than a primary aging driver.

Momentum: Mechanistic only. Recent clinical function trials and ongoing pharmacodynamic/pathway work are identified, but no reliably verified pending exact older-function result was established. UMIN000054187 targets the boundary yet has conflicting published/unpublished fields without an identified result; it is not asserted to be currently running. This coarse label records the limitation of the verified current-work inventory, not a denial of completed clinical causal research.

Stability: Stable. No reliable named pending result was verified: the checked function registry has contradictory publication fields and no result link. Future independent replication could strengthen or overturn the tentative crossing, but a proposed study or ambiguous record is not a verified pending trigger.

Divergence: Contested. The field framing is genuinely split and no single implied level applies: consumer and supplier framing of NMN implies a settled functional benefit well above the assessed level, while the clinical-trial literature itself presents a null-dominated picture at or below it. No single numerical belief gap is therefore inferred, and none is invented from supplement marketing or a provider strength label. These dimensions do not change level or confidence.

PROPOSED DECISIVE EXPERIMENTS

Randomize baseline-defined ≥60 adults to exact NMN formulation and matched placebo for 24 weeks, with gait/strength/capacity prespecified as primary or multiplicity-controlled co-primary, meaningful effect size and complete assignment-based analysis. Include prospectively defined healthy and impaired-function/diabetes strata with interaction testing, independent blinded assessors and proper allocation auditing. Measure muscle NAD and pathway controls separately, and extend functional/disease follow-up.

Readout: Prespecified meaningful gait, grip/knee strength and exercise capacity, adverse events and durability; blood/tissue NAD as mechanistic secondary and lifespan/disease trajectory separate. Controls: Matched formulations, independent blinded function assessment and allocation audit, practice-effect/run-in measurement, full-population estimands, missing-data sensitivity, prospective multiplicity and baseline-stratum interaction. Supporting: A clear replicated functional treatment contrast with adequate precision would strengthen the tentative crossing and map context; mediation needs independently targeted pathway evidence. Falsifying: Exposure increase without multiplicity-controlled function leaves benefit unconfirmed in that context; no posthoc NAD-responder or favorable-test exclusion can rescue the assigned result.

KNOWLEDGE GAPS

Adequate prespecified objective-function replication and clinically interpretable effect size.

Independent verification of exact formulations, target-tissue NAD and necessary functional mediator.

Prospective baseline disease/function/sex and dose interactions rather than cross-trial subgroup narratives.

Complete missing-data, allocation-error and multiplicity audits across older trials.

Longer clinical functional trajectory, disease incidence and survival rather than biological-age algorithms.

Long-term safety and drug/exercise interactions with molecule-specific attribution.

REVIEWER NOTES

70 relevant original-report cards have actual abstract/status reading receipts. Two papers have selected original XML Methods/Results receipts, and Morifuji has an additional honest selected original-PDF web presentation receipt; local PDF download failed and is not claimed. No complete-paper/supplement audit or independent blinded review. The records include exact NMN clinical trials plus separate NR, metformin, mechanism and boundary originals, not 70 older-function NMN trials. One additional DOI-only accepted 2026 primary was actually examined at its publisher and displayed separately from 70 PMID-based originals; exact DOI indexing check returned 0. Twelve observed Consensus original-paper aspect comparisons plus that independently checked publisher lead were reconciled. Registry fields and conflicts are retained without inferred results or verified pending status.

Search leads, reviews, protocols and correction notices do not pad the primary count. Downloaded XML does not earn examination credit. Linked notices remain attached; unexamined correction details limit inference. This is a coordinator source/claim consistency assessment, not independent blinded calibration.

Consensus and original-source reconciliation

Observed Consensus appropriately notes the weak between-group interpretation. Actual original M/R identify physical outcomes as secondary, a nominal sit-to-stand interaction, Bonferroni posthoc within-arm improvement in every group, and largest pre/post Cohen d for NMN-afternoon. A largest within-arm effect is not a demonstrated NMN-placebo treatment difference; sleep primary interaction is also null. Original PMID35215405.

Original Methods actually require ≥65 independently mobile adults without long-term care; three dropouts are carried forward from baseline in ITT. This supports registered age/duration eligibility but does not establish no attrition bias or all older disease populations. Provider subgroup/general-function wording remains bounded to this experiment. Original PMID35215405.

Provider describes twenty completed with a post-week-six deviation. Original M/R identify 42 randomized and a supplier cross-switch in eleven participants per arm, excluding their week-twelve data and leaving 10 per arm. This is not ordinary 20 of 42 follow-up completion; compromised assigned exposure and baseline balance must be explicit. Original PMID35927255.

Original Methods make NAD/body composition primary and function secondary, and explicitly apply no multiple-comparison correction. Gait and left-grip mixed-model signals are exploratory; six-week left-grip/chair-stand findings cannot alone satisfy ≥eight-week registration. Twelve-week gait remains a tentative signal with the small valid sample, rather than certain replicated strength benefit. Original PMID35927255.

Provider accurately separates the null primary and gait secondary. DOI-matched original PDF M/R actually confirm ages 65–75 and baseline-adjusted ANCOVA; stepping, grip and total SPPB scores are null, while four-metre time is positive. The registered review allows gait, so secondary status constrains certainty rather than silently adding a primary-only gate. Original PMID38789831.

Original Results designate all 60 as efficacy set but report unavailable measurements, including two placebo participants at week 12. Original statistics analyze baseline-adjusted timepoints and only twelve-week-positive variables at four weeks; no familywise correction is stated in the examined passage. Provider robust-benefit caution is appropriate, but no unexamined complete-data or correction analysis is claimed. Original PMID38789831.

Provider correctly describes the 24-week 250 mg older-diabetes impaired-function trial. Examined original abstract retains primary grip/walk nulls, fourteen participants and borderline exploratory observations. Small power limits precise exclusion, but frailty/retinal trends cannot be promoted into a positive primary or erase healthy-context signals. No body access is claimed. Original PMID36443648.

Provider correctly distinguishes prediabetic insulin-sensitivity physiology from older physical efficacy. Original abstract reports clamp/signaling/remodeling benefits, rather than a strength/gait/capacity result. Any additional claim of measured grip/fatigability nulls needs the corresponding original passages; absence from our examined abstract is not a measured null. Original PMID33888596.

Original younger/middle-aged six-week runner abstract supports selected ventilatory-threshold improvements while VO2max, O2-pulse and peak power do not differ. Provider aerobic-capacity wording must preserve exact readouts, training and out-of-scope duration/age rather than treating every fitness endpoint as positive. Original PMID34238308.

Provider warns correctly against merging NMN and NR, but its adjacent summary broadly emphasizes NR functional nulls. The actual NICE original abstract reports a six-month NR-PAD walking benefit, with a one-sided 90% interval and distinct adherent-subgroup analysis. This specific positive is retained, with its indexed erratum attached and no transfer to NMN or human longevity. Original PMID38871717.

Provider correctly cites metformin older-function nulls. Actual DEMFOS abstract shows intensive-lifestyle-plus-metformin superiority over less intensive lifestyle, but no advantage over matched intensive-lifestyle-plus-placebo. The useful lifestyle effect cannot be assigned to metformin. Original PMID42532077.

Provider retains the frail-older metformin null and poor tolerability. Original abstract gives a near-zero gait contrast, more observed admissions and an unrelated adjudicated death. These disease-specific findings are relevant harms/function boundaries, not proof of harm or inefficacy for every diabetic use or NMN. Original PMID40147475.

Consensus was used to identify literature and cross-check specific claims about design, endpoints, scope and research gaps. Those aspects were checked against original primary abstracts/status records and selected original Methods/Results passages. Consensus output was not treated as original full text. Provider search omissions are not evidence that a study does not exist. Source access and examination receipts are retained. Scite use or monthly unavailability is recorded per case; provider citation counts do not change causal grades.

Research timeline and gaps: NAD Boosters and Human Function

Selected publication milestones, not an exhaustive history or discovery priority claim.

2014 — Older diabetic observational survival associations vary with frailty and active-drug comparator. Original PMID25506599.

2016 — NR human pharmacokinetics establish exposure rather than older clinical benefit. Original PMID27721479.

2018 — Short NR crossover demonstrates circulating NAD augmentation and bounded vascular leads. Original PMID29599478.

2018 — Metformin older-tissue pathways supply physiological rather than lifespan evidence. Original PMID29383869.

2019 — Metformin/exercise interaction shows blunted fitness/metabolic adaptation in older adults. Original PMID30548390.

2019 — MASTERS separates blunted muscle growth from a nonsignificant strength trend. Original PMID31557380.

2019 — Aged human muscle metabolome responds to NR without changed bioenergetics. Original PMID31412242.

2020 — Single-dose NMN feasibility precedes chronic physical-outcome testing. Original PMID31685720.

2021 — Prediabetic-women NMN clamp physiology establishes its own endpoint and population. Original PMID33888596.

2021 — Young/middle-aged runner threshold effects coexist with peak-capacity nulls. Original PMID34238308.

2022 — Twelve-week older timing trial yields interactions and within-arm improvements, not clear pairwise efficacy. Original PMID35215405.

2022 — Older-men gait leads require supplier-switch, sample and multiplicity interpretation. Original PMID35927255.

2022 — NR/pterostilbene induced-muscle-injury trial gives a direct recovery null. Original PMID35998039.

2023 — Middle-aged NMN walking/exposure dose results remain separate from ≥60 efficacy. Original PMID36482258.

2023 — Older-diabetic impaired-function NMN primary tests are null at 24 weeks. Original PMID36443648.

2023 — MIB-626 changes NAD and selected cardiometabolic measures with physical-performance nulls. Original PMID36740954.

2023 — Mouse isotope tracing challenges assumptions of widespread intact NMN uptake. Original PMID37446292.

2024 — A real secondary gait-time signal occurs alongside stepping, grip and SPPB nulls in older adults. Original PMID38789831.

2024 — NR-PAD supplies a genuine different-molecule walking positive with specific statistical limits. Original PMID38871717.

2024 — Metformin knee-OA adjunct trial retains a distinct pain/function positive. Original PMID38869746.

2025 — MET-PREVENT tests frail-older function directly and finds no gait benefit with tolerability concerns. Original PMID40147475.

2026 — Newer NR-MCI primary cognition remains null despite NAD rise. Original PMID42478598.

2026 — PERMET establishes a direct metformin-PAD walking null. Original PMID41205146.

2026 — DEMFOS distinguishes lifestyle efficacy from absent added metformin function. Original PMID42532077.

2026 — METFORAGING provides a longer biomarker primary null rather than human longevity evidence. Original PMID42023167.

Research gaps

Adequate prespecified objective-function replication and clinically interpretable effect size.

Independent verification of exact formulations, target-tissue NAD and necessary functional mediator.

Prospective baseline disease/function/sex and dose interactions rather than cross-trial subgroup narratives.

Complete missing-data, allocation-error and multiplicity audits across older trials.

Longer clinical functional trajectory, disease incidence and survival rather than biological-age algorithms.

Long-term safety and drug/exercise interactions with molecule-specific attribution.

Boundary experiment

Randomize baseline-defined ≥60 adults to exact NMN formulation and matched placebo for 24 weeks, with gait/strength/capacity prespecified as primary or multiplicity-controlled co-primary, meaningful effect size and complete assignment-based analysis. Include prospectively defined healthy and impaired-function/diabetes strata with interaction testing, independent blinded assessors and proper allocation auditing. Measure muscle NAD and pathway controls separately, and extend functional/disease follow-up.

ADVERSARIAL REVIEW AND APPROVAL

Authoring model: Sol 6.1. Adversarial reviewer: Claude Opus 5.5 (Anthropic). Date: 2026-10-14.

Scope of checks. All 70 REFERENCES PMIDs verified against PubMed metadata for title, first author, journal and year (70/70 resolve to the stated record; 0 wrong identifiers), plus the two linked correction notices (PMID 39134546, Publisher Correction to the NICE trial; PMID 32141718, Aging Cell corrigendum attached to MASTERS) — both correctly recorded as parent-row status flags rather than as separate sources. No retraction or expression of concern was found on any cited record. Fourteen load-bearing claims were spot-checked against the original abstracts: Morifuji (38789831) n=60, 250 mg/day, 12 weeks, null stepping primary with a significant secondary 4-m walking-time difference; Igarashi (35927255) 250 mg/day for 6 or 12 weeks in older men, nominal gait-speed and left-grip improvements, no body-composition effect; Kim (35215405) 108 participants in four timing arms with 5-STS improvement in all groups and the largest effect size in the NMN afternoon arm; Akasaka (36443648) 14 older diabetic men, 24 weeks, 250 mg, primary grip and walking-speed nulls with borderline frailty (P=0.066) and central retinal thickness (P=0.051); Pencina (36740954) 28-day MIB-626 in 30 overweight adults with NAD rise and no strength, fatigability, aerobic-capacity or stair-power difference; Pencina (35182418) 14-day MIB-626 in 32 adults aged 55–80; McDermott NICE (38871717) 90 PAD adults, +17.6 m between-group 6-min walk with a one-sided 90% interval and no added resveratrol benefit; Witham MET-PREVENT (40147475) 72 adults, 4 months, adjusted 4-m walk-speed effect 0.001 m/s and 12/35 versus 3/36 hospital admissions; Nava DEMFOS (42532077) intensive lifestyle plus metformin superior to healthy lifestyle plus metformin (2.5 points) but not to intensive lifestyle plus placebo (0.1 points); Marcelo-Calvo METFORAGING (42023167) 96-week PhenoAge epigenetic-age primary null; Walton MASTERS (31557380) blunted hypertrophy with a non-significant strength trend; Liao (34238308) ventilatory-threshold gains in 48 young and middle-aged runners with no VO2max, O2-pulse or peak-power difference; Yoshino (33888596) muscle insulin sensitivity in prediabetic women; Hazuda (33428709) DPPOS frailty null for metformin. All fourteen were accurately attributed, including direction of effect, species, design and sample size. Scoring logic was re-derived against the framework and skill text: caps 2 and 4 are applied to the marker and association legs and not to the directly measured gait phenotype; the pre-registered aggregation rule (primary-subclaim, SC2) is applied as written and the two alternatives are reported (weakest-link Α, scope-matched Δ); the Δ descriptor is the canonical one.

Findings

Rejected findings (checked, no change)

1. Citation years differing by one from PubMed e-pub dates — references 5 (36443648), 8 (37994989), 23 (28681986), 34 (36482258), 45 (36515353), 47 (37899683), 63 (39363095) and 64 (30548390). Print/issue year versus e-pub year within one year is the house convention; all eight resolve to the stated article.
2. PubMed titles dropping superscripts and italics (NAD+ rendered as NAD, β-NMN, H2O2, RYR1) — a PubMed field artifact, not a citation error.
3. The DOI-only Igarashi 2026 npj Aging source. The review asserts that an exact DOI query returns no PubMed record and that the source is counted outside the 70 PMID-based originals. A PubMed search on 2026-10-14 still returns nothing for that title, so the handling — a separately displayed, non-counted record with no invented PMID — is correct and was retained.
4. Momentum "Mechanistic only". The required artifact is present and names the work it rests on (UMIN000054187 and ongoing pharmacodynamic/pathway trials), and the label does not claim decisive work underway. No change.
5. Δ for SC2 on a secondary endpoint. Argued against: a null trial primary is a strong reason to doubt, and the Igarashi conduct problems are real. But the rubric as adapted here registers measured gait as the phenotype, the Morifuji contrast is randomized, placebo-controlled and baseline-adjusted, and requiring a trial-primary endpoint would add a rule after seeing the result. Δ with Low confidence, with multiplicity and allocation damage stated, is what the framework text supports; Ε is correctly refused for want of prespecified independent confirmation.
6. Aggregation rule. Primary-subclaim was pre-registered with SC2 named and is applied as written; scope-matched would also return Δ because SC2's scope is the central claim's scope. No scope-matched misreading.

Residual limitations

Confidence remains Low and the grade is fragile: the crossing rests on one secondary endpoint in one trial, with no familywise correction stated, two missing placebo week-12 observations, and a second supporting trial whose allocation was disrupted by a supplier cross-switch. Only three sources were examined beyond abstract depth, so no complete-paper or supplement audit supports the numeric claims drawn from the other sixty-seven records. The Igarashi 2026 higher-dose null is read from a publisher abstract only.

Approval: Following adversarial review and the corrections listed above, the revised document is approved. — Claude Opus 5.5 (Anthropic), 2026-10-14.

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43. Igarashi M, Nakagawa-Nagahama Y, Miura M et al. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. npj aging. 2022. PMID 35927255. DOI: 10.1038/s41514-022-00084-z. Access: full_text_partial. Study: NMN-UMIN000036321.

44. Wang H, Sun Y, Pi C et al. Nicotinamide Mononucleotide Supplementation Improves Mitochondrial Dysfunction and Rescues Cellular Senescence by NAD+/Sirt3 Pathway in Mesenchymal Stem Cells. International journal of molecular sciences. 2022. PMID 36499074. DOI: 10.3390/ijms232314739. Access: abstract_metadata. Study: PMID36499074.

45. 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. PMID 36515353. DOI: 10.1111/acel.13754. Access: abstract_metadata. Study: NR-NCT02921659.

46. Okabe K, Yaku K, Uchida Y et al. Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects. Frontiers in nutrition. 2022. PMID 35479740. DOI: 10.3389/fnut.2022.868640. Access: abstract_metadata. Study: PMID35479740.

47. 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. PMID 37899683. DOI: 10.1002/mds.29645. Access: abstract_metadata. Study: PMID37899683.

48. 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. PMID 36797393. DOI: 10.1038/s41598-023-29787-3. Access: abstract_metadata. Study: PMID36797393.

49. 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. PMID 31685720. DOI: 10.1507/endocrj.EJ19-0313. Access: abstract_metadata. Study: PMID31685720.

50. Lapatto HAK, Kuusela M, Heikkinen A et al. Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study. Science advances. 2023. PMID 36638183. DOI: 10.1126/sciadv.add5163. Access: abstract_metadata. Study: PMID36638183.

51. 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. PMID 38016950. DOI: 10.1038/s41467-023-43514-6. Access: abstract_metadata. Study: PMID38016950.

52. 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. PMID 37159264. DOI: 10.1172/jci.insight.167274. Access: abstract_metadata. Study: PMID37159264.

53. Yulug B, Altay O, Li X et al. Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: a randomised, double-blinded, placebo-controlled phase-II trial. Translational neurodegeneration. 2023. PMID 36703196. DOI: 10.1186/s40035-023-00336-2. Access: abstract_metadata. Study: PMID36703196.

54. Nascimento EBM, Moonen MPB, Remie CME et al. Nicotinamide Riboside Enhances In Vitro Beta-adrenergic Brown Adipose Tissue Activity in Humans. The Journal of clinical endocrinology and metabolism. 2021. PMID 33524145. DOI: 10.1210/clinem/dgaa960. Access: abstract_metadata. Study: NR-NCT02835664.

55. Yin X, Abudupataer M, Ming Y et al. Nicotinamide Mononucleotide Alleviates Angiotensin II-Induced Human Aortic Smooth Muscle Cell Senescence in a Microphysiological Model. Journal of cardiovascular pharmacology. 2023. PMID 36652727. DOI: 10.1097/FJC.0000000000001400. Access: abstract_metadata. Study: PMID36652727.

56. 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. PMID 36002548. DOI: 10.1038/s41598-022-18272-y. Access: abstract_metadata. Study: PMID36002548.

57. Kuerec AH, Wang W, Yi L et al. Towards personalized nicotinamide mononucleotide (NMN) supplementation: Nicotinamide adenine dinucleotide (NAD) concentration. Mechanisms of ageing and development. 2024. PMID 38430946. DOI: 10.1016/j.mad.2024.111917. Access: abstract_metadata. Study: NMN-NCT04823260.

58. Han K, Klein RJ, Recupero TC et al. NAD+ augmentation by nicotinamide riboside engages SLIT2/ROBO1 signaling to attenuate Th17 inflammation in psoriasis. JCI insight. 2026. PMID 42048163. DOI: 10.1172/jci.insight.203826. Access: abstract_metadata. Study: PMID42048163.

59. 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. PMID 35998039. DOI: 10.1172/jci.insight.158314. Access: abstract_metadata. Study: PMID35998039.

60. Sauve AA, Wang Q, Zhang N et al. Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD+ Biosynthesis in Whole Mice. International journal of molecular sciences. 2023. PMID 37446292. DOI: 10.3390/ijms241311114. Access: abstract_metadata. Study: PMID37446292.

61. Rosell-Díaz M, Petit-Gay A, Molas-Prat C et al. Metformin-induced changes in the gut microbiome and plasma metabolome are associated with cognition in men. Metabolism: clinical and experimental. 2024. PMID 38871078. DOI: 10.1016/j.metabol.2024.155941. Access: abstract_metadata. Study: PMID38871078.

62. Aiad AAE, El-Haggar SM, El-Barbary AM et al. Metformin as adjuvant therapy in obese knee osteoarthritis patients. Inflammopharmacology. 2024. PMID 38869746. DOI: 10.1007/s10787-024-01495-y. Access: abstract_metadata. Study: PMID38869746.

63. Vinicki M, Pribić T, Vučković F et al. Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome. GeroScience. 2025. PMID 39363095. DOI: 10.1007/s11357-024-01349-z. Access: abstract_metadata. Study: PMID39363095.

64. Konopka AR, Laurin JL, Schoenberg HM et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging cell. 2019. PMID 30548390. DOI: 10.1111/acel.12880. Access: abstract_metadata. Study: PMID30548390.

65. Kulkarni AS, Brutsaert EF, Anghel V et al. Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults. Aging cell. 2018. PMID 29383869. DOI: 10.1111/acel.12723. Access: abstract_metadata. Study: PMID29383869.

66. Nava MLD, Viola V, Aguilar M et al. Metformin added to lifestyle intervention for physical function in older adults with obesity (DEMFOS trial): a randomised controlled trial. The lancet. Healthy longevity. 2026. PMID 42532077. DOI: 10.1016/j.lanhl.2026.100883. Access: abstract_metadata. Study: PMID42532077.

67. Long DE, Kosmac K, Dungan CM et al. Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals. Frontiers in physiology. 2022. PMID 35492586. DOI: 10.3389/fphys.2022.872745. Access: abstract_metadata. Study: MASTERS-NCT02308228.

68. Hazuda HP, Pan Q, Florez H et al. Association of Intensive Lifestyle and Metformin Interventions With Frailty in the Diabetes Prevention Program Outcomes Study. The journals of gerontology. Series A, Biological sciences and medical sciences. 2021. PMID 33428709. DOI: 10.1093/gerona/glaa295. Access: abstract_metadata. Study: DPP-DPPOS.

69. Marcelo-Calvo C, Esteban-Cantos A, Jurado F et al. Metformin and epigenetic age in non-diabetic older people with HIV in Madrid (METFORAGING): a double-blind, randomised, placebo-controlled, pilot trial. EClinicalMedicine. 2026. PMID 42023167. DOI: 10.1016/j.eclinm.2026.103874. Access: abstract_metadata. Study: PMID42023167.

70. Kulkarni AS, Peck BD, Walton RG et al. Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults. Aging. 2020. PMID 33071237. DOI: 10.18632/aging.104096. Access: abstract_metadata. Study: MASTERS-NCT02308228.

Source-specific evidence cards

[1] 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.

Shows: Actual original PDF Methods/Results confirm age 65–75, twelve-week assigned NMN, null stepping/grip/SPPB scores and a baseline-adjusted positive secondary four-metre time.

Does not show: Multiple endpoint testing and selective four-week follow-up limit certainty; two placebo twelve-week observations were missing, and NAD correlation is not mediator necessity or lifespan.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: Original PDF Methods page 3/table 1; web lines136-174, Original PDF Methods/Results pages 6-7; web lines403-445, Original PDF Results figure 2 page 11; web lines670-674. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[2] 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.

Shows: Actual Methods/Results confirm ≥65, twelve-week four-arm timing assignment, secondary physical outcomes and a nominal sit-to-stand interaction.

Does not show: Bonferroni posthoc reports improvement within every group rather than demonstrated NMN-placebo pair superiority; largest within-group effect is not treatment efficacy, and primary sleep interaction was null.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:2. Materials and Methods:paragraph0, 1:2. Materials and Methods:paragraph1, 1:2. Materials and Methods:paragraph2, 1:2. Materials and Methods:paragraph3, 1:2. Materials and Methods:paragraph7, 1:2. Materials and Methods:paragraph8, 2:3. Results:paragraph0, 2:3. Results:paragraph1, 2:3. Results:paragraph2, 2:3. Results:paragraph3. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[3] Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study.

Shows: Twenty-eight-day MIB-626 in 30 overweight adults raised NAD and improved selected weight/lipid/BP measures but not strength, fatigability, aerobic capacity or stair power.

Does not show: Under-eight-week mixed-age physiological trial is outside registered functional scope; markers and cardiometabolic changes cannot replace older-adult function.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[4] MIB-626, an Oral Formulation of a Microcrystalline Unique Polymorph of β-Nicotinamide Mononucleotide, Increases Circulating Nicotinamide Adenine Dinucleotide and its Metabolome in Middle-Aged and Older Adults.

Shows: Fourteen-day microcrystalline NMN dose assignment increased blood NMN/NAD and metabolome measures in 32 adults aged 55–80.

Does not show: Pharmacodynamic exposure and short observed tolerability do not establish older-adult eight-week function, formulation interchangeability or lifespan.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[5] Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study.

Shows: Fourteen older diabetic men with impaired baseline function had no between-group grip or walking benefit after 24 weeks of 250 mg NMN.

Does not show: Small sample limits precision; borderline exploratory frailty/retinal measures do not rescue primary nulls, and healthy versus diabetic baseline context remains distinct.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[6] Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial.

Shows: NICE randomized 90 PAD adults and found a six-month NR six-minute-walk benefit, while resveratrol added no benefit.

Does not show: NR differs from NMN; one-sided 90% interval and adherence-selected analyses require clear labeling, and an indexed erratum remains linked without detailed correction audit.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. Erratum in: PMID 39134546. Subclaims: SC1, SC2, SC3, SC4.

[7] Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults.

Shows: Six-week NR crossover in middle-aged/older adults increased NAD metabolism and reported selected vascular physiology leads.

Does not show: Different molecule, mixed age and short follow-up do not establish registered NMN physical function or human aging/lifespan.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC4.

[8] A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment.

Shows: Ten-week NR in 20 MCI adults increased NAD and selected clocks while cognition remained stable.

Does not show: Uncorrected CBF signals and exploratory clock movement do not establish function or slower aging; drug and disease differ from NMN scope.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[9] 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.

Shows: Eight-week NR dose assignment increased blood NAD with no observed dose-related adverse-event differences.

Does not show: Tolerability and pharmacodynamics are not equivalence to NMN, physical benefit or lifetime healthy-aging safety.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[10] Nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans.

Shows: NR crossover changed selected muscle metabolites/body composition but not insulin sensitivity, mitochondrial function or most metabolic endpoints.

Does not show: Minor fat-free-mass change is not measured strength; six-week obese mixed-age NR exposure cannot replace older NMN function.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC4.

[11] Nicotinamide riboside combined with exercise to treat hypertension in middle-aged and older adults: a pilot randomized clinical trial.

Shows: NR plus exercise did not improve daytime BP more than placebo plus exercise despite higher NAD catabolites.

Does not show: Short hypertensive trial and posthoc medication-free nighttime trends are distinct from verified physical function or a confirmed baseline subgroup.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC4.

[12] A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment.

Shows: A 12-week NR MCI pilot doubled NAD without improved cognitive primary, total CBF or BP.

Does not show: Exploratory regional-CBF hypotheses do not overturn the primary null or establish NMN function and human longevity.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[13] Nicotinamide riboside with pterostilbene (NRPT) increases NAD+ in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI.

Shows: Two-day NR/pterostilbene escalation in hospitalized AKI patients increased selected NAD measures with variable response and short safety observations.

Does not show: Combination exposure, acute disease and biomarker endpoint do not establish older-adult function, recovery efficacy or healthy-aging equivalence.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[14] Energy-replenishing, mitochondria-targeted hydrogel microspheres mitigate sarcopenia via cellular senescence amelioration.

Shows: Local mitochondria-targeted NMN hydrogel reduced dexamethasone muscle-cell senescence/mitochondrial abnormalities in preclinical experiments.

Does not show: Delivery includes SS-31/liposome/scaffold coeffects and induced disease; markers and local injections cannot establish oral human functional efficacy or lifespan.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[15] Long-Term Administration of Nicotinamide Mononucleotide Mitigates High-Fat-Diet-Induced Physiological Decline in Aging Mice.

Shows: Seven-month NMN in aging high-fat-diet mice improved selected grip/locomotor and metabolic/organ measures.

Does not show: High dose, diet, species and autophagy correlations differ from human trials; physiological benefit is not examined human or necessarily mouse lifespan extension.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[16] Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease: The PERMET Randomized Clinical Trial.

Shows: PERMET found no six-month metformin six-minute-walk or secondary functional advantage in 202 PAD adults without diabetes.

Does not show: Metformin and PAD are distinct from NMN; gastrointestinal events and follow-up attrition matter, and nulls do not negate metformin's established other indications.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[17] Metformin and physical performance in older people with probable sarcopenia and physical prefrailty or frailty in England (MET-PREVENT): a double-blind, randomised, placebo-controlled trial.

Shows: MET-PREVENT found no four-month metformin gait benefit in 72 frail/sarcopenic older adults, with poor tolerability and more admissions.

Does not show: Exact older frailty context is bounded; admissions are observed harms requiring attribution rather than proof of every metformin risk, and this is not NMN.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[18] Long-term impact of Diabetes Prevention Program interventions on walking endurance.

Shows: Long-term DPPOS original-group analysis found no sustained walking-endurance differences about 20 years after randomization.

Does not show: Later shared interventions and survival/completer selection differ from maintained blinded treatment; one DPP parent is not new clinical longevity proof.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[19] Association Between Metformin Use and Cognitive and Physical Function in Persons with HIV and Diabetes.

Shows: Small older HIV/diabetes cohort found no metformin association with measured cognition, frailty or physical function.

Does not show: Observational prescribing, restricted disease and low precision do not establish causal absence or equivalence to NMN.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC4.

[20] An epigenetic aging analysis of randomized metformin and weight loss interventions in overweight postmenopausal breast cancer survivors.

Shows: Posthoc metformin/weight-loss factorial trial in breast-cancer survivors found no significant epigenetic-age assignment effects at six months.

Does not show: Clock null does not by itself establish absent clinical benefit; disease and exposure differ from NMN and human life extension remains unmeasured.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[21] Lung function after randomization to metformin, lifestyle intervention or placebo in the Diabetes Prevention Program Outcomes Study (DPPOS).

Shows: DPPOS long-term original assignments were not associated with spirometry or respiratory-symptom differences.

Does not show: Shared DPP cohort with later open-label/cointervention exposure is not independent continuous-dose or NMN evidence.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[22] Short-term exposure to a clinical dose of metformin increases skeletal muscle mitochondrial H2O2 emission and production in healthy, older adults: A randomized controlled trial.

Shows: Two-week metformin in 16 older adults increased muscle H2O2 measures without altering maximal mitochondrial respiration.

Does not show: ROS/biopsy markers and short exposure are not organismal aging or physical benefit; correlations do not establish free-radical causal primacy.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[23] Metformin-associated prevention of weight gain in insulin-treated type 2 diabetic patients cannot be explained by decreased energy intake: A post hoc analysis of a randomized placebo-controlled 4.3-year trial.

Shows: HOME posthoc analysis found less weight gain with metformin but no reported dietary-energy explanation over 4.3 years.

Does not show: Selected completed diet histories and self-reported intake cannot prove mediator absence; diabetic weight effect is not NMN function or nondiabetic longevity.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[24] Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment.

Shows: Metformin pretreatment during brief bedrest altered older-adult muscle atrophy/fibrosis and senescence measures in recovery.

Does not show: Short induced disuse and histology markers do not establish long-term gait, general healthy aging or NMN efficacy; candidate SASP mediation is not isolated.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3, SC4.

[25] METFORMIN-SUSTAINED WEIGHT LOSS AND REDUCED ANDROID FAT TISSUE AT 12 MONTHS IN EMPOWIR (ENHANCE THE METABOLIC PROFILE OF WOMEN WITH INSULIN RESISTANCE): A DOUBLE BLIND, PLACEBO-CONTROLLED, RANDOMIZED TRIAL OF NORMOGLYCEMIC WOMEN WITH MIDLIFE WEIGHT GAIN.

Shows: EMPOWIR diet plus metformin improved selected weight/fat measures in midlife hyperinsulinemic women with completed follow-up.

Does not show: Mixed treatment/rerandomization and body composition are not older physical function or life extension; marker and outcome-specific positives remain bounded.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[26] Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double-blind, placebo-controlled, multicenter trial: The MASTERS trial.

Shows: MASTERS metformin blunted resistance-training muscle growth, with a nonsignificant trend in strength gains.

Does not show: Lean-mass/hypertrophy and strength are distinct; the adverse exercise interaction does not quantify NMN efficacy, and an erratum remains attached.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. Erratum in: PMID 32141718. Subclaims: SC2, SC3, SC4.

[27] Metformin and the Development of Age-Related Macular Degeneration.

Shows: Large matched metformin AMD cohorts found comparable development/progression under their clinical-significance criterion.

Does not show: Some confidence intervals exclude unity despite authors' equivalence-style criterion; do not conflate statistical and meaningful significance or infer NMN equivalence.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[28] Metformin Does Not Significantly Alter Longitudinal Dynamics of Clonal Hematopoiesis.

Shows: Longitudinal diabetic metformin cohorts showed no significant individual-cohort clonal-growth effect but a small pooled association.

Does not show: Small molecular clone-rate association is not clinically established protection or NMN longevity; two cohorts remain components of one reported analysis.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[29] Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study.

Shows: Danish singleton/twin analyses did not reproduce superior survival of metformin-treated diabetes relative to nondiabetic controls.

Does not show: Diabetes status and prescribing confounding prevent inference that metformin causes excess mortality; comparator choice does not establish healthy-person longevity efficacy.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[30] Association of Geroprotective Effects of Metformin and Risk of Open-Angle Glaucoma in Persons With Diabetes Mellitus.

Shows: Diabetic metformin exposure was associated with lower open-angle-glaucoma incidence in a retrospective cohort.

Does not show: Exposure-dose association and model projections are not randomized prevention, human lifespan or equivalence to NAD precursors.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[31] Differential effects of metformin on age related comorbidities in older men with type 2 diabetes.

Shows: Older diabetic-veteran metformin use associated with selected lower age-related comorbidity patterns.

Does not show: Latent classes partly defined by outcomes and residual prescribing confounding cannot establish causal baseline subtypes or nondiabetic geroprotection.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[32] Associations of muscle lipid content with physical function and resistance training outcomes in older adults: altered responses with metformin.

Shows: MASTERS secondary analysis linked muscle density with performance and selected metformin exercise-response patterns.

Does not show: Shared parent and baseline/subgroup associations are not independent causal lines or proof that mass or lipid density is the necessary mediator.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[33] Frailty Attenuates the Impact of Metformin on Reducing Mortality in Older Adults with Type 2 Diabetes.

Shows: Older diabetic veterans had a metformin-versus-sulfonylurea survival association differing by frailty context.

Does not show: Active-drug selection and diabetes indication do not establish healthy-person life extension or NMN equivalence; frailty association is not randomized prevention.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3, SC4.

[34] 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.

Shows: An 80-person 60-day NMN dose trial increased NAD and six-minute-walk response in adults aged 40–65, with no HOMA-IR difference.

Does not show: Mixed middle age is outside the full registered at-least-60 population; algorithmic biological-age score and PP analysis do not establish lifespan or isolated NAD mediation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[35] Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women.

Shows: Ten-week NMN in overweight prediabetic postmenopausal women improved clamp muscle-insulin sensitivity and selected remodeling signals.

Does not show: Clamp/metabolic physiology is not measured strength/gait/exercise capacity or human aging; population and mediators remain distinct.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[36] The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.

Shows: NADPARK NR increased variable brain NAD and molecular measures, with clinical changes among NAD responders.

Does not show: Responder-defined clinical association, one-month disease exposure and another precursor do not establish the NMN older-function gate or confirmed neuroprotection.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[37] Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.

Shows: Early human NR dosing and mouse studies demonstrated NAD-related pharmacokinetics and sensitive NAAD readouts.

Does not show: Single-person lead and short pharmacodynamics are not function/healthspan or proof that intact NR and NMN share identical tissue routes.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[38] NAD+ dyshomeostasis in RYR1-related myopathies.

Shows: RYR1-myopathy patients had heterogeneous blood NAD dysregulation, and patient-cell NR changed selected energetic measures.

Does not show: Disease deficiency and cultured myotube responses are not clinical treatment or age-related oral NMN benefit; mouse redox findings did not reproduce all human patterns.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC4.

[39] The acute effect of different NAD+ precursors included in the combined metabolic activators.

Shows: One-day combined-activator precursor comparisons changed metabolomic NAD products with precursor-specific effects and niacin flushing.

Does not show: Mixture, acute dosing and plasma products do not establish function or interchangeability; direct NMN uptake and health benefit cannot be inferred from ranks.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC4.

[40] Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study.

Shows: Six-week NMN plus training improved selected ventilatory-threshold measures in younger/middle-aged runners, while VO2max and peak power did not differ.

Does not show: Outside registered age/duration, training cointervention and outcome multiplicity; ventilatory threshold is not equivalent to peak aerobic capacity or slower aging.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[41] Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial.

Shows: NR in stable COPD lowered sputum IL8 and increased NAD, with selected persistent marker effects.

Does not show: Inflammation and exploratory clock signatures do not establish pulmonary function, generalized aging or NMN efficacy; drug/disease/time differ.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[42] Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures.

Shows: Twenty-one-day NR in aged men increased muscle NAD metabolites and lowered selected inflammatory signatures without altered bioenergetics.

Does not show: Target engagement is not physical-function efficacy; short other-precursor exposure cannot cross the registered NMN eight-week gate.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC4.

[43] Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men.

Shows: Actual Methods/Results report nominal gait/left-grip signals, NAD augmentation and no mass effect; a supplier switched supplements in 22 of 42 at week 6, leaving ten per arm at week 12.

Does not show: Randomized balance was disrupted; every analysis was exploratory without P correction, and six-week left-grip/mixed-duration results cannot alone satisfy the registered ≥eight-week gate.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Results:paragraph0, 1:Results:paragraph2, 1:Results:paragraph3, 1:Results:paragraph10, 1:Results:paragraph11, 1:Results:paragraph133, 1:Results:paragraph214, 2:Discussion:paragraph9, 3:Methods:paragraph1, 3:Methods:paragraph2, 3:Methods:paragraph3, 3:Methods:paragraph4, 3:Methods:paragraph22, 3:Methods:paragraph23, 3:Methods:paragraph24. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[44] Nicotinamide Mononucleotide Supplementation Improves Mitochondrial Dysfunction and Rescues Cellular Senescence by NAD+/Sirt3 Pathway in Mesenchymal Stem Cells.

Shows: NMN/Sirt3 manipulations changed cultured MSC mitochondrial and senescence measures.

Does not show: Replicative-cell senescence, overexpression and inhibitor effects are not organismal aging or physical function in human recipients; pharmacological specificity remains bounded.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[45] Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin.

Shows: NR-trial secondary neuronal-enriched-vesicle analysis changed NAD and selected pathology-associated markers.

Does not show: Shared six-week precursor trial and vesicle enrichment do not establish actual brain function, neuron-specific origin certainty or prevented neurodegeneration.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[46] Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects.

Shows: Thirty healthy subjects receiving 12-week NMN had higher blood NAD/NAMN and no observed major laboratory abnormalities.

Does not show: Pharmacodynamics and limited safety do not establish older-adult physical improvement, intact NMN uptake or lifetime healthy aging.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[47] Long-Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia.

Shows: Long-term open-label NR in ataxia-telangiectasia showed selected coordination/eye-movement changes relative to historical expectations.

Does not show: No concurrent randomized control, all-age rare disease and different molecule; historical trajectories and practice effects constrain causal transfer to NMN older adults.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[48] Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial.

Shows: Twelve-week NMN increased serum nicotinamide in middle-aged adults, but arterial-stiffness between-group difference was nonsignificant.

Does not show: Metabolite and trend are not proven function or age slowing; middle age and vascular outcome differ from the physical gate.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[49] Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men.

Shows: Single-dose NMN in ten men changed pharmacokinetic metabolites with no major short-term examined clinical effects.

Does not show: Uncontrolled hours-long dosing does not establish eight-week function, durable safety or longevity.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[50] Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study.

Shows: Five-month NR twin study altered NAD, mitochondrial and stem-cell measures without improved adiposity/metabolic health.

Does not show: Both twins received NR without placebo, and cellular mitochondrial function differs from measured physical performance; distinct precursor cannot establish NMN efficacy.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC4.

[51] NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson's disease.

Shows: NR-SAFE four-week high-dose NR increased NAD with no observed major safety problem and a clinical PD score signal.

Does not show: Clinical change also tracked shorter levodopa-dose interval; short pharmacological timing confounding prevents unique NR or broader healthy-aging attribution.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[52] Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease.

Shows: CKD crossover NR/CoQ10 altered metabolic/lipid measures without greater VO2peak, work or work efficiency.

Does not show: Submaximal oxygen changes do not overturn primary exercise nulls; six-week disease-specific other-molecule results are not NMN efficacy.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC4.

[53] Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: a randomised, double-blinded, placebo-controlled phase-II trial.

Shows: An AD combined-metabolic-activator trial reported within-group cognition change and a selected higher-baseline treatment contrast.

Does not show: NR is one of four ingredients; subgroup and within-arm analyses do not establish component necessity or general healthy-aging benefit.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[54] Nicotinamide Riboside Enhances In Vitro Beta-adrenergic Brown Adipose Tissue Activity in Humans.

Shows: NR stimulated cultured human BAT uncoupling but did not increase in vivo human BAT activity/thermogenesis.

Does not show: Actual cell-to-human dissociation bounds translation; another precursor and brown-fat endpoint do not establish older NMN physical function.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC4.

[55] Nicotinamide Mononucleotide Alleviates Angiotensin II-Induced Human Aortic Smooth Muscle Cell Senescence in a Microphysiological Model.

Shows: NMN pretreatment increased NAD and reduced angiotensin-II smooth-muscle-cell senescence in a mechanically stimulated organ-on-chip.

Does not show: A microphysiological induced-cell model is not prevented clinical aneurysm, human physical function or lifespan extension.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[56] Safety evaluation of β-nicotinamide mononucleotide oral administration in healthy adult men and women.

Shows: Four-week high-dose NMN in 31 adults aged 20–65 had no major examined safety abnormality.

Does not show: Short mixed-age tolerability does not establish older function, long-term tumor risk or a universal safe dose.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[57] Towards personalized nicotinamide mononucleotide (NMN) supplementation: Nicotinamide adenine dinucleotide (NAD) concentration.

Shows: Shared 80-person NMN posthoc analysis associated NAD change with walk/SF36 response and modeled marker doses.

Does not show: Achieved marker associations and selected response models do not randomize the NAD mediator, validate personalised dosing or add a causal trial.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3.

[58] NAD+ augmentation by nicotinamide riboside engages SLIT2/ROBO1 signaling to attenuate Th17 inflammation in psoriasis.

Shows: NR psoriasis trial and cellular genetic/pharmacological work linked marker immune suppression to SLIT2/ROBO1 signaling.

Does not show: Four-week immune pathway endpoints are not older physical healthspan; mechanism in psoriasis cannot supply NMN aging necessity or equivalence.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[59] A randomized placebo-controlled trial of nicotinamide riboside and pterostilbene supplementation in experimental muscle injury in elderly individuals.

Shows: NR/pterostilbene in an older induced-muscle-injury trial did not improve stem-cell recruitment or muscle-recovery measures.

Does not show: Combination and injury model differ from chronic older NMN use; tissue changes and short follow-up need separate clinical interpretation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC4.

[60] Triple-Isotope Tracing for Pathway Discernment of NMN-Induced NAD+ Biosynthesis in Whole Mice.

Shows: Triple-isotope mouse tracing indicated NMN-induced NAD largely arises through nicotinamide/NR salvage with little intact uptake.

Does not show: Route/tissue mouse pharmacodynamics cannot establish identical human delivery or function and prevents assuming oral NMN directly enters every target cell.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3.

[61] Metformin-induced changes in the gut microbiome and plasma metabolome are associated with cognition in men.

Shows: Metformin cohorts and pilot samples associated microbiome/metabolite patterns with cognition mainly in a sex-stratified analysis.

Does not show: Whole-cohort microbial ratio association was null; exploratory sex stratification and mixed designs do not isolate a necessary gut mediator or NMN equivalence.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[62] Metformin as adjuvant therapy in obese knee osteoarthritis patients.

Shows: Metformin added to celecoxib improved WOMAC pain/function and selected markers in obese knee-OA patients over twelve weeks.

Does not show: A genuine disease-specific adjunct positive is retained, with retrospective registration; it is not equivalent to NMN physical-aging or life-extension evidence.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[63] Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome.

Shows: In younger men, testosterone changed IgG glycan measures while metformin did not significantly alter glycosylation.

Does not show: GlycanAge and another age/molecule are not physical efficacy or human healthspan; null marker response does not prove all clinical effects absent.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[64] Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults.

Shows: Metformin attenuated exercise VO2max/insulin-sensitivity and mitochondrial adaptations in older adults despite training benefits.

Does not show: Variable individual response is not a responder-defined efficacy scope; this exercise interaction does not negate established diabetic indications or determine NMN efficacy.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[65] Metformin regulates metabolic and nonmetabolic pathways in skeletal muscle and subcutaneous adipose tissues of older adults.

Shows: Six-week metformin in about-70-year-old adults changed tissue gene pathways and selected postprandial metabolic responses.

Does not show: Omics and physiology do not establish physical performance, slower aging or necessary mTOR/MYC mediation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[66] Metformin added to lifestyle intervention for physical function in older adults with obesity (DEMFOS trial): a randomised controlled trial.

Shows: DEMFOS found lifestyle-related performance benefit but no added six-month metformin effect over matched intensive lifestyle.

Does not show: The correct randomized additive-drug contrast is null; benefit versus weaker lifestyle cannot be attributed to metformin or equivalent NMN action.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[67] Potential Benefits of Combined Statin and Metformin Therapy on Resistance Training Response in Older Individuals.

Shows: MASTERS statin secondary analysis found an apparent growth-response modification but no significant strength benefit.

Does not show: Shared parent and nonrandom baseline statin use cannot establish randomized drug synergy; hypertrophy does not equal strength or longevity.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[68] Association of Intensive Lifestyle and Metformin Interventions With Frailty in the Diabetes Prevention Program Outcomes Study.

Shows: DPPOS follow-up found lower frailty odds after original lifestyle assignment but not metformin assignment.

Does not show: Shared long-term parent and later cointerventions limit isolated maintenance effects; a genuine lifestyle signal does not prove metformin or NMN geroprotection.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3, SC4.

[69] Metformin and epigenetic age in non-diabetic older people with HIV in Madrid (METFORAGING): a double-blind, randomised, placebo-controlled, pilot trial.

Shows: METFORAGING found no significant 96-week primary PhenoAge difference in a small older-HIV metformin trial.

Does not show: Under-recruited PP analysis, biomarkers and disease-specific population do not establish lifespan or equivalent healthy-aging benefit.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3, SC4.

[70] Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults.

Shows: MASTERS transcriptomic secondary analysis found altered exercise/aging-signature pathways alongside the parent's blunted hypertrophy.

Does not show: Youthful expression alongside adverse growth response illustrates marker/function separation; shared biopsies do not add an independent trial or unique mediator proof.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2, SC3, SC4.

Documentary record

Every grade on this site is reproducible from its record. The files below are the posted edition exactly as assessed.

• ADVERSARIAL_REVIEW.md
• CONSENSUS_CROSSCHECK.html
• CONSENSUS_CROSSCHECK.md
• RESEARCH_TIMELINE.html
• RESEARCH_TIMELINE.md
• SHA256.txt
• adversarial-findings.json
• codex-correction-provenance.json
• consensus-validation.json
• edition-approval-audit.json
• nad-boosters-human-function.review.md
• nad-boosters-human-function.scorecard.json
• reader-summary.json
• research-timeline.json
• validation-report.json
• validation-round2-2026-10-14.json
• validation.txt
• video-insert.md
• web-page.md

Sources: 70 · load-bearing claims: 75 · verified: 75 · unverified: 0 · contradicted: 0 · schema 5.3