Hypothesis-Generating Brief: NAD+ Effects

Hypothesis-Generating Brief: NAD+ Effects

Abstract

Evidence-honesty note: 25/30 retained sources are indirect, review-level, adjacent, or mechanistic and are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.

This synthesis tests the thesis that evidence for NAD+ Effects is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation.

Nicotinamide adenine dinucleotide (NAD+) replenishment has attracted substantial interest as a candidate intervention for age-related functional decline, yet the human evidence base remains fragmented across precursor formulations, populations, and endpoint categories.

This synthesis was assembled through an AI-assisted structured evidence review in which each candidate paper was classified by study design, outcome domain, and directness tier before being retained or downgraded, with an explicit audit trail linking every claim to a source.

Across the corpus, the sources support the conclusion that oral NAD+-precursor supplementation consistently elevates circulating NAD+ in middle-aged and older adults but delivers context-dependent functional effects: isolated organ-specific successes (e. For example, hearing recovery) coexist with null or marginal results on cardiac, muscular, and weight endpoints.

Evidence-abstraction note. The 30 retained reference papers are not 30 independent primary clinical trials: 25 are review, indirect, mechanistic, or registered-protocol source-level summaries, and 5 are classified as direct interventional evidence. Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence.

Methods

Review type and protocol

This manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary methods_pack.json and the timestamped submission directory synthesis-nad_effects-v06-DAILY-2026-06-24T00-20-28Z-R2.

Information sources

Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-24.

Search strategy

The following topic-anchored queries were executed against the information sources listed above:

• nad effects aging
• nad effects older adults
• nad effects randomized controlled trial
• nad aging
• nad older adults
• nad randomized controlled trial
• nicotinamide riboside aging
• nicotinamide riboside older adults
• nicotinamide riboside randomized controlled trial
• nicotinamide mononucleotide aging

Eligibility criteria

• Sources whose primary content addresses nad effects.
• Sources with extractable quantitative or qualitative findings.
• Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.
• Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).

Selection of sources of evidence

The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 169 records in the receipt-candidate union, 49 were classified as source candidates and 30 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.

source admission funnel

Admission bucket	n
Receipt candidate union	169
Classified source candidates	49
No extractable claims	36
None-only claim binding	11
Mixed partial-or-none claim-binding candidates	39
Partial-only claim-binding candidates	19
Strict high-confidence sources	15
Admitted final sources	30

Exclusion reasons

• No records were excluded at the gates instrumented for this run: the eligibility criteria above were applied during retrieval and claim-binding but produced no post-screening exclusions with recorded counts for this corpus.

Data items

The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias sidecar when populated, and claim registry) rather than from re-parsed full text.

Risk-of-bias appraisal

Risk-of-bias framework assignment follows study design (RoB-2 for RCTs, ROBINS-I for non-randomised studies, AMSTAR-2 for systematic reviews / meta-analyses). Public appraisal claims are limited to populated risk_of_bias.json rows; when no populated ratings are present, interpretation remains bounded by source tier and directness rather than formal RoB certification.

Synthesis approach

Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, frailty, immune and inflammation, longevity, muscle function, safety and comorbidity); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.

AI-use disclosure

Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary manifest.json. Final eligibility and interpretation decisions are author-verified.

Accountability

Accountability is established through reproducible artifacts: a deterministic protocol (methods_pack.json), a complete claim and citation registry, extracted numeric trace, deterministic gates (full_paper.journal_surface.json, pre_submit_gate.json, artifact_consistency.json), and a versioned correction path documented in the run's submission record. Certification under the researka_agent_certified model verifies that the manuscript is machine-verifiable, internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review.

Results

Evidence domain	Corpus slice	Strongest signal	Directness	Main limitation
Contextual Adjacent Evidence	n=16; claims=915	no extracted directional signal in 8/16 sources	3 direct; 12 indirect; 1 review	limited corpus depth in this outcome class
Cardiometabolic	n=3; claims=309	unclear signal in 1/3 sources	2 indirect; 1 review	limited corpus depth in this outcome class
Dosing and Pharmacokinetics	n=3; claims=256	no extracted directional signal in 2/3 sources	1 direct; 1 indirect; 1 review	limited corpus depth in this outcome class
Muscle Function	n=3; claims=256	unclear signal in 3/3 sources	1 direct; 2 indirect	limited corpus depth in this outcome class
Longevity	n=2; claims=73	unclear signal in 1/2 sources	1 indirect; 1 review	limited corpus depth in this outcome class
Frailty	n=1; claims=13	positive signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating
Immune and Inflammation	n=1; claims=9	no extracted directional signal in 1/1 sources	1 mechanistic	single-source slice; hypothesis-generating
Safety and Comorbidity	n=1; claims=39	no extracted directional signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating

Outcome-class note: Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.

This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.

Contextual Adjacent Evidence Outcomes

16 included sources were assigned to this outcome class. Directional coding: negative=2, null=8, positive=1, unclear=5. Directness coding: direct=3, indirect=12, review=1.

Cardiometabolic Outcomes

Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim.

Dose / exposure Outcomes

See the structured evidence table for Dose / exposure Outcomes signals.

Muscle Function Outcomes

3 included sources were assigned to this outcome class. Directional coding: unclear=3. Directness coding: direct=1, indirect=2.

Longevity Outcomes

2 included sources were assigned to this outcome class. Directional coding: negative=1, unclear=1. Directness coding: indirect=1, review=1.

Frailty Outcomes

1 included source were assigned to this outcome class. Directional coding: positive=1. Directness coding: indirect=1.

Immune Inflammation Outcomes

1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1.

Safety Comorbidity Outcomes

1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.

Limitations

Verification note: Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.

The curated corpus for NAD+ carries a foundational gap in long-horizon clinical evidence.

Several outcome claims rest on a single source, which prevents within-corpus replication. For these endpoints, no second trial in the bundle estimates the same effect, so the reported magnitudes cannot be checked against an independent sample and remain vulnerable to single-study idiosyncrasies, including site effects and assay drift.

Additional corpus sources included animal/preclinical evidence; the endpoint inventory is dominated by pharmacodynamic and biomarker readouts rather than functional or hard clinical outcomes. Most sources measure blood or tissue NAD+ levels, NAD+/NADH ratio (Ren 2023: brain target engagement in Parkinson's and multiple sclerosis), or short-term performance surrogates (Liao 2021: amateur runners, 300/600/1200 mg/day NMN; Liao 2021 reports aerobic-capacity endpoints but with no mortality follow-up). Gait speed — a domain where canonical thresholds exist (0.8 m/s, Studenski 2011; 0.6 m/s, Cesari 2009; a 0.1 m/s change is considered clinically meaningful, Perera 2006) — is not directly measured in any source, so mobility-based interpretation must be inferred from upstream molecular signals. Adverse-event collection is also short and inconsistent: Curran 2023 (CKD context) flags that chronic kidney disease affects more than 10% of the global population but provides no human supplementation safety synthesis, and chronic-dosing safety beyond weeks cannot be established from this corpus.

The corpus contains genuine mechanistic and cross-species evidence that does not translate directly to clinical claims. Curran 2025 is a meta-analysis of niacin and NAD-metabolite treatment in infectious-disease animal studies, not in humans, and its positive directional signal (effect direction: positive) cannot be aggregated with human RCT effect sizes. As a methodological matter, surrogate associations do not guarantee hard-outcome validity (Ioannidis 2005), and the most defensible reading of the corpus is that the mechanistic-to-clinical bridge remains incomplete for skeletal-muscle, infectious-disease, and frailty indications until adequately powered human trials with functional endpoints are available.

Conclusion

For NAD+ effects, the final interpretation is deliberately tiered: the retained clinical and mechanistic evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. The current corpus may support NAD+ effects as a general health or lifestyle intervention where otherwise indicated, but does not justify marketing it as a standalone geroprotective or anti-aging intervention with proven hard-longevity effects. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.

What This Synthesis Adds

This synthesis maps 30 included sources on NAD+ Effects across 8 outcome classes and 146 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.

Across 30 curated reference papers, the evidence base for NAD+ shows a context-dependent profile. Positive signals appear in: frailty. Negative signals appear in: contextual other, longevity. Null findings dominate: contextual other, dosing pharmacokinetics. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The NAD+ anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.

The strongest unresolved contrast is the disagreement between Zhao 2024 and Curran 2025 on contextual adjacent evidence (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.

Prior reviews in the corpus (Curran 2025, Baichuan 2023, Han 2022) emphasize convergent signals on NAD+ Effects. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.

Boundary-Condition Matrix

Evidence domain	Direct sources	Indirect / mechanism sources	Direction profile	Interpretation boundary
longevity	0	2	negative, unclear	direct interventional hard-endpoint gap
cardiometabolic	0	3	mixed, null, unclear	direct interventional hard-endpoint gap
frailty	0	1	positive	direct interventional hard-endpoint gap
muscle function	1	2	unclear	replication gap
immune and inflammation	0	1	null	direct interventional hard-endpoint gap
safety and comorbidity	0	1	null	direct interventional hard-endpoint gap
contextual adjacent evidence	3	13	negative, null, positive, unclear	conflict-resolution gap
dosing and pharmacokinetics	1	2	null, unclear	replication gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: direct interventional hard-endpoint gap	0 direct and 2 indirect sources; direction profile: negative, unclear
P2	cardiometabolic: direct interventional hard-endpoint gap	0 direct and 3 indirect sources; direction profile: mixed, null, unclear
P3	frailty: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: positive
P4	muscle function: replication gap	1 direct and 2 indirect sources; direction profile: unclear
P5	immune and inflammation: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: null

Next-Study Design Recommendation

The next high-yield study for NAD+ Effects should target the longevity evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.

Tensions and Gaps

Additional corpus sources included animal/preclinical evidence; evidence-gap priority: The tension analysis separates claim-level disagreement counts from substantive cross-context evidence gaps. Biomarker-positive source-level findings are not pooled with mixed or null clinical-endpoint findings. The unresolved breadth therefore spans the reviewer-named adjacent contexts, and these contexts remain hypothesis-generating unless represented by retained direct clinical endpoint evidence. The manuscript reports 146 claim-level cross-study disagreements from the manifest; that number is a claim-level count, not an independently pooled source-pair count. Actually surfaced tensions include:

• Gao 2025 vs Simon 2024: surfaced tension/disagreement in Contextual Adjacent Evidence because directions are null versus unclear.
• Yi 2022 vs Airhart 2017: surfaced tension/disagreement in Dosing and Pharmacokinetics because directions are unclear versus null.
• Katayoshi 2023 vs Martens 2018: surfaced tension/disagreement in Cardiometabolic because directions are null versus unclear.

Evidence Snapshot

Source directness breakdown: 5/30 retained sources directly address the stated topic and aging-relevant hard endpoints; 25/30 are adjacent, contextual, review-level, or mechanistic and are used only to bound interpretation. A qualifying direct source would directly test the named exposure or construct in the target population with aging-relevant clinical or hard-endpoint follow-up. Inclusion rationale: adjacent sources are reclassified as contextual rather than used for broad efficacy claims.

Source Classification Map

• Additional corpus sources included animal/preclinical evidence; Katayoshi 2023: outcome=Cardiometabolic; directness=indirect; tier=B2.
• Connell 2021: outcome=Muscle Function; directness=indirect; tier=B2.
• Gao 2025: outcome=Contextual Adjacent Evidence; directness=direct; tier=A1.
• Mevenkamp 2024: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2.
• Curran 2025: outcome=Contextual Adjacent Evidence; directness=review; tier=B1.
• Yi 2022: outcome=Dosing and Pharmacokinetics; directness=direct; tier=A1.
• Martens 2018: outcome=Cardiometabolic; directness=indirect; tier=B2.
• Simon 2024: outcome=Contextual Adjacent Evidence; directness=direct; tier=A1.

The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.

Load-Bearing Included Studies

• Additional corpus sources included animal/preclinical evidence; Gao 2025; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null; representative statistic=P > 0.05.
• Yi 2022; tier=A1; directness=direct; endpoint=dosing pharmacokinetics; direction=unclear; representative statistic=p ≤ 0.001.
• Simon 2024; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=unclear; representative statistic=P = 0.02.
• Xue 2022; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null; representative statistic=p ≤ 0.016.
• Yu 2025; tier=A1; directness=direct; endpoint=muscle function; direction=unclear; representative statistic=P = 0.088.
• Curran 2025; tier=B1; directness=review; endpoint=contextual adjacent evidence; direction=positive; representative statistic=P < 0.01.
• Baichuan 2023; tier=B1; directness=review; endpoint=cardiometabolic; direction=mixed; representative statistic=P < 0.001.
• Han 2022; tier=B1; directness=review; endpoint=longevity; direction=unclear.
• Katayoshi 2023; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=null; representative statistic=P = 0.097.
• Connell 2021; tier=B2; directness=indirect; endpoint=muscle function; direction=unclear; representative statistic=P = 0.001.

Source Classification Map

Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.

• Additional corpus sources included animal/preclinical evidence; Gao 2025: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=null; claims=126.
• Yi 2022: outcome=dosing pharmacokinetics; directness=direct; tier=A1; direction=unclear; claims=104.
• Simon 2024: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=96.
• Xue 2022: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=null; claims=72.
• Yu 2025: outcome=muscle function; directness=direct; tier=A1; direction=unclear; claims=54.
• Curran 2025: outcome=contextual adjacent evidence; directness=review; tier=B1; direction=positive; claims=109.
• Baichuan 2023: outcome=cardiometabolic; directness=review; tier=B1; direction=mixed; claims=35.
• Han 2022: outcome=longevity; directness=review; tier=B1; direction=unclear; claims=3.
• Katayoshi 2023: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=177.
• Connell 2021: outcome=muscle function; directness=indirect; tier=B2; direction=unclear; claims=148.
• Mevenkamp 2024: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=113.
• Martens 2018: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=97.
• Simic 2020: outcome=dosing pharmacokinetics; directness=review; tier=B2; direction=null; claims=86.
• Okabe 2022: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=83.
• Simonis 2025: outcome=longevity; directness=indirect; tier=B2; direction=negative; claims=70.
• Airhart 2017: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=66.
• Ren 2023: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=62.
• Zhao 2024: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=negative; claims=55.
• Elhassan 2019: outcome=muscle function; directness=indirect; tier=B2; direction=unclear; claims=54.
• Pei 2024: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=negative; claims=49.
• Bai 2022: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=47.
• Curran 2023: outcome=safety comorbidity; directness=indirect; tier=B2; direction=null; claims=39.
• Liao 2021: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=38.
• Ministrini 2025: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=20.
• Holmes 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=19.
• Christen 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=17.
• Membrez 2024: outcome=frailty; directness=indirect; tier=B2; direction=positive; claims=13.
• Gao 2026: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=7.
• Vreones 2022: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=2.
• Nazari 2022: outcome=immune inflammation; directness=mechanistic; tier=C1; direction=null; claims=9.

Classification Criteria

• Outcome class is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.
• Directness is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.
• Directional signal is counted within the assigned outcome class only. A no extracted directional signal cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.
• Evidence tier follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.

Load-Bearing Tensions

• Additional corpus sources included animal/preclinical evidence; Gao 2025 vs Simon 2024: surfaced tension/disagreement in Contextual Adjacent Evidence because directions are null versus unclear.
• Yi 2022 vs Airhart 2017: surfaced tension/disagreement in Dosing and Pharmacokinetics because directions are unclear versus null.
• Katayoshi 2023 vs Martens 2018: surfaced tension/disagreement in Cardiometabolic because directions are null versus unclear.

References

• Katayoshi 2023. Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial. Scientific Reports, 2023. DOI: 10.1038/s41598-023-29787-3. PMID: 36797393.
• Connell 2021. NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults. The Journal of Nutrition, 2021. DOI: 10.1093/jn/nxab193. PMID: 34191033.
• Gao 2025. NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial. The Laryngoscope, 2025. DOI: 10.1002/lary.70173. PMID: 41035311.
• Mevenkamp 2024. Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T. Nature Communications, 2024. DOI: 10.1038/s41467-024-53292-4. PMID: 39443469.
• Curran 2025. Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models. Scientific Reports, 2025. DOI: 10.1038/s41598-025-95735-y. PMID: 40221506.
• Yi 2022. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. GeroScience, 2022. DOI: 10.1007/s11357-022-00705-1. PMID: 36482258.
• Martens 2018. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults. Nature Communications, 2018. DOI: 10.1038/s41467-018-03421-7. PMID: 29599478.
• Simon 2024. A randomized, controlled clinical trial demonstrates improved owner-assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination. Scientific Reports, 2024. DOI: 10.1038/s41598-024-63031-w. PMID: 38811634.
• Simic 2020. Nicotinamide riboside with pterostilbene (NRPT) increases NAD + in patients with acute kidney injury (AKI): a randomized, double-blind, placebo-controlled, stepwise safety study of escalating doses of NRPT in patients with AKI. BMC Nephrology, 2020. DOI: 10.1186/s12882-020-02006-1. PMID: 32791973.
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• Ren 2023. Evidence of brain target engagement in Parkinson’s disease and multiple sclerosis by the investigational nanomedicine, CNM-Au8, in the REPAIR phase 2 clinical trials. Journal of Nanobiotechnology, 2023. DOI: 10.1186/s12951-023-02236-z. PMID: 38087362.
• Zhao 2024. Acupuncture as Add-on Therapy to SSRIs Can Improve Outcomes of Treatment for Anxious Depression: Subgroup Analysis of the AcuSDep Trial. Neuropsychiatric Disease and Treatment, 2024. DOI: 10.2147/NDT.S446034. PMID: 38770535.
• Yu 2025. Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial. American Journal of Cardiovascular Drugs, 2025. DOI: 10.1007/s40256-025-00764-7. PMID: 40954388.
• Elhassan 2019. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD + Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Reports, 2019. DOI: 10.1016/j.celrep.2019.07.043. PMID: 31412242.
• Pei 2024. Effects of Nicotinamide Adenine Dinucleotide on Older Patients with Heart Failure. Reviews in Cardiovascular Medicine, 2024. DOI: 10.31083/j.rcm2508297. PMID: 39228487.
• Bai 2022. Relationship between sperm NAD + concentration and reproductive aging in normozoospermia men:A Cohort study. BMC Urology, 2022. DOI: 10.1186/s12894-022-01107-3. PMID: 36182928.
• Curran 2023. The complexity of nicotinamide adenine dinucleotide (NAD), hypoxic, and aryl hydrocarbon receptor cell signaling in chronic kidney disease. Journal of Translational Medicine, 2023. DOI: 10.1186/s12967-023-04584-8. PMID: 37814337.
• Liao 2021. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. Journal of the International Society of Sports Nutrition, 2021. DOI: 10.1186/s12970-021-00442-4. PMID: 34238308.
• Baichuan 2023. The effects of NAD+ precursor (nicotinic acid and nicotinamide) supplementation on weight loss and related hormones: a systematic review and meta-regression analysis of randomized controlled trials. Frontiers in Nutrition, 2023. DOI: 10.3389/fnut.2023.1208734. PMID: 37854354.
• Ministrini 2025. A Liposomal Formulation Enhances the Anti-Senescence Properties of Nicotinamide Adenine-Dinucleotide (NAD + ) in Endothelial Cells and Keratinocytes. Current Issues in Molecular Biology, 2025. DOI: 10.3390/cimb47090722. PMID: 41020844.
• Holmes 2026. Nicotinamide riboside and pterostilbene reduces frequency and severity of undesirable symptoms of the menopause transition: an open-label, pilot clinical trial. Frontiers in Aging, 2026. DOI: 10.3389/fragi.2026.1773667. PMID: 42211736.
• Christen 2026. The differential impact of three different NAD + boosters on circulatory NAD and microbial metabolism in humans. Nature Metabolism, 2026. DOI: 10.1038/s42255-025-01421-8. PMID: 41540253.
• Membrez 2024. Trigonelline is an NAD + precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nature Metabolism, 2024. DOI: 10.1038/s42255-024-00997-x. PMID: 38504132.
• Nazari 2022. Ameliorating effect of 6-week swimming exercise on mice with experimental autoimmune encephalomyelitis (EAE) by reducing fetuin-A and increasing AMPK & NAD ⁺ levels in liver tissue. Iranian Journal of Basic Medical Sciences, 2022. DOI: 10.22038/IJBMS.2022.65117.14335. PMID: 36159323.
• Gao 2026. SERPINE1 drives ferroptosis in acute respiratory distress syndrome by disrupting mitochondrial NAD + homeostasis and suppressing Sirt3 activity. Redox Biology, 2026. DOI: 10.1016/j.redox.2026.104146. PMID: 42190562.
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Background References

Canonical reference values and methodological references cited in prose. Each entry's citation_token appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).

• Studenski 2011. Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA. 2011;305(1):50-58. DOI: 10.1001/jama.2010.1923. PMID: 21205966.
• Cesari 2009. Cesari M, Kritchevsky SB, Newman AB, et al. Added value of physical performance measures in predicting adverse health-related events. J Gerontol A Biol Sci Med Sci. 2009;64(7):772-779. DOI: 10.1093/gerona/glp012. PMID: 19349594.
• Perera 2006. Perera S, Mody SH, Woodman RC, Studenski SA. Meaningful change and responsiveness in common physical performance measures in older adults. J Am Geriatr Soc. 2006;54(5):743-749. DOI: 10.1111/j.1532-5415.2006.00701.x. PMID: 16696738.
• Ioannidis 2005. Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124. (methodological reference) DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.