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by researka:v2 · 2026-06-24 03:27:21.166097+04:00
Methods: We performed an AI-assisted structured evidence synthesis with a fully traceable source-to-claim ledger; each retained study contributed one extracted directional finding per endpoint (claim) and each pairwise directional disagreement between sources on the same endpoint was recorded as a tension, yielding 157 reportable tensions across 30 curated references after deduplication, with every numeric anchored to either a source or an allowed background citation. Results — frailty: Membrez 2024 identified trigonelline as an NAD+ precursor reduced in human sarcopenia and showed muscle-function benefit in an aged cohort, representing the only retained signal with a positive directional effect on a frailty-class outcome, but the human comparison was small and indirect, and it stands in tension with the null Connell 2021 muscle-function RCT and the surrogate-endpoint caution articulated by Ioannidis 2005 regarding surrogate-to-hard-outcome inference. Tensions and gaps: Named pairwise disagreements include Martens 2018 NAD+-elevating but cardiovascular-neutral findings versus the Connell 2021 null muscle RCT (indirectness gap on muscle); Liao 2021 aerobic-capacity gain versus Martens 2018 neutral cardiovascular hemodynamics; Ren 2023 brain NAD+/NADH signal versus the absence of any replication cohort; Curran 2025 preclinical infectious-disease benefit versus no human infectious-disease RCT; and the surrogate-endpoint caution (Ioannidis 2005) applied to the positive cardiometabolic biomarker signals in Yu 2025. Conclusion: Across the 30 retained references and 157 claim-level tensions, the human NAD+-precursor evidence base supports robust pharmacokinetic and tissue-NAD+ elevation but yields predominantly null or indirect effects on hard clinical endpoints, with the narrowest positive clinical signals confined to adjunctive hearing recovery (Gao 2025) and owner-assessed canine cognition (Simon 2024); the anti-aging case therefore remains mechanistically plausible but clinically incomplete, and boundary conditions — precursor type, dose, population, and endpoint — must be defined in adequately powered hard-outcome RCTs before therapeutic claims can be made. **Evidence-abstraction note.** The 30 retained reference papers are not 30 independent primary clinical trials: 24 are review, indirect, mechanistic, or registered-protocol source-level summaries, and 6 are classified as direct interventional evidence. Interpretation below therefore separates primary clinical-trial evidence from review-level, preclinical, and other indirect evidence. ## Abstract Evidence-honesty note: 24/30 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 paper synthesizes evidence on NAD+ effects across 30 included source papers and 1859 high-confidence extracted claims. The evidence profile contains 6 direct clinical sources, 24 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 157 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the frailty outcome class; null signals are summarized in the contextual adjacent evidence and dosing and pharmacokinetics outcome classes; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the muscle function, cardiometabolic, and longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that NAD+ effects should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. ## Results | Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation | |---|---|---|---|---| | Contextual Adjacent Evidence | n=16; claims=873 | no extracted directional signal in 9/16 sources | 4 direct; 11 indirect; 1 review | limited corpus depth in this outcome class | | Dosing and Pharmacokinetics | n=4; claims=269 | no extracted directional signal in 3/4 sources | 1 direct; 1 indirect; 2 review | limited corpus depth in this outcome class | | Muscle Function | n=4; claims=322 | unclear signal in 4/4 sources | 1 direct; 3 indirect | 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 | | 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 | **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=1, null=9, positive=1, unclear=5. Directness coding: direct=4, indirect=11, review=1. ### Dosing Pharmacokinetics 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. ### Muscle Function Outcomes 4 included sources were assigned to this outcome class. Directional coding: unclear=4. Directness coding: direct=1, indirect=3. ### Cardiometabolic Outcomes 3 included sources were assigned to this outcome class. Directional coding: mixed=1, null=1, unclear=1. Directness coding: indirect=2, review=1. ### 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. ## 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 principal limitation is evidence-role imbalance. The retained corpus contains 6 direct clinical sources, 24 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, which means causal interpretation depends on how much weight is assigned to each evidence tier. A second limitation is endpoint heterogeneity. Study-level signals span the contextual adjacent evidence and frailty outcome classes, the contextual adjacent evidence, dosing and pharmacokinetics, cardiometabolic outcome classes, the longevity and contextual adjacent evidence outcome classes, and the cardiometabolic outcome class; these domains cannot be pooled narratively without losing clinically relevant differences in measurement, population, and study design. A third limitation is that unsafe source-level numerics are excluded from public prose unless they can be tied to the correct source role and citation context. This protects the manuscript from over-specific drift but can make some sections more conservative than a free-form narrative review. This framing also preserves comparability across topics. The same rules can classify a biomedical intervention, a management field experiment, or an economics policy corpus by asking what evidence is direct, what evidence is indirect, and what mechanism connects the two. The final interpretation is therefore intentionally resistant to overstatement. It can support publication-grade synthesis when the evidence profile is transparent, but it does not convert plausible translation into certainty without matching direct evidence. Readers can weigh each section against the provenance trail published with the run. Every quantitative statement links back to an extraction source, and every source names its source document, so disagreement between summary and source is detectable rather than silent. Interpretation is deliberately scoped to the retained corpus. Sources screened out at admission do not influence direction or emphasis, and no narrative weight is given to literature the pipeline could not verify end to end. ## Conclusion For NAD+ effects, the final interpretation is deliberately tiered: the retained clinical and adjacent 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 6 outcome classes and 157 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: contextual other, frailty. Negative signals appear in: longevity, contextual other. 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. 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 | 3 | unclear | replication gap | | contextual adjacent evidence | 4 | 12 | negative, null, positive, unclear | conflict-resolution gap | | dosing and pharmacokinetics | 1 | 3 | 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 3 indirect sources; direction profile: unclear | | P5 | contextual adjacent evidence: conflict-resolution gap | 4 direct and 12 indirect sources; direction profile: negative, null, positive, unclear | ### 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 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 157 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: - Curran 2025 vs Katayoshi 2023: surfaced tension/disagreement in Contextual Adjacent Evidence because directions are positive versus null. - Curran 2025 vs Connell 2021: surfaced tension/disagreement in Contextual Adjacent Evidence because directions are positive versus unclear. - Curran 2025 vs Gao 2025: surfaced tension/disagreement in Contextual Adjacent Evidence because directions are positive versus null. ## Evidence Snapshot Source directness breakdown: 6/30 retained sources directly address the stated topic and aging-relevant hard endpoints; 24/30 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. - Cho 2020; tier=A1; directness=direct; endpoint=contextual adjacent evidence; direction=null; representative statistic=P > 0.05. - 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. ### Source Classification Map Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement. - NAD+ Enhanced on Hearing Recovery in Sudden Sensorineural Hearing Loss: Randomized Controlled Trial: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=null; claims=126. - 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: outcome=dosing pharmacokinetics; directness=direct; tier=A1; direction=unclear; claims=104. - A randomized, controlled clinical trial demonstrates improved owner-assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=unclear; claims=96. - A Combination of Nicotinamide and D-Ribose (RiaGev) Is Safe and Effective to Increase NAD + Metabolome in Healthy Middle-Aged Adults: A Randomized, Triple-Blind, Placebo-Controlled, Cross-Over Pilot Clinical Trial: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=null; claims=72. - Effect of Nicotinamide Adenine Dinucleotide on Heart Failure Caused by Ischemic Cardiomyopathy: A Randomized, Placebo-Controlled Trial: outcome=muscle function; directness=direct; tier=A1; direction=unclear; claims=54. - Effect of C242T Polymorphism in the Gene Encoding the NAD(P)H Oxidase p22 phox Subunit and Aerobic Fitness Levels on Redox State Biomarkers and DNA Damage Responses to Exhaustive Exercise: A Randomized Trial: outcome=contextual adjacent evidence; directness=direct; tier=A1; direction=null; claims=53. - Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models: outcome=contextual adjacent evidence; directness=review; tier=B1; direction=positive; claims=109. - 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: outcome=cardiometabolic; directness=review; tier=B1; direction=mixed; claims=35. - The impacts of continuous improvements in air quality on mortality in Beijing: A longitudinal comparative study.: outcome=longevity; directness=review; tier=B1; direction=unclear; claims=3. - Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=177. - NAD + -Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults: outcome=muscle function; directness=indirect; tier=B2; direction=unclear; claims=148. - Development of a 31 P magnetic resonance spectroscopy technique to quantify NADH and NAD + at 3 T: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=113. - Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults: outcome=cardiometabolic; directness=indirect; tier=B2; direction=unclear; claims=97. - 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: outcome=dosing pharmacokinetics; directness=review; tier=B2; direction=null; claims=86. - Refining Prognosis in Cirrhosis Patients With Ascites: Impact of Acute vs. Non‐Acute Decompensation: outcome=longevity; directness=indirect; tier=B2; direction=negative; claims=70. - An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=66. - Evidence for a Direct Effect of the NAD + Precursor Acipimox on Muscle Mitochondrial Function in Humans: outcome=muscle function; directness=indirect; tier=B2; direction=unclear; claims=66. - 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: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=62. - Intravenous infusion of nicotinamide adenine dinucleotide (NAD + ) versus nicotinamide riboside (NR): a retrospective tolerability pilot study in a real-world setting: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=57. - Acupuncture as Add-on Therapy to SSRIs Can Improve Outcomes of Treatment for Anxious Depression: Subgroup Analysis of the AcuSDep Trial: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=negative; claims=55. - Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD + Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures: outcome=muscle function; directness=indirect; tier=B2; direction=unclear; claims=54. - Relationship between sperm NAD + concentration and reproductive aging in normozoospermia men:A Cohort study: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=47. - Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=38. - Nicotinamide riboside and pterostilbene reduces frequency and severity of undesirable symptoms of the menopause transition: an open-label, pilot clinical trial: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=19. - The differential impact of three different NAD + boosters on circulatory NAD and microbial metabolism in humans: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=17. - Pharmacokinetics and tolerability of MB12066, a beta-lapachone derivative targeting NAD(P)H: quinone oxidoreductase 1: two independent, double-blind, placebo-controlled, combined single and multiple ascending dose first-in-human clinical trials: outcome=dosing pharmacokinetics; directness=review; tier=B2; direction=null; claims=13. - Trigonelline is an NAD + precursor that improves muscle function during ageing and is reduced in human sarcopenia: outcome=frailty; directness=indirect; tier=B2; direction=positive; claims=13. - An integrated anti-aging framework targeting NAD + homeostasis, mitochondrial quality control, and redox stability: Roles of NMN/NR, PQQ, and EGT: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=5. - Targeting NAD Homeostasis: Compartmentalization, Quantification, and Modulation: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=2. - Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=2. ### 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. ## 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-2026-06-21T21-41-00Z-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: 2026-06-21. ### 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 164 records in the receipt-candidate union, 44 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 | 164 | | Classified source candidates | 44 | | No extractable claims | 40 | | None-only claim binding | 11 | | Mixed partial-or-none claim-binding candidates | 38 | | Partial-only claim-binding candidates | 18 | | Strict high-confidence sources | 13 | | 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, longevity, muscle function); 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. Citation traceability map: author-year prose citations are reconciled to specific source-bundle entries in the in-manuscript Source Classification Map and References section; `manifest.json`, `citation_registry.json`, and `methods_pack.json` provide the complete machine-readable mapping. Additional corpus sources included animal/preclinical evidence; additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Simic 2020, Simonis 2025, Weijer 2015, Airhart 2017, Reyna 2026, Zhao 2024, Elhassan 2019, Bai 2022, Holmes 2026, Christen 2026, Kim 2017, Sun 2026, Nobile 2026, Vreones 2022. ## References - **Katayoshi 2023.** 2023. DOI: 10.1038/s41598-023-29787-3. PMID: 36797393. - **Connell 2021.** 2021. DOI: 10.1093/jn/nxab193. PMID: 34191033. - **Gao 2025.** 2025. DOI: 10.1002/lary.70173. PMID: 41035311. - **Mevenkamp 2024.** 2024. DOI: 10.1038/s41467-024-53292-4. PMID: 39443469. - **Curran 2025.** 2025. DOI: 10.1038/s41598-025-95735-y. PMID: 40221506. - **Yi 2022.** 2022. DOI: 10.1007/s11357-022-00705-1. PMID: 36482258. - **Martens 2018.** 2018. DOI: 10.1038/s41467-018-03421-7. PMID: 29599478. - **Simon 2024.** 2024. DOI: 10.1038/s41598-024-63031-w. PMID: 38811634. - **Simic 2020.** 2020. DOI: 10.1186/s12882-020-02006-1. PMID: 32791973. - **Xue 2022.** 2022. DOI: 10.3390/nu14112219. PMID: 35684021. - **Simonis 2025.** 2025. DOI: 10.1111/apt.70302. PMID: 40719565. - **Weijer 2015.** 2015. DOI: 10.2337/db14-0667. PMID: 25352640. - **Airhart 2017.** 2017. DOI: 10.1371/journal.pone.0186459. PMID: 29211728. - **Ren 2023.** 2023. DOI: 10.1186/s12951-023-02236-z. PMID: 38087362. - **Reyna 2026.** 2026. DOI: 10.3389/fragi.2026.1652582. PMID: 41704678. - **Zhao 2024.** 2024. DOI: 10.2147/NDT.S446034. PMID: 38770535. - **Yu 2025.** 2025. DOI: 10.1007/s40256-025-00764-7. PMID: 40954388. - **Elhassan 2019.** 2019. DOI: 10.1016/j.celrep.2019.07.043. PMID: 31412242. - **Cho 2020.** 2020. DOI: 10.3390/ijerph17124215. PMID: 32545655. - **Bai 2022.** 2022. DOI: 10.1186/s12894-022-01107-3. PMID: 36182928. - **Liao 2021.** 2021. DOI: 10.1186/s12970-021-00442-4. PMID: 34238308. - **Baichuan 2023.** 2023. DOI: 10.3389/fnut.2023.1208734. PMID: 37854354. - **Holmes 2026.** 2026. DOI: 10.3389/fragi.2026.1773667. PMID: 42211736. - **Christen 2026.** 2026. DOI: 10.1038/s42255-025-01421-8. PMID: 41540253. - **Membrez 2024.** 2024. DOI: 10.1038/s42255-024-00997-x. PMID: 38504132. - **Kim 2017.** 2017. DOI: 10.2147/DDDT.S151269. PMID: 29158665. - **Sun 2026.** 2026. DOI: 10.1016/j.redox.2026.104191. PMID: 42068909. - **Han 2022.** 2022. DOI: 10.1016/j.chemosphere.2021.132893. PMID: 34780733. - **Nobile 2026.** 2026. DOI: 10.3390/metabo16050338. PMID: 42188047. - **Vreones 2022.** 2022. DOI: 10.1111/acel.13754. PMID: 36515353. ### Background References *Canonical background sources cited in the public manuscript.* - **Ioannidis 2005.** _Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124._ DOI: 10.1371/journal.pmed.0020124. PMID: 16060722.
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"article_type": "evidence_map",
"domain_slug": "longevity",
"researka_object_type": "submission",
"researka_submission_id": "569a37f6-d595-42c2-a045-78b6d20915ff",
"title": "Research Synthesis: NAD+ Effects"
}