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# Research Synthesis: NAD+ Effects — full paper ## 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. Additional corpus sources included animal/preclinical evidence; restoring nicotinamide adenine dinucleotide (NAD+) has been proposed as a unifying intervention against age-related functional decline, yet the human evidence base remains fragmented across precursors, endpoints, and trial designs (Gao 2025, Yi 2022, Xue 2022, Katayoshi 2023, Martens 2018, Elhassan 2019, Connell 2021, Liao 2021, Vreones 2022, Ren 2023, Pei 2024, Holmes 2026, Okabe 2022, Airhart 2017, Simic 2020, Christen 2026, Membrez 2024, Yu 2025, Simon 2024, Vreones 2022). This matters because surrogate biomarker engagement does not guarantee hard-outcome validity, a caution that is especially relevant when precursor supplements such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) reliably raise circulating NAD+ but inconsistently translate into functional gains, a gap that the Ioannidis 2005 surrogate-endpoint framework was developed to highlight. We performed an AI-assisted structured evidence synthesis with an explicit audit trail, applying direct/indirect tagging, outcome-class categorization, and per-source effect-direction coding; no post-screening exclusions occurred, and 30 sources entered the map. 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-2026-06-18T12-21-38Z-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: 2026-06-18. ### 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 | 42 | | None-only claim binding | 11 | | Mixed partial-or-none claim-binding candidates | 38 | | Partial-only claim-binding candidates | 15 | | Strict high-confidence sources | 14 | | 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 appraisal, and claim registry) rather than from re-parsed full text. ### Risk-of-bias appraisal Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). ### 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 **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. | 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 | no extracted directional 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 | 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. ### Dosing Pharmacokinetics Outcomes See the structured evidence table for Dosing Pharmacokinetics 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: null=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. Corpus scope. The 30-paper curated set concentrates heavily on short-duration biomarker and pharmacokinetic readouts and contains no long-term hard-outcome randomized trial with mortality, major adverse cardiovascular events, or incident frailty as a primary endpoint. Several oft-cited trial programs (large phase 3 outcome trials of nicotinamide riboside or nicotinamide mononucleotide in non-diabetic older adults; long-term functional-endpoint RCTs in sarcopenic or frail populations) do not appear in the corpus, leaving headline conclusions about anti-aging efficacy anchored to short, indirect readouts. Single-trial generalization risk. Several clinically relevant signals rest on a single source and therefore cannot be replicated within the corpus. Ren 2023 stands alone as the human evidence of brain NAD+/NADH ratio engagement in Parkinson's disease and multiple sclerosis. Effect estimates from these single-trial outcomes should not be treated as class effects, because no second independent dataset in the corpus supports or contradicts them. Population specificity. The included trials enrolled narrow populations that limit external validity. Women, non-Asian ethnicities, obese adults (BMI ≥ 30 kg/m² per WHO 2000), and patients with multiple chronic conditions are under-represented, so functional and cardiometabolic effect sizes cannot be extrapolated to the general adult population the anti-aging claim implicitly addresses. Endpoint scope. Most retained sources measure pharmacokinetic or surrogate biomarker endpoints rather than the functional outcomes that motivate consumer and clinical interest. Per Ioannidis 2005, surrogate endpoint associations do not guarantee hard-outcome validity, so the corpus cannot adjudicate whether biomarker NAD+ elevation translates into clinically meaningful functional change. Mechanism-to-clinic gap. Mechanistic plausibility outpaces clinical confirmation across several outcome classes. Nazari 2022 provides only preclinical (murine experimental autoimmune encephalomyelitis) evidence that 6 weeks of swimming exercise raises hepatic AMPK and NAD+ levels, with no human replication. Curran 2025 — a systematic review of NAD metabolite and niacin treatment in infectious-disease animal studies (n = 44 NAD metabolite, n = 9 niacin, n = 3 both) — reports benefit signals that remain unconfirmed in clinically relevant human models, and Curran 2023 (chronic kidney disease) is mechanistic and does not bear on the same safety question. The mechanistic evidence therefore cannot substitute for the missing long-term clinical trials. ## 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: contextual other. 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 | null | 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: null | | 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. ## 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. - 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. - 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 31P 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. - Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=83. - 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 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. - 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. - Effects of Nicotinamide Adenine Dinucleotide on Older Patients with Heart Failure: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=negative; claims=49. - 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. - The complexity of nicotinamide adenine dinucleotide (NAD), hypoxic, and aryl hydrocarbon receptor cell signaling in chronic kidney disease: outcome=safety comorbidity; directness=indirect; tier=B2; direction=null; claims=39. - 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. - A Liposomal Formulation Enhances the Anti-Senescence Properties of Nicotinamide Adenine-Dinucleotide (NAD + ) in Endothelial Cells and Keratinocytes: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=20. - 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. - Trigonelline is an NAD + precursor that improves muscle function during ageing and is reduced in human sarcopenia: outcome=frailty; directness=indirect; tier=B2; direction=null; claims=13. - SERPINE1 drives ferroptosis in acute respiratory distress syndrome by disrupting mitochondrial NAD + homeostasis and suppressing Sirt3 activity: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=7. - 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. - 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: outcome=immune inflammation; directness=mechanistic; tier=C1; direction=null; claims=9. Translational relevance to humans remains uncertain. ### 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 - Severity 5 disagreement: Zhao 2024 vs Curran 2025; Zhao 2024 reports negative effect on contextual other; Curran 2025 reports positive on the same outcome — direct conflict - Severity 5 disagreement: Pei 2024 vs Curran 2025; Pei 2024 reports negative effect on contextual other; Curran 2025 reports positive on the same outcome — direct conflict - Severity 4 null vs negative: Zhao 2024 vs Ministrini 2025; Zhao 2024 (negative on contextual other) vs Ministrini 2025 (null on contextual other) — partial conflict - Severity 4 null vs negative: Zhao 2024 vs Christen 2026; Zhao 2024 (negative on contextual other) vs Christen 2026 (null on contextual other) — partial conflict - Severity 4 null vs negative: Zhao 2024 vs Holmes 2026; Zhao 2024 (negative on contextual other) vs Holmes 2026 (null on contextual other) — partial conflict - Severity 4 null vs negative: Zhao 2024 vs Gao 2026; Zhao 2024 (negative on contextual other) vs Gao 2026 (null on contextual other) — partial conflict - Severity 4 null vs negative: Zhao 2024 vs Bai 2022; Zhao 2024 (negative on contextual other) vs Bai 2022 (null on contextual other) — partial conflict - Severity 4 null vs negative: Zhao 2024 vs Vreones 2022; Zhao 2024 (negative on contextual other) vs Vreones 2022 (null on contextual other) — partial conflict Additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Simonis 2025, Cruz-Jentoft 2019. ## 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 31P 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. 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