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# Hypothesis-Generating Brief: NAD+ Metabolism Effects — full paper ## Abstract Evidence-honesty note: 13/19 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. 18/19 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+ metabolism effects across 19 accepted source papers and 1054 high-confidence extracted claims. The evidence profile contains 1 direct clinical source, 18 adjacent clinical sources, and no sources classified primarily as mechanistic or model-system evidence, with 18 cross-study disagreements across the evidence base. Positive study-level signals are summarized in the frailty outcome class, null signals in the contextual adjacent evidence, dosing and pharmacokinetics, cardiometabolic outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that NAD+ metabolism effects remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. ## 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_metabolism_effects-v06-DAILY-2026-06-21T16-27-12Z-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 metabolism effects aging` - `nad metabolism effects older adults` - `nad metabolism effects randomized controlled trial` - `nad aging` - `nad older adults` - `nad randomized controlled trial` - `metabolism aging` - `metabolism older adults` - `metabolism randomized controlled trial` - `nicotinamide riboside aging` ### Eligibility criteria - Sources whose primary content addresses nad metabolism 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 333 records in the receipt-candidate union, 119 were classified as source candidates and 19 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 | 333 | | Classified source candidates | 119 | | No extractable claims | 73 | | None-only claim binding | 15 | | Mixed partial-or-none claim-binding candidates | 82 | | Partial-only claim-binding candidates | 27 | | Strict high-confidence sources | 17 | | Admitted final sources | 19 | ### 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, deficiency prevalence, dosing and pharmacokinetics, frailty, 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. ## Evidence Landscape ### Source Outcome-Class Map Signal-accounting note: biomarker-positive source-level findings are separated from clinical-endpoint mixed/null rows; biomarker elevation is not counted as clinical efficacy unless the mapped outcome class and endpoint support it. Role-accounting note: retained translational or mechanistic-with-human-correlational evidence is mapped by its public outcome and directness row; preclinical or mechanistic records that are not retained in the source map are excluded from clinical outcome-class tallies. Tension-accounting note: disagreement counts are claim-level. Substantive tension still remains between biomarker-elevating studies and mixed/null clinical-endpoint studies across cognition, menopause, acute-care, so these contrasts are treated as unresolved evidence gaps. 2 reviewer-named sources are not retained in this source map and are not counted in clinical outcome-class tallies unless listed below. - Berven 2026: The NAD-brain pharmacokinetic study of NAD augmentation in blood and brain using oral precursor supplementation: outcome=Dosing and Pharmacokinetics; directness=indirect; tier=B2. - Katayoshi 2023: 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. - 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: outcome=Muscle Function; directness=indirect; tier=B2. - Conze 2019: Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults: outcome=Safety and Comorbidity; directness=review; tier=B2. - Martens 2018: Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults: outcome=Cardiometabolic; directness=indirect; tier=B2. - Yulug 2023: Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial: outcome=Contextual Adjacent Evidence; directness=review; tier=B2. - In animal/preclinical evidence, Elhassan 2019: Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD + Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures: outcome=Muscle Function; directness=indirect; tier=B2. - In animal/preclinical evidence, Chen 2024: Effects of Nicotinamide Mononucleotide on Glucose and Lipid Metabolism in Adults: A Systematic Review and Meta-analysis of Randomised Controlled Trials: outcome=Cardiometabolic; directness=review; tier=B1. - Pencina 2025: Oral MIB‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With COVID‐19 and Acute Kidney Injury: A Randomized Controlled Trial: outcome=Safety and Comorbidity; directness=direct; tier=A1. - Ryu 2022: Nicotinamide riboside and caffeine partially restore diminished NAD availability but not altered energy metabolism in Alzheimer's disease: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2. - Holmes 2026: 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. - Christen 2026: The differential impact of three different NAD + boosters on circulatory NAD and microbial metabolism in humans: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2. - Yu 2026: Double‐Pronged NAD Preservation: Delaying Cellular Senescence and Initiating Musculoskeletal Regeneration: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2. - Membrez 2024: Trigonelline is an NAD + precursor that improves muscle function during ageing and is reduced in human sarcopenia: outcome=Frailty; directness=indirect; tier=B2. - In animal/preclinical evidence, Bozon 2025: Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency‐Driven Congenital Malformation Risk: outcome=Deficiency Prevalence; directness=indirect; tier=B2. - In animal/preclinical evidence, Richard 2026: NAD + and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2. - Visalli 2026: Mitochondrial Resilience in Glaucoma: Targeting NAD + Metabolism and Oxidative Stress in Retinal Ganglion Cell Degeneration with Nicotinamide Riboside and Berberine: Preliminary Clinical Evidence: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2. - In animal/preclinical evidence, Harasim-Krawcewicz 2026: NAD + Enhancer Nicotinamide Riboside Alters Extracellular Purine Metabolism in Human Endothelial Cells: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2. - Imai 2025: From Bench to Clinic: The 2024 FASEB Scientific Research Conference on NAD Metabolism and Signaling: outcome=Contextual Adjacent Evidence; directness=indirect; tier=B2. ## Results | Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation | |---|---|---|---|---| | Contextual Adjacent Evidence | n=9; claims=176 | no extracted directional signal in 9/9 sources | 8 indirect; 1 review | limited corpus depth in this outcome class | | Cardiometabolic | n=3; claims=306 | unclear signal in 2/3 sources | 2 indirect; 1 review | limited corpus depth in this outcome class | | Muscle Function | n=2; claims=202 | unclear signal in 2/2 sources | 2 indirect | limited corpus depth in this outcome class | | Safety and Comorbidity | n=2; claims=167 | unclear signal in 1/2 sources | 1 direct; 1 review | limited corpus depth in this outcome class | | Deficiency Prevalence | n=1; claims=12 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating | | Dosing and Pharmacokinetics | n=1; claims=178 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating | | 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 9 included sources were assigned to this outcome class. Directional coding: null=9. Directness coding: indirect=8, review=1. ### Cardiometabolic Outcomes 3 included sources were assigned to this outcome class. Directional coding: null=1, unclear=2. Directness coding: indirect=2, review=1. ### Muscle Function Outcomes 2 included sources were assigned to this outcome class. Directional coding: unclear=2. Directness coding: indirect=2. ### Safety Comorbidity Outcomes 2 included sources were assigned to this outcome class. Directional coding: null=1, unclear=1. Directness coding: direct=1, review=1. ### Deficiency Prevalence Outcomes 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1. ### Dosing Pharmacokinetics Outcomes 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=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 curated corpus has no long-term mortality or hard cardiovascular endpoint trial of NAD-precursor supplementation in non-diabetic, community-dwelling adults, which constrains how far the cardiometabolic inferences can be taken. The result is that any 'metabolic benefit' statement derived from this corpus is, at best, an inference from sub-3-month biomarker changes, not from adjudicated events. Additional corpus sources included animal/preclinical evidence; several clinically important outcomes in this domain are touched by a single source, which means they cannot be internally replicated within the corpus and can be interpreted as hypothesis-generating rather than confirmatory. Similarly, Bozon 2025 is the only corpus entry addressing maternal NAD deficiency-driven congenital malformation risk, and Visalli 2026 is the only entry on glaucoma / retinal ganglion cell degeneration (NR 300 mg + berberine), and Holmes 2026 is the only entry on menopausal symptoms (NRPT, NCT04841499); conclusions in each of these outcome lanes are single-trial and should be quarantined from pooled claims. Population specificity places hard boundaries on external validity. Endpoint scope is narrower than the headline claims require. The disconnect between the surrogate biomarker endpoints actually measured and the clinical endpoints the field invokes is a structural limitation of this evidence base, not a defect of any single trial; the methodological caution that surrogate associations do not guarantee hard-outcome validity (Ioannidis 2005) applies directly to the NAD+-rise → clinical-benefit chain that several of these sources imply. Several claims that the broader literature treats as clinically relevant are supported in this corpus only by mechanistic or preclinical evidence, which the synthesis cannot promote to clinical inference. Because the synthesis must not fuse mechanistic evidence on one outcome with direct interventional hard-endpoint evidence on another (a constraint surfacing in the 18 tension pairs that pair Pencina 2025 against entries such as Christen 2026, Martens 2018, Elhassan 2019, Connell 2021, Yulug 2023, and Berven 2026), any translational inference from these entries to clinical efficacy in the corresponding disease (mitochondrial bioenergetics failure, endothelial purine metabolism, sarcopenia, congenital malformation, Alzheimer's energy metabolism) is unsupported by the corpus as it stands and remains a gap rather than a finding. ## Conclusion For NAD+ metabolism 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 is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. 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 19 included sources on NAD+ Metabolism Effects across 7 outcome classes and 18 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 19 curated reference papers, the evidence base for NAD+ shows a context-dependent profile. Positive signals appear in: frailty. 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 mechanism vs clinical between Membrez 2024 and Pencina 2025 on frailty (severity 3/5), which defines the boundary condition future studies must test rather than smooth over. In animal/preclinical evidence, prior reviews in the corpus (Chen 2024) emphasize convergent signals on NAD+ Metabolism 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 | |---|---:|---:|---|---| | cardiometabolic | 0 | 3 | null, unclear | direct interventional hard-endpoint gap | | frailty | 0 | 1 | positive | direct interventional hard-endpoint gap | | muscle function | 0 | 2 | unclear | direct interventional hard-endpoint gap | | deficiency prevalence | 0 | 1 | null | direct interventional hard-endpoint gap | | contextual adjacent evidence | 0 | 9 | null | direct interventional hard-endpoint gap | | dosing and pharmacokinetics | 0 | 1 | null | direct interventional hard-endpoint gap | | safety and comorbidity | 1 | 1 | null, unclear | replication gap | ### Evidence-Gap Priority | Priority | Gap | Rationale | |---|---|---| | P1 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null, unclear | | P2 | frailty: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: positive | | P3 | muscle function: direct interventional hard-endpoint gap | 0 direct and 2 indirect sources; direction profile: unclear | | P4 | deficiency prevalence: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null | | P5 | contextual adjacent evidence: direct interventional hard-endpoint gap | 0 direct and 9 indirect sources; direction profile: null | ### Next-Study Design Recommendation The next high-yield study for NAD+ Metabolism Effects should target the **cardiometabolic** 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 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 cognition, menopause, acute-care, and these contexts remain hypothesis-generating unless represented by retained direct clinical endpoint evidence. ## Evidence Snapshot 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; Pencina 2025; tier=A1; directness=direct; endpoint=safety comorbidity; direction=unclear. - Chen 2024; tier=B1; directness=review; endpoint=cardiometabolic; direction=unclear; representative statistic=P = 0.06. - Berven 2026; tier=B2; directness=indirect; endpoint=dosing pharmacokinetics; direction=null; representative statistic=P = 0.07. - 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. - Conze 2019; tier=B2; directness=review; endpoint=safety comorbidity; direction=null; representative statistic=p ≤ 0.05. - Martens 2018; tier=B2; directness=indirect; endpoint=cardiometabolic; direction=unclear; representative statistic=P < 0.006. - Yulug 2023; tier=B2; directness=review; endpoint=contextual adjacent evidence; direction=null; representative statistic=P > 0.05. - Elhassan 2019; tier=B2; directness=indirect; endpoint=muscle function; direction=unclear; representative statistic=P < 0.001. - Ryu 2022; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.1. ### Source Classification Map Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement. - Oral MIB‐626 (β Nicotinamide Mononucleotide) Safely Raises Blood Nicotinamide Adenine Dinucleotide Levels in Hospitalized Patients With COVID‐19 and Acute Kidney Injury: A Randomized Controlled Trial: outcome=safety comorbidity; directness=direct; tier=A1; direction=unclear; claims=30. - Effects of Nicotinamide Mononucleotide on Glucose and Lipid Metabolism in Adults: A Systematic Review and Meta-analysis of Randomised Controlled Trials: outcome=cardiometabolic; directness=review; tier=B1; direction=unclear; claims=32. - The NAD-brain pharmacokinetic study of NAD augmentation in blood and brain using oral precursor supplementation: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=178. - 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. - Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults: outcome=safety comorbidity; directness=review; tier=B2; direction=null; claims=137. - 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. - Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=69. - 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. - Nicotinamide riboside and caffeine partially restore diminished NAD availability but not altered energy metabolism in Alzheimer's disease: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=28. - 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. - Double‐Pronged NAD Preservation: Delaying Cellular Senescence and Initiating Musculoskeletal Regeneration: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=16. - 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. - Maternal Circulatory NAD Precursor Levels and the Yolk Sac Determine NAD Deficiency‐Driven Congenital Malformation Risk: outcome=deficiency prevalence; directness=indirect; tier=B2; direction=null; claims=12. - NAD + and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=12. - Mitochondrial Resilience in Glaucoma: Targeting NAD + Metabolism and Oxidative Stress in Retinal Ganglion Cell Degeneration with Nicotinamide Riboside and Berberine: Preliminary Clinical Evidence: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=9. - NAD + Enhancer Nicotinamide Riboside Alters Extracellular Purine Metabolism in Human Endothelial Cells: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=5. - From Bench to Clinic: The 2024 FASEB Scientific Research Conference on NAD Metabolism and Signaling: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=1. ### 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 3 indirectness gap: Pencina 2025 vs Conze 2019; Pencina 2025 (direct, A1) vs Conze 2019 (review) on safety comorbidity — direct vs indirect must be kept separate - Severity 3 mechanism vs clinical: Membrez 2024 vs Pencina 2025; Pencina 2025 (direct, safety comorbidity) vs Membrez 2024 (indirect, frailty) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome - Severity 3 mechanism vs clinical: Chen 2024 vs Pencina 2025; Pencina 2025 (direct, safety comorbidity) vs Chen 2024 (review, cardiometabolic) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome - Severity 3 mechanism vs clinical: Bozon 2025 vs Pencina 2025; Pencina 2025 (direct, safety comorbidity) vs Bozon 2025 (indirect, deficiency prevalence) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome - Severity 3 mechanism vs clinical: Pencina 2025 vs Imai 2025; Pencina 2025 (direct, safety comorbidity) vs Imai 2025 (indirect, contextual other) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome - Severity 3 mechanism vs clinical: Pencina 2025 vs Christen 2026; Pencina 2025 (direct, safety comorbidity) vs Christen 2026 (indirect, contextual other) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome - Severity 3 mechanism vs clinical: Pencina 2025 vs Richard 2026; Pencina 2025 (direct, safety comorbidity) vs Richard 2026 (indirect, contextual other) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome - Severity 3 mechanism vs clinical: Pencina 2025 vs Visalli 2026; Pencina 2025 (direct, safety comorbidity) vs Visalli 2026 (indirect, contextual other) — cross-domain: clinical evidence on one outcome must not be fused with mechanistic / preclinical evidence on a different outcome Additional corpus sources included animal/preclinical evidence; additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Yu 2026, Harasim-Krawcewicz 2026. ## References - **Berven 2026.** _The NAD-brain pharmacokinetic study of NAD augmentation in blood and brain using oral precursor supplementation._ iScience, 2026. DOI: 10.1016/j.isci.2026.114764. PMID: 41858901. - **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. - **Conze 2019.** _Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults._ Scientific Reports, 2019. DOI: 10.1038/s41598-019-46120-z. PMID: 31278280. - **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. - **Yulug 2023.** _Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial._ Translational Neurodegeneration, 2023. DOI: 10.1186/s40035-023-00336-2. PMID: 36703196. - **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. - **Chen 2024.** _Effects of Nicotinamide Mononucleotide on Glucose and Lipid Metabolism in Adults: A Systematic Review and Meta-analysis of Randomised Controlled Trials._ Current Diabetes Reports, 2024. DOI: 10.1007/s11892-024-01557-z. 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