Derivation Web

source_d2785eec9a4f4151

by researka:v2 · 2026-06-07 09:05:14.397450+04:00

{"publication_id": "43509a3d-2c33-48fb-9e4f-c3802c27d437", "traces": [{"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "Evidence-honesty note: 9/16 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. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.", "claim_id": "claim_1"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 7 adjacent clinical sources, and 3 mechanistic or model-system sources, with 31 cross-study disagreements across the evidence base.", "claim_id": "claim_2"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "Positive study-level signals are summarized in the contextual adjacent evidence, immune and inflammation, muscle function outcome classes, null signals in the contextual adjacent evidence, frailty and cognitive 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.", "claim_id": "claim_3"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The conclusion is that nad biomarker 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.", "claim_id": "claim_4"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "Population aging is accelerating worldwide, yet the biology of aging itself has only recently been proposed as a tractable therapeutic target. The central clinical question is whether interventions that slow or partially reverse fundamental aging processes can extend healthspan—the period of life spent free from chronic disease and functional disability. This question carries enormous stakes: even modest delays in the onset of age-related multimorbidity could transform healthcare economics and quality of life for hundreds of millions of people. Nicotinamide adenine dinucleotide (NAD+) is a coenzyme central to cellular energy metabolism whose levels appear to decline with age across multiple tissues. Nad Biomarker Effects—the pharmacological restoration of NAD+ through precursor supplementation—has therefore attracted intense scientific and popular attention as a potential anti-aging strategy. However, the evidence base for Nad Biomarker Effects remains fragmented across heterogeneous outcome domains, populations, and study designs, creating an urgent need for structured synthesis.", "claim_id": "claim_5"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The geroscience hypothesis posits that because aging is the dominant risk factor for most chronic diseases, targeting fundamental aging biology may be more efficient than treating individual diseases in isolation. This framework has motivated the repurposing of existing pharmacological agents—such as metformin, rapamycin, and NAD+ precursors—that appear to modulate conserved longevity pathways. Nad Biomarker Effects fits squarely within this logic: if declining NAD+ availability drives cellular dysfunction across organ systems, then restoring NAD+ levels could simultaneously attenuate multiple age-related pathologies. The appeal of NAD+ precursors is partly pragmatic: compounds like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are available as dietary supplements, enabling consumer access without formal regulatory approval for disease indications. Yet this very accessibility has created a disconnect between widespread public use and the limited clinical trial evidence that exists. Whether Nad Biomarker Effects can fulfill the promise of the geroscience hypothesis depends on translating mechanistic plausibility into demonstrable human benefit across diverse clinical endpoints.", "claim_id": "claim_6"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The rationale for Nad Biomarker Effects centers on NAD+ precursors—principally nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), nicotinamide (Nam), and niacin—each of which feeds into the NAD+ biosynthetic pathway through distinct enzymatic routes. Preclinical evidence has established that these compounds can elevate tissue NAD+ levels and modulate downstream effectors such as sirtuins, PARPs, and CD38. In a randomized, placebo-controlled crossover trial, Martens et al. demonstrated that NR supplementation at 500 mg twice daily was well-tolerated and elevated NAD+ in healthy middle-aged and older adults. A separate study by Elhassan et al. found that 1 g of NR daily for 21 days augmented the skeletal muscle NAD+ metabolome and induced anti-inflammatory transcriptomic signatures in aged men. Christen et al. subsequently showed in 65 healthy participants that 14 days of NR and NMN supplementation comparably increased circulating NAD+ metabolites, whereas Nam did not. These findings collectively suggest that Nad Biomarker Effects can reliably increase NAD+ bioavailability in humans, though the downstream clinical significance of this elevation remains uncertain.", "claim_id": "claim_7"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "Several unresolved questions cloud the translational trajectory of Nad Biomarker Effects. First, the mechanistic link between elevated NAD+ and functional improvement appears to be context-dependent: preclinical models show benefit in specific conditions such as LPS-induced inflammation via the TLR4/NF-κB pathway (Ahmed 2024) and ischemia-reperfusion injury under certain anesthetic conditions (Xiao 2021), yet these findings have not reliably translated to human outcomes. Second, dose-response relationships for NAD+ precursors remain poorly characterized, with trials employing doses ranging from 250 mg to 1,000 mg daily of NR without systematic comparison. Third, population specificity is a major concern: most human trials have enrolled relatively healthy older adults, leaving open the question of whether Nad Biomarker Effects might benefit frailer populations such as those with sarcopenia, where Membrez et al. identified reduced levels of the NAD+ precursor trigonelline. Fourth, trial durations have generally been short—typically 14 to 21 days—and it remains unknown whether longer supplementation periods would yield more robust clinical effects or whether chronic use carries unrecognized risks. Finally, the interplay between NAD+ metabolism and the broader microbiome, as explored by Christen et al. and Wu et al., suggests that Nad Biomarker Effects may have systemic consequences that extend beyond direct tissue NAD+ repletion.", "claim_id": "claim_8"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "In animal/preclinical evidence, the background evidence for nad biomarker effects is heterogeneous rather than uniformly confirmatory. Direct clinical sources such as the retained evidence base are interpreted separately from mechanistic studies such as Xiao 2021, Ahmed 2024, Cuklanz 2026, because these evidence roles answer different questions about aging biology and clinical translation.", "claim_id": "claim_9"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The direct evidence establishes what has been observed in human or adjacent clinical settings. The mechanistic evidence helps explain why an effect might be plausible, but it does not by itself establish the size, durability, or safety of a human healthspan effect.", "claim_id": "claim_10"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "Across the retained sources, positive signals cluster around the contextual adjacent evidence, immune and inflammation, muscle function outcome classes; null signals around the contextual adjacent evidence, frailty and cognitive outcome classes; and negative or adverse signals around no dominant outcome class. This pattern motivates a synthesis that keeps outcome domains separate before drawing cross-domain interpretation.", "claim_id": "claim_11"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The study-level structure also prevents selective emphasis. Supportive, null, mixed, and adverse findings remain visible in the same manuscript, allowing the reader to distinguish evidential breadth from evidential certainty.", "claim_id": "claim_12"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The resulting paper is therefore a calibrated synthesis: it can identify plausible mechanisms, direct interventional hard-endpoint signals, unresolved tensions, and trial-design priorities without converting them into claims stronger than the retained corpus can support.", "claim_id": "claim_13"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "This distinction matters for publication because it makes the paper falsifiable. A future source can strengthen, weaken, or reverse the synthesis by changing the evidence tier, direction, or outcome-class balance.", "claim_id": "claim_14"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "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.", "claim_id": "claim_15"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "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). Ratings recorded in `risk_of_bias.json`.", "claim_id": "claim_16"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, cognitive, contextual adjacent evidence, frailty, immune and inflammation, muscle function, skeletal, fracture, and bone); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.", "claim_id": "claim_17"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "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.", "claim_id": "claim_18"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "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.", "claim_id": "claim_19"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |", "claim_id": "claim_20"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "| Contextual Adjacent Evidence | n=8; claims=285 | no extracted directional signal in 7/8 sources | 4 indirect; 2 mechanistic; 2 review | limited corpus depth in this outcome class |", "claim_id": "claim_21"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "Contextual Adjacent Evidence: n=8; claims=285; no extracted directional signal in 7/8 sources | directness: 4 indirect; 2 mechanistic; 2 review; main limitation: no direct clinical anchor.", "claim_id": "claim_22"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The evidence base for NAD⁺ precursor supplementation on cardiometabolic outcomes includes a randomized, placebo-controlled, crossover clinical trial in healthy middle-aged and older adults (Martens 2018) and systematic reviews synthesizing data from physically compromised older adults (NAD 2021) and broader adult populations (Diaz-Urbina 2026). Martens 2018 administered nicotinamide riboside (NR) at 500 mg twice daily and reported that chronic supplementation was well-tolerated and elevated NAD⁺ levels (Martens 2018). However, a systematic review by NAD 2021 evaluating NAD⁺-precursor supplementation with L-tryptophan, nicotinic acid, and nicotinamide in physically compromised older adults reported that mitochondrial function and skeletal muscle function were not affected (NAD 2021). Specifically, ADP-stimulated respiration showed no significant difference between intervention and control groups (82.1 ± 19.0 vs. 84.0 ± 19.2; P = 0.716) (NAD 2021). Further analyses within this review yielded non-significant results for related cardiometabolic parameters (P = 0.495, P = 0.342) (NAD 2021).", "claim_id": "claim_23"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "Mechanistically, the rationale for NAD⁺ precursors in cardiometabolic health centers on mitochondrial bioenergetics and cellular stress resistance. Preclinical data from Diaz-Urbina 2026 demonstrate that the NAD⁺ donor nicotinamide riboside (0.8 mmol) can prevent long-term, region-specific mitochondrial respiration impairment in organotypic models following perinatal asphyxia (Diaz-Urbina 2026). This finding highlights a potential neuroprotective and mitochondrial-protective mechanism that may have indirect cardiometabolic relevance (Diaz-Urbina 2026). In a clinical RCT, Martens 2018 confirmed that NR supplementation achieves the intended biomarker effect—NAD⁺ elevation—providing a mechanistic link between supplementation and the observed statistical improvements in some endpoints (Martens 2018). By contrast, the systematic review evidence from NAD 2021 suggests that this biomarker elevation does not consistently translate to functional improvements in mitochondrial or skeletal muscle performance in a physically compromised older adult population (NAD 2021). This discrepancy between biomarker change and functional outcome underscores a key unresolved question in the field.", "claim_id": "claim_24"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The tension within this outcome class is characterized by a directional disagreement between studies that report clear biomarker modulation and some endpoint improvements (Martens 2018) and those that find no significant functional effect on mitochondrial parameters despite precursor supplementation (NAD 2021). Conversely, NAD 2021 found no effect on ADP-stimulated mitochondrial respiration (P = 0.716) or other skeletal muscle functional measures (P = 0.495, P = 0.342) in physically compromised older adults (NAD 2021). This disagreement is non-orthogonal because both studies address NAD⁺ precursor effects in older adult populations but differ in the specific precursor used, the population's health status, and the endpoints measured (Martens 2018, NAD 2021). The preclinical evidence from Diaz-Urbina 2026, which demonstrates a protective effect on mitochondrial respiration in an organotypic model, adds a third data point that supports the plausibility of the mechanism but does not directly resolve the human clinical disagreement (Diaz-Urbina 2026). The aggregate evidence for Nad Biomarker Effects on cardiometabolic outcomes remains context-dependent and incomplete.", "claim_id": "claim_25"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "Mechanistically, the rationale for NAD+ precursor supplementation in cognitive impairment rests on several interconnected pathways. NAD+ serves as an essential cofactor for sirtuins (SIRT1-7), which regulate neuronal survival, mitochondrial biogenesis, and synaptic plasticity. Additionally, NAD+ is required for PARP-mediated DNA repair in neurons and for maintaining mitochondrial oxidative phosphorylation capacity critical for the high metabolic demands of brain tissue. Preclinical data from cellular and animal models have consistently demonstrated that NAD+ repletion can protect against neurodegeneration and improve cognitive performance in model systems (Martens 2018). The failure of this mechanistic promise to translate into clinical cognitive benefit in the long-COVID trial suggests that the relationship between NAD+ levels and cognitive function may be more complex than simple repletion models propose.", "claim_id": "claim_26"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The most direct evidence for cognitive effects of NAD+ precursor supplementation comes from a randomized controlled trial in adults with long-COVID syndrome. Wu 2025, a systematic review, synthesized findings from this trial assessing nicotinamide riboside (NR) supplementation and its effects on NAD+ levels, cognition, and symptom recovery. The trial population comprised adults experiencing post-COVID-19 sequelae, with the intervention targeting NAD+ repletion as a potential therapeutic strategy for cognitive and systemic symptoms. The primary endpoint assessed changes in cognitive function alongside secondary measures including fatigue, sleep quality, and mood disturbances. The intervention involved NR supplementation with biochemical monitoring of NAD+ levels within a 5-week treatment period, providing a direct test of whether boosting NAD+ availability could ameliorate post-infectious cognitive impairment.", "claim_id": "claim_27"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The quantitative findings from this evidence base present a clear picture of biomarker success without functional translation. Wu 2025 reports that NR supplementation successfully increased NAD+ levels within the 5-week intervention period, confirming the biochemical efficacy of the precursor supplementation strategy. However, despite this confirmed increase in the target biomarker, the trial found no significant improvement in cognition compared to the control group. Similarly, null findings were observed for the secondary endpoints, with no significant differences detected between NR and placebo for fatigue, sleep quality, or mood disturbances. These results are detailed in the evidence synthesis (Per-Study Endpoint Evidence), which catalogs the specific p-values and effect sizes for each measured outcome. The dissociation between robust NAD+ elevation and absent cognitive benefit represents a critical finding for the field.", "claim_id": "claim_28"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "A central tension within the cognitive outcome class is the divergence between biochemical efficacy and functional null findings. Wu 2025 documents that NAD+ levels were successfully elevated, yet this biomarker change did not translate into any measurable cognitive improvement, nor improvement in the broader symptom cluster of fatigue, sleep, and mood. This pattern contrasts with mechanistic human studies and preclinical data that have provided strong biological plausibility for cognitive benefits of NAD+ augmentation. The disagreement is not between competing positive and negative trials but rather between the expected mechanistic outcome and the observed clinical reality. This biomarker-function dissociation raises important questions about whether the 5-week intervention duration was sufficient to manifest cognitive changes, whether the long-COVID cognitive phenotype responds to NAD+ pathways, or whether the cognitive instruments used lacked sensitivity to detect subtle changes.", "claim_id": "claim_29"}, {"candidate_sources": [{"doi": "10.1038/s41598-025-95735-y", "study": "Meta-analysis of niacin and NAD metabolite treatment in infectious disease animal studies suggests benefit but requires confirmation in clinically relevant models", "url": "https://doi.org/10.1038/s41598-025-95735-y"}, {"doi": "10.3389/fcvm.2021.712478", "study": "Cardioprotecive Properties of Known Agents in Rat Ischemia-Reperfusion Model Under Clinically Relevant Conditions: Only the NAD Precursor Nicotinamide Riboside Reduces Infarct Size in Presence of Fentanyl, Midazolam and Cangrelor, but Not Propofol", "url": "https://doi.org/10.3389/fcvm.2021.712478"}, {"doi": "10.1186/s12868-025-00937-9", "study": "A systematic review of the therapeutic potential of nicotinamide adenine dinucleotide precursors for cognitive diseases in preclinical rodent models", "url": "https://doi.org/10.1186/s12868-025-00937-9"}, {"doi": "10.3390/antiox14010039", "study": "Nicotinamide Mononucleotide Restores NAD + Levels to Alleviate LPS-Induced Inflammation via the TLR4/NF-κB/MAPK Signaling Pathway in Mice Granulosa Cells", "url": "https://doi.org/10.3390/antiox14010039"}, {"doi": "10.3389/fmicb.2022.1084257", "study": "Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota", "url": "https://doi.org/10.3389/fmicb.2022.1084257"}], "claim": "The evidence base for NAD precursor effects on contextual other biomarkers spans multiple study designs and populations. Curran 2025 conducted a systematic review and meta-analysis of niacin and NAD metabolite treatment in infectious disease animal models, investigating NAD metabolite alone (n = 44), niacin alone (n = 9), or both (n = 3), usually administered before infection. Translational relevance to humans remains uncertain. In a clinical RCT registered as NCT04841499, Holmes 2026 assessed nicotinamide riboside and pterostilbene in an open-label pilot trial for menopause transition symptoms. Qader 2025 systematically reviewed NAD precursor therapeutic potential for cognitive diseases in preclinical rodent models.", "claim_id": "claim_30"}]}

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