{"publication_id":"49fee64b-298a-43fc-b595-36c94c769e98","content_hash":"sha256:82b30641b55126e85441d2cec5b44e2f1cd5859db2cd76287d0171b6714c01ef","nodes":[{"id":"49fee64b-298a-43fc-b595-36c94c769e98","type":"publication","title":"Adjacent Evidence Brief: Longevity vitamin — full paper"},{"id":"claim_1","type":"claim","text":"This paper synthesizes evidence on Longevity vitamin across 22 accepted source papers and 559 high-confidence extracted claims."},{"id":"claim_2","type":"claim","text":"The evidence profile contains no sources classified primarily as direct clinical evidence, 18 adjacent clinical sources, and 4 mechanistic or model-system sources, with 15 cross-study disagreements across the evidence base."},{"id":"claim_3","type":"claim","text":"Positive study-level signals are summarized in the cardiometabolic, mechanism and contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, immune and inflammation, deficiency prevalence 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."},{"id":"claim_4","type":"claim","text":"The conclusion is that Longevity vitamin 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."},{"id":"claim_5","type":"claim","text":"This manuscript is reported as a 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-ergothioneine-v06-DAILY-2026-06-21T11-33-30Z-R2`."},{"id":"claim_6","type":"claim","text":"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."},{"id":"claim_7","type":"claim","text":"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."},{"id":"claim_8","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, frailty, immune and inflammation, mechanism); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates."},{"id":"claim_9","type":"claim","text":"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."},{"id":"claim_10","type":"claim","text":"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."},{"id":"claim_11","type":"claim","text":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |"},{"id":"claim_12","type":"claim","text":"| Contextual Adjacent Evidence | n=12; claims=244 | no extracted directional signal in 11/12 sources | 12 indirect | limited corpus depth in this outcome class |"},{"id":"claim_13","type":"claim","text":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate."},{"id":"claim_14","type":"claim","text":"12 included sources were assigned to this outcome class. Directional coding: null=11, positive=1. Directness coding: indirect=12."},{"id":"claim_15","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=1, positive=2. Directness coding: indirect=2, review=1."},{"id":"claim_16","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: indirect=2."},{"id":"claim_17","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=2. Directness coding: mechanistic=2."},{"id":"claim_18","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=1, positive=1. Directness coding: mechanistic=2."},{"id":"claim_19","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_20","type":"claim","text":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim."},{"id":"claim_21","type":"claim","text":"In animal/preclinical evidence, a defining limitation of this synthesis is the near-total absence of long-term, hard-outcome randomized trials of ergothioneine supplementation in non-diabetic older adults. No source in the curated corpus represents a mortality, incident-frailty, or incident-dementia randomized trial in humans, so any translation of the Katsube 2024 mechanism-of-action findings into a clinical anti-aging claim rests on an inferential chain that the present evidence cannot close. The headline synthesis therefore describes a context-dependent profile (positive on cardiometabolic and mechanism, null or mixed on immune-inflammation and contextual endpoints) but cannot anchor that profile to a human efficacy benchmark."},{"id":"claim_22","type":"claim","text":"Several clinically relevant outcome domains are touched by only a single source, which prevents any within-corpus replication of the finding. Where only one source speaks to an outcome, the synthesis cannot distinguish a true biological effect from a study-specific artifact, and any conclusion stated at the outcome level carries single-trial generalization risk that the evidence synthesis's per-domain risk-of-bias columns cannot adjudicate."},{"id":"claim_23","type":"claim","text":"The population evidence in the corpus is narrow, and that narrowness bounds the external validity of every cross-cutting statement. Non-diabetic community-dwelling adults, women, and non-Asian populations are under-represented or absent, so the dose, dietary, and serum-level findings cannot be transported outside the studied demographics."},{"id":"claim_24","type":"claim","text":"Finally, the corpus contains a mechanism-to-clinic gap: claims with direct human-health relevance are currently backed only by mechanistic or preclinical evidence, while the sources coded to the most clinically actionable endpoints are non-interventional. The dementia-risk association in Meng 2025 is observational and cannot establish that raising serum ergothioneine would lower dementia incidence; the AMD signal in Cheah 2026 is likewise observational; the oxaliplatin-induced peripheral neuropathy attenuation in Yamada 2025 (P = 0.011) is a murine chemotherapy-neuropathy model; and the spinal-muscular-atrophy pup phenotype work in Cadile 2025 is preclinical. Five sources (Liu 2026, Wang 2025, Yu 2020, Fu 2025, Villalain 2025) describe bioprocess engineering, bibliometric mapping, or membrane biophysics rather than clinical outcomes, and they are retained only as boundary context; they do not extend the clinical-evidence map. Until a human RCT closes the mechanism-to-clinic loop, the synthesis can describe plausibility but cannot quantify clinical benefit."},{"id":"claim_25","type":"claim","text":"The strongest supportive evidence is the Katsube 2024 preclinical lifespan and frailty signal, whereas the strongest counter-evidence is the absence of direct human randomized trials and the divergent mechanistic readouts between Katsube 2024 (positive) and Roda 2023 (null on mechanism, P < 0.01 to P < 0.05). Observational dose-response in older adults — Meng 2025 reporting an inverse association between serum ergothioneine and dementia risk, and Cheah 2026 reporting lower serum ergothioneine in age-related macular degeneration — strengthens the hypothesis without supplying interventional confirmation. Pending such trials, current evidence supports a hypothesis that ergothioneine may contribute to healthy aging but does not yet justify marketing a proven standalone anti-aging intervention; dietary patterns that elevate ergothioneine — including mushroom intake — retain their general-health support independent of any anti-aging claim."},{"id":"claim_26","type":"claim","text":"Additional corpus sources included animal/preclinical evidence; the most load-bearing caveat is the gap between mechanistic plausibility and clinical RCT confirmation: the cross-study disagreements catalogued in the synthesis span cardiometabolic, mechanism, and contextual outcome classes, and several of the most-cited entries (Liu 2026, Wang 2025, Yu 2020, Fu 2025, Villalain 2025) are bioprocess or bibliometric in nature and can be interpreted as boundary or methods context rather than efficacy evidence. Off-label geroprotective use of ergothioneine supplements is not supported by the current evidence base and should remain pending further trials; the absence of a single high-confidence human efficacy trial — combined with heterogeneous doses (e. For example, 4–5 mg/kg/day in Katsube 2024 versus 100 mg/kg/day in Li 2026) and heterogeneous populations — means the synthesis cannot yet set dose, duration, or target-population boundaries for clinical recommendation. In practice, clinicians may reasonably monitor serum ergothioneine as a candidate biomarker of dietary and oxidative-stress status, and counsel patients that mushroom-rich dietary patterns remain sensible on general-health grounds, but they should not represent ergothioneine supplementation as a validated anti-aging therapy. The field's most tractable near-term contribution is therefore infrastructural — standardized serum assays, consensus dose-ranging, and adjudicated endpoints — rather than therapeutic, so that a future RCT can resolve whether the mechanistic and observational signals translate into measurable clinical benefit."},{"id":"claim_27","type":"claim","text":"This synthesis maps 22 included sources on Ergothioneine across 6 outcome classes and 15 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."},{"id":"claim_28","type":"claim","text":"Across 22 curated reference papers, the evidence base for ergothioneine shows a context-dependent profile. Positive signals appear in: cardiometabolic, mechanism. Null findings dominate: contextual other, immune inflammation. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The ergothioneine 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."},{"id":"claim_29","type":"claim","text":"In animal/preclinical evidence, the strongest unresolved contrast is the null vs positive between Katsube 2024 and Roda 2023 on mechanism (severity 4/5), which defines the boundary condition future studies must test rather than smooth over."},{"id":"claim_30","type":"claim","text":"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."},{"id":"source_1","type":"source","study":"Ergothioneine promotes longevity and healthy aging in male mice","year":2024,"doi":"10.1007/s11357-024-01111-5","url":"https://doi.org/10.1007/s11357-024-01111-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_2","type":"source","study":"Ergothioneine-rich water extracts of Hericium erinaceus HE-17 alleviate Alzheimer’s disease in mice by regulating oxidative stress, inflammation, and the gut microenvironment","year":2026,"doi":"10.3389/fnut.2026.1835714","url":"https://doi.org/10.3389/fnut.2026.1835714","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_3","type":"source","study":"Ergothioneine Ameliorates Alcoholic Fatty Liver Disease: A Dual Strategy of Accelerated Ethanol Elimination and Reducing Oxidative Stress","year":2026,"doi":"10.1002/jbt.70899","url":"https://doi.org/10.1002/jbt.70899","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_4","type":"source","study":"Ergothioneine attenuates whole-abdominal irradiation-induced multi-organ injury via the gut-heart-brain axis by modulating calcium voltage-gated channel subunit alpha1 C (Cacna1c) expression","year":2026,"doi":"10.1186/s43556-025-00402-3","url":"https://doi.org/10.1186/s43556-025-00402-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_5","type":"source","study":"The Current Situation and Future Trends of Ergothioneine in Biology and Medical Research: A Bibliometric Analysis","year":2025,"doi":"10.2147/JMDH.S547548","url":"https://doi.org/10.2147/JMDH.S547548","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_6","type":"source","study":"Engineering Escherichia coli for Ergothioneine Production via Metabolic Engineering and Fermentation Optimization","year":2026,"doi":"10.3390/microorganisms14051088","url":"https://doi.org/10.3390/microorganisms14051088","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_7","type":"source","study":"Ergothioneine supplementation improves pup phenotype and survival in a murine model of spinal muscular atrophy","year":2025,"doi":"10.1002/1873-3468.70136","url":"https://doi.org/10.1002/1873-3468.70136","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_8","type":"source","study":"Successful biosynthesis of natural antioxidant ergothioneine in Saccharomyces cerevisiae required only two genes from Grifola frondosa","year":2020,"doi":"10.1186/s12934-020-01421-1","url":"https://doi.org/10.1186/s12934-020-01421-1","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_9","type":"source","study":"Ergothioneine rescues obesity-induced testicular dysfunction via dual restoration of steroidogenesis and mitochondrial redox homeostasis","year":2026,"doi":"10.1016/j.redox.2026.104090","url":"https://doi.org/10.1016/j.redox.2026.104090","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_10","type":"source","study":"Enhanced production of ergothioneine in Aspergillus oryzae","year":2025,"doi":"10.1007/s00253-025-13505-2","url":"https://doi.org/10.1007/s00253-025-13505-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_11","type":"source","study":"Ergothioneine as a potential protective agent against macular degeneration and other eye disorders","year":2026,"doi":"10.1038/s41598-026-48438-x","url":"https://doi.org/10.1038/s41598-026-48438-x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_12","type":"source","study":"Serum ergothioneine and risk of dementia in a general older Japanese population: the Hisayama Study","year":2025,"doi":"10.1111/pcn.13893","url":"https://doi.org/10.1111/pcn.13893","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_13","type":"source","study":"Ergothioneine Attenuates Oxaliplatin-Induced Peripheral Neuropathy Without Compromising Antitumor Efficacy","year":2025,"doi":"10.3390/ijms262110263","url":"https://doi.org/10.3390/ijms262110263","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_14","type":"source","study":"The Association Between Serum Ergothioneine Concentration and Japanese Dietary Habits: The Third Survey of the ROAD Study","year":2025,"doi":"10.3390/nu17030517","url":"https://doi.org/10.3390/nu17030517","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_15","type":"source","study":"Searching for a Longevity Food, We Bump into Hericium erinaceus Primordium Rich in Ergothioneine: The “Longevity Vitamin” Improves Locomotor Performances during Aging","year":2022,"doi":"10.3390/nu14061177","url":"https://doi.org/10.3390/nu14061177","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_16","type":"source","study":"Cognitive Healthy Aging in Mice: Boosting Memory by an Ergothioneine-Rich Hericium erinaceus Primordium Extract","year":2023,"doi":"10.3390/biology12020196","url":"https://doi.org/10.3390/biology12020196","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_17","type":"source","study":"Uncovering the Potential Mechanisms of Ergothioneine in Neuroinflammation Through Network Pharmacology, Molecular Docking, Molecular Dynamics Simulation, and In Vitro Validation","year":2026,"doi":"10.3390/ijms27052179","url":"https://doi.org/10.3390/ijms27052179","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_18","type":"source","study":"Advances and prospects of ergothioneine in the treatment of cognitive frailty","year":2025,"doi":"10.1080/07853890.2025.2555742","url":"https://doi.org/10.1080/07853890.2025.2555742","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_19","type":"source","study":"Ergothioneine Thione Spontaneously Binds to and Detaches from the Membrane Interphase","year":2025,"doi":"10.3390/membranes15110328","url":"https://doi.org/10.3390/membranes15110328","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_20","type":"source","study":"Potential Protection Against Parkinson’s Disease by Ergothioneine—Nature’s Multifactorial Neuroprotectant","year":2026,"doi":"10.3390/antiox15040519","url":"https://doi.org/10.3390/antiox15040519","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"id":"source_21","type":"source","study":"Anserine, Balenine, and Ergothioneine: Impact of Histidine-Containing Compounds on Exercise Performance—A Narrative 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slices.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_24","type":"source","study":"**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.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_25","type":"source","study":"**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.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_26","type":"source","study":"**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.","year":null,"doi":null,"url":null,"population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_27","type":"source","study":"Perera 2006","year":null,"doi":"10.1111/j.1532-5415.2006.00701.x","url":"https://doi.org/10.1111/j.1532-5415.2006.00701.x","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_28","type":"source","study":"Cruz-Jentoft 2019","year":null,"doi":"10.1093/ageing/afy169","url":"https://doi.org/10.1093/ageing/afy169","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"id":"source_29","type":"source","study":"Ioannidis 2005","year":null,"doi":"10.1371/journal.pmed.0020124","url":"https://doi.org/10.1371/journal.pmed.0020124","population":"not 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