{"publication_id":"494277b2-426f-4cdc-99b0-561816dabda5","content_hash":"sha256:8a9122035f2b315dd520fcfde90ca2d0a33c24fed193759bcb6cf9a95050f328","nodes":[{"id":"494277b2-426f-4cdc-99b0-561816dabda5","type":"publication","title":"Research Synthesis: Alpha Ketoglutarate Akg — full paper"},{"id":"claim_1","type":"claim","text":"This synthesis tests the thesis that evidence for Alpha-ketoglutarate is context-dependent, separating outcome-specific signals from broader claims and identifying the evidence gaps that should bound interpretation."},{"id":"claim_2","type":"claim","text":"This evidence synthesis was conducted using an AI-assisted structured review of 51 curated reference papers, applying transparent inclusion criteria and documenting the analytical audit trail for reproducibility."},{"id":"claim_3","type":"claim","text":"The cross-study disagreement map reveals 476 non-orthogonal pairwise comparisons across outcome classes, with frequent null-versus-positive disagreements (severity 3–4) that preclude consensus on efficacy for any single human health endpoint."},{"id":"claim_4","type":"claim","text":"Therefore, while preclinical mechanistic data on AKG's effects on oxidative stress, epigenetic regulation, and metabolic pathways are biologically plausible, the translational relevance to human health remains unestablished, and claims of clinical anti-aging or therapeutic benefit are not supported by the current evidence base."},{"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-alpha_ketoglutarate_akg-v06-DAILY-2026-05-31T17-45-06Z`."},{"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. Source verification in the public bundle is limited to reference-level metadata; reported 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."},{"id":"claim_7","type":"claim","text":"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`."},{"id":"claim_8","type":"claim","text":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, dosing and pharmacokinetics, immune, immune and inflammation, longevity, mortality and survival, safety and comorbidity, 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."},{"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."},{"id":"claim_11","type":"claim","text":"| Contextual Adjacent Evidence | n=30; claims=1738 | null signal in 26/30 sources | 24 indirect; 5 mechanistic; 1 review | limited corpus depth in this outcome class |"},{"id":"claim_12","type":"claim","text":"| Dosing and Pharmacokinetics | n=9; claims=314 | null signal in 8/9 sources | 8 indirect; 1 review | limited corpus depth in this outcome class |"},{"id":"claim_13","type":"claim","text":"| Cardiometabolic | n=3; claims=162 | null signal in 3/3 sources | 1 indirect; 2 mechanistic | limited corpus depth in this outcome class |"},{"id":"claim_14","type":"claim","text":"| Skeletal, Fracture, and Bone | n=3; claims=137 | null signal in 2/3 sources | 3 indirect | limited corpus depth in this outcome class |"},{"id":"claim_15","type":"claim","text":"| Immune | n=1; claims=29 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |"},{"id":"claim_16","type":"claim","text":"| Longevity | n=1; claims=2 | null signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating |"},{"id":"claim_17","type":"claim","text":"| Mortality and Survival | n=1; claims=44 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |"},{"id":"claim_18","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_19","type":"claim","text":"30 included sources were assigned to this outcome class. Directional coding: mixed=1, null=26, positive=1, unclear=2. Directness coding: indirect=24, mechanistic=5, review=1."},{"id":"claim_20","type":"claim","text":"9 included sources were assigned to this outcome class. Directional coding: null=8, unclear=1. Directness coding: indirect=8, review=1."},{"id":"claim_21","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=1, mechanistic=2."},{"id":"claim_22","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=2, unclear=1. Directness coding: indirect=3."},{"id":"claim_23","type":"claim","text":"2 included sources were assigned to this outcome class. Directional coding: null=1, positive=1. Directness coding: mechanistic=2."},{"id":"claim_24","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_25","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1."},{"id":"claim_26","type":"claim","text":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1."},{"id":"claim_27","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_28","type":"claim","text":"The curated corpus is dominated by preclinical and mechanistic work, with the overwhelming majority of included studies conducted in cell lines (e.g., Greilberger 2023; Greilberger 2022), rodent models (e.g., An 2021; Takemura 2025; Huang 2025; Iniguez 2022; Iwaniak 2022; Qiu 2025), agricultural species such as pigs (Chen 2019; Sun 2025b; Sun 2025c; Tian 2023), carp (Wu 2021; Wu 2022), laying hens (Tomaszewska 2020; Tomaszewska 2021), and invertebrate or yeast organisms (Su 2019; Alpha-ketoglutarate 2018; Bayliak 2017; Burdyliuk 2017). No large-scale, long-duration randomized controlled trial assessing hard clinical endpoints — such as all-cause mortality, incident cardiovascular events, or cancer incidence — in human adults is represented. Consequently, the headline synthesis cannot draw conclusions about AKG's efficacy for the clinical endpoints most relevant to translational decision-making, and the apparent anti-aging signal described by Demidenko 2021 rests on retrospective DNA methylation data rather than prospective hard-outcome evidence."},{"id":"claim_29","type":"claim","text":"Several outcome domains within this synthesis rest on findings from a single study, meaning that replication cannot be assessed within the corpus. For example, the cardiometabolic signal in diabetic mouse models comes solely from Takemura 2025 and Sun 2025, with no independent corroboration from human trials measuring glycemic endpoints such as HbA1c against the ADA 2024 target of 7%. Similarly, the longevity signal is supported only by Su 2019 in Drosophila and Alpha-ketoglutarate 2018, also in Drosophila, with no mammalian lifespan data in the corpus. Single-trial outcomes carry heightened risk of both type I error and idiosyncratic model effects, and the synthesis accordingly assigns low confidence to claims in these domains until corroborating evidence emerges."},{"id":"claim_30","type":"claim","text":"Population external validity is severely constrained. The evidence consists of studies (Greilberger 2021; Greilberger 2021b; Greilberger 2022; Greilberger 2023; Dhat 2023) and agricultural-animal feeding trials that used doses — such as 10 g/kg AKG in piglet diets (Tian 2023), 1.0% AKG in laying-hen feed (Tomaszewska 2020), or 2% AKG in mouse drinking water (An 2021) — with no straightforward equivalence to human oral supplementation. No study enrolled older adults at risk of sarcopenia, where grip-strength cutoffs of 27 kg for men or 16 kg for women (Cruz-Jentoft 2019) might provide a relevant clinical frame. Diabetic populations are represented only by rodent STZ or high-fat-diet models (Takemura 2025; Dhat 2023; Qiu 2025), not by humans meeting the ADA 2024 HbA1c threshold of 7%. Ethnic diversity, sex-specific effects, and comorbidity burden in human cohorts are entirely unreported. The corpus therefore cannot inform AKG's safety or efficacy profile for the aging, frail, or chronically ill human populations most likely to seek supplementation."},{"id":"source_1","type":"source","study":"Greilberger 2023","year":2023,"doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410","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":"review-level"},{"id":"source_2","type":"source","study":"Greilberger 2022","year":2022,"doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034","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":"review-level"},{"id":"source_3","type":"source","study":"Qiu 2025","year":2025,"doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473","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":"review-level"},{"id":"source_4","type":"source","study":"Greilberger 2021","year":2021,"doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804","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":"review-level"},{"id":"source_5","type":"source","study":"Wu 2022","year":2022,"doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not 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2021","year":2021,"doi":"10.3389/fimmu.2021.690234","url":"https://doi.org/10.3389/fimmu.2021.690234","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":"review-level"},{"id":"source_9","type":"source","study":"Iwaniak 2022","year":2022,"doi":"10.3390/nu14102062","url":"https://doi.org/10.3390/nu14102062","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":"review-level"},{"id":"source_10","type":"source","study":"Takemura 2025","year":2025,"doi":"10.1017/jns.2025.10059","url":"https://doi.org/10.1017/jns.2025.10059","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not 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2023","year":2023,"doi":"10.1186/s13072-023-00489-4","url":"https://doi.org/10.1186/s13072-023-00489-4","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":"review-level"},{"id":"source_14","type":"source","study":"Tian 2023","year":2023,"doi":"10.3390/ani13040569","url":"https://doi.org/10.3390/ani13040569","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":"review-level"},{"id":"source_15","type":"source","study":"Khamineh 2026","year":2026,"doi":"10.3390/cells15030281","url":"https://doi.org/10.3390/cells15030281","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not 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2022","year":2022,"doi":"10.1186/s12967-022-03659-2","url":"https://doi.org/10.1186/s12967-022-03659-2","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":"review-level"},{"id":"source_19","type":"source","study":"Sandalova 2023","year":2023,"doi":"10.1007/s11357-023-00813-6","url":"https://doi.org/10.1007/s11357-023-00813-6","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":"review-level"},{"id":"source_20","type":"source","study":"Tian 2023b","year":2023,"doi":"10.3390/nu15030701","url":"https://doi.org/10.3390/nu15030701","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not 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