{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"494277b2-426f-4cdc-99b0-561816dabda5","name":"Research Synthesis: Alpha Ketoglutarate Akg — full paper","doi":"10.17605/OSF.IO/EJKFY","doi_status":"minted","osf_url":"https://osf.io/ejkfy/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_cf8a45076b5b4261/chain","content_hash":"sha256:8a9122035f2b315dd520fcfde90ca2d0a33c24fed193759bcb6cf9a95050f328","provenance_passport":{"publication_id":"494277b2-426f-4cdc-99b0-561816dabda5","submission_id":"f6be1577-da7d-422e-946a-563c25efa9a0","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:8a9122035f2b315dd520fcfde90ca2d0a33c24fed193759bcb6cf9a95050f328","persistent_identifiers":{"doi":"10.17605/OSF.IO/EJKFY","osf_url":"https://osf.io/ejkfy/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":null,"provenance":{"dw_artifact_id":"claim_cf8a45076b5b4261","dw_chain_url":"https://provenance.researka.org/artifacts/claim_cf8a45076b5b4261/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"494277b2-426f-4cdc-99b0-561816dabda5","object_type":"publication","parent_object_id":"f6be1577-da7d-422e-946a-563c25efa9a0","title":"Research Synthesis: Alpha Ketoglutarate Akg — full paper","body_markdown":"# Research Synthesis: Alpha Ketoglutarate Akg — full paper\n\n## Abstract\n\nThis 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.\n\nAlpha-ketoglutarate (AKG), a central Krebs cycle intermediate and a cofactor for dioxygenases that regulate epigenetic marks, has drawn increasing attention as a potential modulator of aging, metabolic, and disease-related pathways.\n\nThis 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.\n\nThe included literature spans preclinical, animal, and models, but is overwhelmingly preclinical or mechanistic in design, with only a single registered randomized controlled trial protocol identified (Sandalova 2023).\n\nTranslational relevance to humans remains uncertain.\n\nThe 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.\n\nTherefore, 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.\n\n## Methods\n\n### Review type and protocol\nThis 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`.\n\n### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-05-31.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n- `alpha-ketoglutarate AND aging AND human`\n- `calcium alpha-ketoglutarate AND biological age`\n- `AKG AND longevity AND trial`\n- `alpha ketoglutarate AND epigenetic clock`\n- `Ca-AKG AND safety AND human`\n\n### Eligibility criteria\n- Sources whose primary content addresses alpha ketoglutarate akg.\n- Sources with extractable quantitative or qualitative findings.\n- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.\n- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).\n\n### Selection of sources of evidence\nThe synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 184 records in the receipt-candidate union, 64 were classified as source candidates and 51 were admitted as traceable synthesis sources. No additional records were excluded after final source admission.\n\n### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 184 |\n| Classified source candidates | 64 |\n| No extractable claims | 36 |\n| None-only claim binding | 3 |\n| Partial/none-only claim binding | 58 |\n| Partial-only candidates | 15 |\n| Strict high-confidence sources | 8 |\n| Admitted final sources | 51 |\n\n### Exclusion reasons\n- Non-traceable findings (claim could not be linked to source text): 0 records.\n- Wrong population / off-topic sources excluded at screening.\n- Duplicate records deduplicated by DOI / PMID before screening.\n\n### Data items\nThe 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.\n\n### Risk-of-bias appraisal\nPer-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`.\n\n### Synthesis approach\nEvidence-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.\n\n### AI-use disclosure\nSource 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.\n\n### Accountability\nAccountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. This run is certified under the `researka_agent_certified` accountability model — trust is machine-verifiable rather than dependent on author signoff.\n\n## Results\n\n**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence.\n\n| Outcome class | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| 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 |\n| Dosing and Pharmacokinetics | n=9; claims=314 | null signal in 8/9 sources | 8 indirect; 1 review | limited corpus depth in this outcome class |\n| Cardiometabolic | n=3; claims=162 | null signal in 3/3 sources | 1 indirect; 2 mechanistic | limited corpus depth in this outcome class |\n| Skeletal, Fracture, and Bone | n=3; claims=137 | null signal in 2/3 sources | 3 indirect | limited corpus depth in this outcome class |\n| Safety and Comorbidity | n=2; claims=215 | positive signal in 1/2 sources | 2 mechanistic | limited corpus depth in this outcome class |\n| Immune | n=1; claims=29 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Immune and Inflammation | n=1; claims=155 | unclear signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n| Longevity | n=1; claims=2 | null signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating |\n| Mortality and Survival | n=1; claims=44 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n\nThis evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.\n\n### Contextual Adjacent Evidence Outcomes\n\n30 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.\n\n### Dosing Pharmacokinetics Outcomes\n\n9 included sources were assigned to this outcome class. Directional coding: null=8, unclear=1. Directness coding: indirect=8, review=1.\n\n### Cardiometabolic Outcomes\n\n3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=1, mechanistic=2.\n\n### Skeletal Fracture Bone Outcomes\n\n3 included sources were assigned to this outcome class. Directional coding: null=2, unclear=1. Directness coding: indirect=3.\n\n### Safety Comorbidity Outcomes\n\n2 included sources were assigned to this outcome class. Directional coding: null=1, positive=1. Directness coding: mechanistic=2.\n\n### Immune Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\n### Immune Inflammation Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: unclear=1. Directness coding: indirect=1.\n\n### Longevity Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1.\n\n### Mortality Survival Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.\n\n## Limitations\n\n**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.\n\nThe 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.\n\nSeveral 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.\n\nPopulation 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.\n\nCritical clinical endpoints were not measured in this corpus. The sole mortality-survival class entry (Huang 2025) reports flap survival in a murine skin-flap angiogenesis model, not human mortality. Additionally, the mechanism-to-clinic gap is substantial: most positive signals arise from mechanistic pathways — mTOR inhibition and AMPK activation in Drosophila (Su 2019), PI3K/Akt/HIF-1α-mediated angiogenesis (Huang 2025), NF-κB suppression (He 2017; Tian 2023b), and epigenetic histone demethylation (Sekita 2021; Hasegawa 2026) — yet no clinical trial in the corpus has tested whether these mechanistic effects translate to measurable patient-relevant benefit.\n\n## Conclusion\n\nFor alpha ketoglutarate akg, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence.\n\nThe strongest interpretation is that positive study-level signals are summarized in the safety and comorbidity and contextual adjacent evidence outcome classes, null signals in the contextual adjacent evidence, dosing and pharmacokinetics and cardiometabolic outcome classes, and negative signals in no dominant outcome class. That profile supports further targeted research and careful hypothesis refinement, not unqualified clinical or public-health claims.\n\nPending further trials, the intervention should not be used off-label for geroprotection or anti-aging purposes outside clinical-trial settings given current evidence. The safer translation path is a registered trial that specifies the endpoint layer in advance, pairs dosing with monitoring for metabolic and immune safety, and reports null or adverse signals with the same visibility as favorable results.\n\nIn animal/preclinical evidence, future work should prioritize studies that connect mechanistic studies (Qiu 2025, An 2021, Iwaniak 2022) to direct clinical outcomes represented by the retained evidence base. Until that bridge is stronger, alpha ketoglutarate akg remains a promising but bounded geroscience case whose most useful contribution is to define the next trial rather than to justify current clinical adoption.\n\nThe decisive unresolved question is not whether the intervention can move selected biomarkers or pathway markers, but whether those changes improve durable human function without offsetting harm, adherence failure, or loss in another clinically relevant domain. That question should set the bar for future claims, clinical translation, future study design, and any public recommendation.\n\n## What This Synthesis Adds\n\nThis synthesis maps 51 included sources on Alpha-ketoglutarate across 9 outcome classes and 476 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.\n\nAcross 51 curated reference papers, the evidence base for Alpha-ketoglutarate shows a context-dependent profile. Positive signals appear in: safety comorbidity, contextual other. Null findings dominate: contextual other, dosing pharmacokinetics. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Alpha-ketoglutarate 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.\n\nAdditional corpus sources included animal/preclinical evidence; the strongest unresolved contrast is the disagreement between Dhat 2023 and Qiu 2025 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.\n\nThis 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.\n\n### Boundary-Condition Matrix\n\n| Outcome class | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| longevity | 0 | 1 | null | direct clinical gap |\n| cardiometabolic | 0 | 3 | null | direct clinical gap |\n| immune | 0 | 1 | null | direct clinical gap |\n| contextual adjacent evidence | 0 | 30 | mixed, null, positive, unclear | conflict-resolution gap |\n| dosing and pharmacokinetics | 0 | 9 | null, unclear | direct clinical gap |\n| safety and comorbidity | 0 | 2 | null, positive | direct clinical gap |\n| skeletal, fracture, and bone | 0 | 3 | null, unclear | direct clinical gap |\n| immune and inflammation | 0 | 1 | unclear | direct clinical gap |\n| mortality and survival | 0 | 1 | null | direct clinical gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | longevity: direct clinical gap | 0 direct and 1 indirect source; direction profile: null |\n| P2 | cardiometabolic: direct clinical gap | 0 direct and 3 indirect sources; direction profile: null |\n| P3 | immune: direct clinical gap | 0 direct and 1 indirect source; direction profile: null |\n| P4 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 30 indirect sources; direction profile: mixed, null, positive, unclear |\n| P5 | dosing and pharmacokinetics: direct clinical gap | 0 direct and 9 indirect sources; direction profile: null, unclear |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Alpha-ketoglutarate should target the **longevity** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction.\n\n## Evidence Snapshot\n\nThe manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.\n\n### Load-Bearing Included Studies\n\nAdditional corpus sources included animal/preclinical evidence; - Greilberger 2023; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual other; direction=null; representative statistic=P < 0.01.\n- Greilberger 2022; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual other; direction=null; representative statistic=P < 0.01.\n- Greilberger 2021; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual other; direction=null; representative statistic=P < 0.01.\n- Wu 2022; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=immune inflammation; direction=unclear; representative statistic=P < 0.05.\n- Tomaszewska 2020; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=skeletal fracture bone; direction=null.\n- Wu 2021; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=dosing pharmacokinetics; direction=unclear; representative statistic=P < 0.05.\n- Dhat 2023; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual other; direction=null; representative statistic=P < 0.0001.\n- Tian 2023; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=dosing pharmacokinetics; direction=null; representative statistic=P < 0.05.\n- Chen 2018; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual other; direction=unclear; representative statistic=P = 0.027.\n- Chen 2019; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=dosing pharmacokinetics; direction=null; representative statistic=P < 0.05.\n\n### Load-Bearing Tensions\n\nAdditional corpus sources included animal/preclinical evidence; - Severity 4 disagreement: Dhat 2023 vs Qiu 2025; Dhat 2023 (null) vs Qiu 2025 (mixed) on contextual other\n- Severity 4 disagreement: Greilberger 2023 vs Qiu 2025; Greilberger 2023 (null) vs Qiu 2025 (mixed) on contextual other\n- Severity 4 disagreement: Lamichhane 2023 vs Qiu 2025; Lamichhane 2023 (null) vs Qiu 2025 (mixed) on contextual other\n- Severity 4 disagreement: Mohammadi 2025 vs Qiu 2025; Mohammadi 2025 (null) vs Qiu 2025 (mixed) on contextual other\n- Severity 4 disagreement: Qiu 2025 vs Khamineh 2026; Qiu 2025 (mixed) vs Khamineh 2026 (null) on contextual other\n- Severity 4 disagreement: Qiu 2025 vs Hasegawa 2026; Qiu 2025 (mixed) vs Hasegawa 2026 (null) on contextual other\n- Severity 4 disagreement: Qiu 2025 vs Singh 2013; Qiu 2025 (mixed) vs Singh 2013 (null) on contextual other\n- Severity 4 disagreement: Qiu 2025 vs Stuart 2014; Qiu 2025 (mixed) vs Stuart 2014 (null) on contextual other\n\nAdditional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Kaawaj 2020, Wang 2020, Showalter 2017, Liu 2022, Dilimulati 2026, Ruiz 2023, Cai 2016, Csaban 2021, Gai 2022, Mizerska-Kowalska 2022, Lin 2015, Wu 2016, Zhang 2020, Doroftei 2024, Fiehn 2016, Tinetti 1988.\n## References\n\n- **Greilberger 2023.** _Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF._ Current Issues in Molecular Biology, 2023. DOI: 10.3390/cimb45080410. PMID: 37623229.\n- **Greilberger 2022.** _Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways._ International Journal of Molecular Sciences, 2022. DOI: 10.3390/ijms23169034. PMID: 36012295.\n- **Qiu 2025.** _Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice._ Frontiers in Pharmacology, 2025. DOI: 10.3389/fphar.2025.1656473. PMID: 41181587.\n- **Greilberger 2021.** _Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells._ Antioxidants, 2021. DOI: 10.3390/antiox10111804. PMID: 34829675.\n- **Wu 2022.** _Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )._ Frontiers in Immunology, 2022. DOI: 10.3389/fimmu.2022.915657. PMID: 35720284.\n- **An 2021.** _Alpha-ketoglutarate ameliorates pressure overload-induced chronic cardiac dysfunction in mice._ Redox Biology, 2021. DOI: 10.1016/j.redox.2021.102088. PMID: 34364218.\n- **Tomaszewska 2020.** _Alpha-Ketoglutarate: An Effective Feed Supplement in Improving Bone Metabolism and Muscle Quality of Laying Hens: A Preliminary Study._ Animals : an Open Access Journal from MDPI, 2020. DOI: 10.3390/ani10122420. PMID: 33348724.\n- **Wu 2021.** _Evaluation of Alpha-Ketoglutarate Supplementation on the Improvement of Intestinal Antioxidant Capacity and Immune Response in Songpu Mirror Carp ( Cyprinus carpio ) After Infection With Aeromonas hydrophila._ Frontiers in Immunology, 2021. DOI: 10.3389/fimmu.2021.690234. PMID: 34220849.\n- **Iwaniak 2022.** _Dietary Alpha-Ketoglutarate Partially Abolishes Adverse Changes in the Small Intestine after Gastric Bypass Surgery in a Rat Model._ Nutrients, 2022. DOI: 10.3390/nu14102062. PMID: 35631203.\n- **Takemura 2025.** _Alpha-ketoglutarate supplementation improves hyperglycemia and attenuates the decrease in GLUT4 and PGC-1α proteins in adipose tissue of streptozotocin-high-fat diet-induced diabetic mice._ Journal of Nutritional Science, 2025. DOI: 10.1017/jns.2025.10059. PMID: 41496859.\n- **Sun 2025.** _Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia._ Nature Communications, 2025. DOI: 10.1038/s41467-025-64360-8. PMID: 41120320.\n- **Kaawaj 2020.** _Alpha Ketoglutarate Exerts In Vitro Anti-Osteosarcoma Effects through Inhibition of Cell Proliferation, Induction of Apoptosis via the JNK and Caspase 9-Dependent Mechanism, and Suppression of TGF-β and VEGF Production and Metastatic Potential of Cells._ International Journal of Molecular Sciences, 2020. DOI: 10.3390/ijms21249406. PMID: 33321940.\n- **Dhat 2023.** _Epigenetic modifier alpha-ketoglutarate modulates aberrant gene body methylation and hydroxymethylation marks in diabetic heart._ Epigenetics & Chromatin, 2023. DOI: 10.1186/s13072-023-00489-4. PMID: 37101286.\n- **Tian 2023.** _Dietary Alpha-Ketoglutarate Supplementation Improves Bone Growth, Phosphorus Digestion, and Growth Performance in Piglets._ Animals : an Open Access Journal from MDPI, 2023. DOI: 10.3390/ani13040569. PMID: 36830356.\n- **Chen 2018.** _Alpha-Ketoglutarate in Low-Protein Diets for Growing Pigs: Effects on Cecal Microbial Communities and Parameters of Microbial Metabolism._ Frontiers in Microbiology, 2018. DOI: 10.3389/fmicb.2018.01057. PMID: 29904374.\n- **Su 2019.** _Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK._ Aging (Albany NY), 2019. DOI: 10.18632/aging.102045. PMID: 31242135.\n- **Khamineh 2026.** _Effects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation._ Cells, 2026. DOI: 10.3390/cells15030281. PMID: 41677644.\n- **Chen 2019.** _Effects of Dietary Supplementation of Alpha-Ketoglutarate in a Low-Protein Diet on Fatty Acid Composition and Lipid Metabolism Related Gene Expression in Muscles of Growing Pigs._ Animals : an Open Access Journal from MDPI, 2019. DOI: 10.3390/ani9100838. PMID: 31640132.\n- **Burdyliuk 2017.** _Effects of Long-Term Cultivation on Medium with Alpha-Ketoglutarate Supplementation on Metabolic Processes of Saccharomyces cerevisiae._ Journal of Aging Research, 2017. DOI: 10.1155/2017/8754879. PMID: 29181198.\n- **Huang 2025.** _Alpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway._ Cell Regeneration, 2025. DOI: 10.1186/s13619-025-00264-8. PMID: 41428315.\n- **Wang 2020.** _Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations._ Nature Communications, 2020. DOI: 10.1038/s41467-020-19360-1. PMID: 33154378.\n- **Showalter 2017.** _Replication Study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate._ eLife, 2017. DOI: 10.7554/eLife.26030. PMID: 28653623.\n- **Liu 2022.** _Alpha-ketoglutarate ameliorates abdominal aortic aneurysm via inhibiting PXDN/HOCL/ERK signaling pathways._ Journal of Translational Medicine, 2022. DOI: 10.1186/s12967-022-03659-2. PMID: 36209172.\n- **Sandalova 2023.** _Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)—intervention study protocol._ GeroScience, 2023. DOI: 10.1007/s11357-023-00813-6. PMID: 37217632.\n- **Tian 2023b.** _Elevation of Intracellular Alpha-Ketoglutarate Levels Inhibits Osteoclastogenesis by Suppressing the NF-κB Signaling Pathway in a PHD1-Dependent Manner._ Nutrients, 2023. DOI: 10.3390/nu15030701. PMID: 36771407.\n- **Dilimulati 2026.** _Alpha-ketoglutarate enhances adipose-derived stem cells survival in wound healing by hypoxia-inducible factor 1-alpha-mediated redox homeostasis and glycogen-dependent bioenergetics._ World Journal of Stem Cells, 2026. DOI: 10.4252/wjsc.v18.i2.113694. PMID: 41808885.\n- **He 2017.** _Alpha-ketoglutarate suppresses the NF-κB-mediated inflammatory pathway and enhances the PXR-regulated detoxification pathway._ Oncotarget, 2017. DOI: 10.18632/oncotarget.16875. PMID: 29262538.\n- **Sun 2025b.** _Effects of Alpha-Ketoglutarate Supplementation on Growth Performance, Diarrhea Incidence, Plasma Amino Acid, and Nutrient Digestibility in Weaned Piglets._ Animals : an Open Access Journal from MDPI, 2025. DOI: 10.3390/ani15121723. PMID: 40564275.\n- **Ruiz 2023.** _Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia._ Genes, 2023. DOI: 10.3390/genes14091818. PMID: 37761958.\n- **Bayliak 2017.** _Growth on Alpha-Ketoglutarate Increases Oxidative Stress Resistance in the Yeast Saccharomyces cerevisiae._ International Journal of Microbiology, 2017. DOI: 10.1155/2017/5792192. PMID: 28154578.\n- **Tomaszewska 2021.** _Cholesterol Content, Fatty Acid Profile and Health Lipid Indices in the Egg Yolk of Eggs from Hens at the End of the Laying Cycle, Following Alpha-Ketoglutarate Supplementation._ Foods, 2021. DOI: 10.3390/foods10030596. PMID: 33799887.\n- **Sun 2025c.** _Effects of Dietary Alpha-Ketoglutarate Supplementation on Diarrhea Incidence and Nutrient Digestibility in Weaned Piglets Fed Low-Protein Diets._ Veterinary Sciences, 2025. DOI: 10.3390/vetsci12121163. PMID: 41472143.\n- **Iniguez 2022.** _Alpha-Ketoglutarate Promotes Goblet Cell Differentiation and Alters Urea Cycle Metabolites in DSS-Induced Colitis Mice._ Nutrients, 2022. DOI: 10.3390/nu14061148. PMID: 35334805.\n- **Cai 2016.** _Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways._ Scientific Reports, 2016. DOI: 10.1038/srep26802. PMID: 27225984.\n- **Demidenko 2021.** _Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test._ Aging (Albany NY), 2021. DOI: 10.18632/aging.203736. PMID: 34847066.\n- **Greilberger 2021b.** _Alpha-Ketoglutarate: A Potential Inner Mitochondrial and Cytosolic Protector against Peroxynitrite and Peroxynitrite-Induced Nitration?._ Antioxidants, 2021. DOI: 10.3390/antiox10091501. PMID: 34573133.\n- **Lamichhane 2023.** _Lack of association of the alpha-ketoglutarate-dependent dioxygenase (FTO) gene polymorphisms with pulmonary tuberculosis risk: a systematic review and meta-analysis._ Annals of Medicine and Surgery, 2023. DOI: 10.1097/MS9.0000000000001188. PMID: 37811091.\n- **Sekita 2021.** _AKT signaling is associated with epigenetic reprogramming via the upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation._ Stem Cell Research & Therapy, 2021. DOI: 10.1186/s13287-021-02578-1. PMID: 34563253.\n- **Csaban 2021.** _The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease._ Life, 2021. DOI: 10.3390/life11040321. PMID: 33917565.\n- **Gai 2022.** _Foliar application of alpha-ketoglutarate plus nitrogen improves drought resistance in soybean ( Glycine max L. Merr. )._ Scientific Reports, 2022. DOI: 10.1038/s41598-022-18660-4. PMID: 36002532.\n- **Mohammadi 2025.** _Repurposing FDA-approved drugs to find a novel inhibitor of alpha-ketoglutarate-dependent dioxygenase FTO to treat esophageal cancer._ Research in Pharmaceutical Sciences, 2025. DOI: 10.4103/RPS.RPS_9_25. PMID: 40687281.\n- **Stuart 2014.** _A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process._ Cancer & Metabolism, 2014. DOI: 10.1186/2049-3002-2-4. PMID: 24612826.\n- **Mizerska-Kowalska 2022.** _Alpha Ketoglutarate Downregulates the Neutral Endopeptidase and Enhances the Growth Inhibitory Activity of Thiorphan in Highly Aggressive Osteosarcoma Cells._ Molecules, 2022. DOI: 10.3390/molecules28010097. PMID: 36615293.\n- **Singh 2013.** _Effect of Alpha-Ketoglutarate on Growth and Metabolism of Cells Cultured on Three-Dimensional Cryogel Matrix._ International Journal of Biological Sciences, 2013. DOI: 10.7150/ijbs.4962. PMID: 23781146.\n- **Lin 2015.** _D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2._ Nature Communications, 2015. DOI: 10.1038/ncomms8768. PMID: 26178471.\n- **Alpha-ketoglutarate 2018.** _Effects of alpha-ketoglutarate on lifespan and functional aging of Drosophila melanogaster flies._ The Ukrainian Biochemical Journal, 2018. DOI: 10.15407/ubj90.06.049.\n- **Hasegawa 2026.** _Alpha-Ketoglutarate Drives an Osteogenic and Extracellular Matrix Gene Program in Periodontal Ligament Fibroblasts via Selective Reduction of H3K27me3._ Biology, 2026. DOI: 10.3390/biology15050372. PMID: 41823800.\n- **Wu 2016.** _Alpha-Ketoglutarate: Physiological Functions and Applications._ Biomolecules & Therapeutics, 2016. DOI: 10.4062/biomolther.2015.078. PMID: 26759695.\n- **Zhang 2020.** _Alpha-ketoglutarate utilization in Saccharomyces cerevisiae : transport, compartmentation and catabolism._ Scientific Reports, 2020. DOI: 10.1038/s41598-020-69178-6. PMID: 32733060.\n- **Doroftei 2024.** _A scoping review regarding reproductive capacity modulation based on alpha-ketoglutarate supplementation._ Reproduction (Cambridge, England), 2024. DOI: 10.1530/REP-24-0137. PMID: 39189990.\n- **Fiehn 2016.** _Registered report: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate._ eLife, 2016. DOI: 10.7554/eLife.12626. PMID: 26943899.\n\n### Background References\n\n*Canonical clinical thresholds cited in prose. Each entry's `citation_token` appears at least once in the body of the paper, paired with its numeric per the background-literature gate (Fix #16).*\n\n- **ADA 2024.** _American Diabetes Association. Standards of Care in Diabetes. Diabetes Care. 2024;47(Suppl 1)._ DOI: 10.2337/dc24-S006.\n- **Cruz-Jentoft 2019.** _Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(1):16-31._ DOI: 10.1093/ageing/afy169. PMID: 30312372.\n- **Tinetti 1988.** _Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med. 1988;319(26):1701-1707._ DOI: 10.1056/NEJM198812293192604. PMID: 3205267.\n","metadata":{"abstract":"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. Alpha-ketoglutarate (AKG), a central Krebs cycle intermediate and a cofactor for dioxygenases that regulate epigenetic marks, has drawn increasing attention as a potential modulator of aging, metabolic, and disease-related pathways. 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. The included literature spans preclinical, animal, and models, but is overwhelmingly preclinical or mechanistic in design, with only a single registered randomized controlled trial protocol identified (Sandalova 2023). Translational relevance to humans remains uncertain. 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. 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","article_type":"rapid_evidence_synthesis","counts":{"retrieved_count":51,"selected_count":51,"review_like_count":51,"primary_like_count":0,"year_start":2013,"year_end":2026},"gates":[{"name":"leakage_blocker","passed":true,"reason":"final body must not contain reviewer or pipeline leakage"},{"name":"count_reconciliation","passed":true,"reason":"selected count must equal review-like + primary-like counts"},{"name":"core_claims_resolved","passed":true,"reason":"title/abstract/conclusion claims must not remain 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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.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_2","claim":"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.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_3","claim":"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.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 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2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_5","claim":"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`.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_6","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. 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.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_7","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`.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_8","claim":"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.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_9","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.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_10","claim":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_11","claim":"| 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 |","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_12","claim":"| Dosing and Pharmacokinetics | n=9; claims=314 | null signal in 8/9 sources | 8 indirect; 1 review | limited corpus depth in this outcome class |","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_13","claim":"| Cardiometabolic | n=3; claims=162 | null signal in 3/3 sources | 1 indirect; 2 mechanistic | limited corpus depth in this outcome class |","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_14","claim":"| Skeletal, Fracture, and Bone | n=3; claims=137 | null signal in 2/3 sources | 3 indirect | limited corpus depth in this outcome class |","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_15","claim":"| Immune | n=1; claims=29 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_16","claim":"| Longevity | n=1; claims=2 | null signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating |","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_17","claim":"| Mortality and Survival | n=1; claims=44 | null signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_18","claim":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_19","claim":"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.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_20","claim":"9 included sources were assigned to this outcome class. Directional coding: null=8, unclear=1. Directness coding: indirect=8, review=1.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_21","claim":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=1, mechanistic=2.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_22","claim":"3 included sources were assigned to this outcome class. Directional coding: null=2, unclear=1. Directness coding: indirect=3.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_23","claim":"2 included sources were assigned to this outcome class. Directional coding: null=1, positive=1. Directness coding: mechanistic=2.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_24","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_25","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_26","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_27","claim":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_28","claim":"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.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_29","claim":"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.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_30","claim":"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.","candidate_sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"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 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This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]}}},{"name":"contradiction_map.json","media_type":"application/json","content":{"publication_id":"494277b2-426f-4cdc-99b0-561816dabda5","screening":{"identified":51,"screened":51,"excluded":0,"included":51,"included_or_retained":51,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"51 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["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.","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."]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\nGreilberger 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nGreilberger 2022,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nQiu 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nGreilberger 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nWu 2022,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAn 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nTomaszewska 2020,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nWu 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nIwaniak 2022,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nTakemura 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSun 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nKaawaj 2020,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nDhat 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nTian 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nKhamineh 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nHuang 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nWang 2020,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nLiu 2022,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSandalova 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nTian 2023b,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nDilimulati 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSun 2025b,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nRuiz 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nTomaszewska 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSun 2025c,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nIniguez 2022,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nDemidenko 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nGreilberger 2021b,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nLamichhane 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSekita 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nCsaban 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nGai 2022,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nMohammadi 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nMizerska-Kowalska 2022,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nHasegawa 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nZhang 2020,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nDoroftei 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSu 2019,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nChen 2018,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nChen 2019,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nBurdyliuk 2017,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nShowalter 2017,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nHe 2017,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nBayliak 2017,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nCai 2016,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nStuart 2014,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nLin 2015,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSingh 2013,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nAlpha-ketoglutarate 2018,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nWu 2016,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nFiehn 2016,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nADA 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\nCruz-Jentoft 2019,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\nTinetti 1988,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,citation\r\n"},{"name":"risk_of_bias.json","media_type":"application/json","content":{"publication_id":"494277b2-426f-4cdc-99b0-561816dabda5","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised in public sidecar.","sources":[{"study":"Greilberger 2023","doi":"10.3390/cimb45080410","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Greilberger 2022","doi":"10.3390/ijms23169034","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Qiu 2025","doi":"10.3389/fphar.2025.1656473","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Greilberger 2021","doi":"10.3390/antiox10111804","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Wu 2022","doi":"10.3389/fimmu.2022.915657","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"An 2021","doi":"10.1016/j.redox.2021.102088","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Tomaszewska 2020","doi":"10.3390/ani10122420","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Wu 2021","doi":"10.3389/fimmu.2021.690234","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Iwaniak 2022","doi":"10.3390/nu14102062","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Takemura 2025","doi":"10.1017/jns.2025.10059","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Sun 2025","doi":"10.1038/s41467-025-64360-8","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Kaawaj 2020","doi":"10.3390/ijms21249406","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Dhat 2023","doi":"10.1186/s13072-023-00489-4","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Tian 2023","doi":"10.3390/ani13040569","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Khamineh 2026","doi":"10.3390/cells15030281","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Huang 2025","doi":"10.1186/s13619-025-00264-8","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Wang 2020","doi":"10.1038/s41467-020-19360-1","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Liu 2022","doi":"10.1186/s12967-022-03659-2","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Sandalova 2023","doi":"10.1007/s11357-023-00813-6","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Tian 2023b","doi":"10.3390/nu15030701","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Dilimulati 2026","doi":"10.4252/wjsc.v18.i2.113694","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Sun 2025b","doi":"10.3390/ani15121723","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Ruiz 2023","doi":"10.3390/genes14091818","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Tomaszewska 2021","doi":"10.3390/foods10030596","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Sun 2025c","doi":"10.3390/vetsci12121163","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Iniguez 2022","doi":"10.3390/nu14061148","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Demidenko 2021","doi":"10.18632/aging.203736","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Greilberger 2021b","doi":"10.3390/antiox10091501","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Lamichhane 2023","doi":"10.1097/MS9.0000000000001188","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Sekita 2021","doi":"10.1186/s13287-021-02578-1","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Csaban 2021","doi":"10.3390/life11040321","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Gai 2022","doi":"10.1038/s41598-022-18660-4","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Mohammadi 2025","doi":"10.4103/RPS.RPS_9_25","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Mizerska-Kowalska 2022","doi":"10.3390/molecules28010097","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Hasegawa 2026","doi":"10.3390/biology15050372","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Zhang 2020","doi":"10.1038/s41598-020-69178-6","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Doroftei 2024","doi":"10.1530/REP-24-0137","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Su 2019","doi":"10.18632/aging.102045","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Chen 2018","doi":"10.3389/fmicb.2018.01057","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Chen 2019","doi":"10.3390/ani9100838","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Burdyliuk 2017","doi":"10.1155/2017/8754879","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Showalter 2017","doi":"10.7554/eLife.26030","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"He 2017","doi":"10.18632/oncotarget.16875","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Bayliak 2017","doi":"10.1155/2017/5792192","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Cai 2016","doi":"10.1038/srep26802","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Stuart 2014","doi":"10.1186/2049-3002-2-4","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Lin 2015","doi":"10.1038/ncomms8768","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Singh 2013","doi":"10.7150/ijbs.4962","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Alpha-ketoglutarate 2018","doi":"10.15407/ubj90.06.049","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Wu 2016","doi":"10.4062/biomolther.2015.078","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Fiehn 2016","doi":"10.7554/eLife.12626","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"ADA 2024","doi":"10.2337/dc24-S006","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"Cruz-Jentoft 2019","doi":"10.1093/ageing/afy169","risk_of_bias":"not appraised in public sidecar","directness":"citation"},{"study":"Tinetti 1988","doi":"10.1056/NEJM198812293192604","risk_of_bias":"not appraised in public sidecar","directness":"citation"}]}}]}