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# Research Synthesis: Alpha-ketoglutarate — full paper ## Abstract Evidence-honesty note: 47/54 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes evidence on Alpha-ketoglutarate across 54 included source papers and 2928 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 39 adjacent clinical sources, and 13 mechanistic or model-system sources, with 489 cross-study disagreements across the evidence base. Positive study-level signals are not the dominant direction in any outcome class; null signals are summarized in the contextual adjacent evidence, dosing and pharmacokinetics, cardiometabolic, immune and inflammation, skeletal, fracture, and bone, immune, longevity, and mortality and survival outcome classes; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the safety and comorbidity outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect. The conclusion is that Alpha-ketoglutarate should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim. ## Results **Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim. | Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation | |---|---|---|---|---| | Contextual Adjacent Evidence | n=30; claims=1720 | no extracted directional signal in 27/30 sources | 22 indirect; 7 mechanistic; 1 review | limited corpus depth in this outcome class | | Dosing and Pharmacokinetics | n=10; claims=348 | no extracted directional signal in 9/10 sources | 8 indirect; 1 mechanistic; 1 review | limited corpus depth in this outcome class | | Cardiometabolic | n=3; claims=162 | no extracted directional signal in 3/3 sources | 1 indirect; 2 mechanistic | limited corpus depth in this outcome class | | Immune and Inflammation | n=3; claims=271 | no extracted directional signal in 2/3 sources | 3 indirect | limited corpus depth in this outcome class | | Skeletal, Fracture, and Bone | n=3; claims=137 | no extracted directional signal in 2/3 sources | 3 indirect | limited corpus depth in this outcome class | | Safety and Comorbidity | n=2; claims=215 | positive signal in 1/2 sources | 2 mechanistic | limited corpus depth in this outcome class | | Immune | n=1; claims=29 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating | | Longevity | n=1; claims=2 | no extracted directional signal in 1/1 sources | 1 mechanistic | single-source slice; hypothesis-generating | | Mortality and Survival | n=1; claims=44 | no extracted directional signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating | This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate. ### Contextual Adjacent Evidence Outcomes 30 included sources were assigned to this outcome class. Directional coding: mixed=1, null=27, positive=1, unclear=1. Directness coding: indirect=22, mechanistic=7, review=1. ### Dosing Pharmacokinetics Outcomes Evidence for this outcome class is represented in the structured results table, but the retained narrative paragraphs were more strongly assigned to adjacent outcome classes. The synthesis therefore treats this class as context for cross-domain interpretation rather than as a standalone prose claim. ### Cardiometabolic Outcomes 3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=1, mechanistic=2. ### Immune Inflammation Outcomes 3 included sources were assigned to this outcome class. Directional coding: null=2, unclear=1. Directness coding: indirect=3. ### Skeletal Fracture Bone Outcomes 3 included sources were assigned to this outcome class. Directional coding: null=2, unclear=1. Directness coding: indirect=3. ### Safety Comorbidity Outcomes 2 included sources were assigned to this outcome class. Directional coding: null=1, positive=1. Directness coding: mechanistic=2. ### Immune Outcomes 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1. ### Longevity Outcomes 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: mechanistic=1. ### Mortality Survival Outcomes 1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1. ## Limitations **Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim. The corpus does not contain a long-term, adequately powered randomized controlled trial of alpha-ketoglutarate in non-diabetic, community-dwelling older adults, and this absence is the single most consequential limitation. The literature on 0.8 m/s gait speed (Studenski 2011) and the 0.1 m/s substantial-improvement threshold (Perera 2006) therefore cannot be applied to AKG, because no source supplies a functional-performance outcome measured against either cutoff. Any inference about clinical anti-aging benefit is therefore inferential, not evidentiary. Several clinically relevant outcomes are represented by only a single source each, and the corpus therefore cannot adjudicate whether those signals are reproducible. Liu 2024 likewise stands alone for dose-dependent dual effects in cumulus-oocyte complexes, with no parallel dosing study in oocytes from another group. The single-trial generalization risk is amplified because the directness flag on most sources is “indirect” or “mechanistic,” and design heterogeneity across these lone studies precludes any pooled or vote-counting interpretation. Population specificity further constrains external validity. With the exception of Aragones 2016 (morbidly obese women, non-alcoholic fatty liver disease) and Sandalova 2023 (planned middle-aged adult enrolment), virtually every clinical-adjacent source enrolled either a non-human population, a model organism, or a patient cohort defined by a specific surgical or disease state. An 2021, Sun 2025, Sun 2025b, Vatashchuk 2023, and Iniguez 2022 used mice (often C57BL/6 males); Tomaszewska 2020 and Tomaszewska 2021 enrolled Bovans Brown laying hens; Tian 2023b used RAW264.7 cells and bone-marrow macrophages; Wu 2022 and Wu 2021 used Cyprinus carpio; Burdyliuk 2017 and Bayliak 2017 used Saccharomyces cerevisiae. Translational relevance to humans remains uncertain. The mechanism-to-clinic gap is wide and is not closed by any source in the corpus. The Rejuvant® formulation reported in Demidenko 2021 co-administers vitamins, so the AKG-specific contribution cannot be isolated. Ioannidis 2005 cautions more generally that surrogate associations do not guarantee hard-outcome validity, and the present corpus offers little counter-evidence to that caution. The net consequence is that alpha-ketoglutarate's anti-aging case is currently mechanistic-with-sparse-clinical rather than clinically demonstrated. ## Conclusion For Alpha-ketoglutarate, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation. Pending further trials, the intervention should not be used off-label for geroprotection or anti-aging purposes outside clinical-trial settings given current evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging. ## What This Synthesis Adds This synthesis maps 54 included sources on Alpha-ketoglutarate across 9 outcome classes and 489 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit. Across 54 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. Additional corpus sources included animal/preclinical evidence; the strongest unresolved contrast is the disagreement between Dhat 2023 and Qiu 2025 on contextual adjacent evidence , which defines the boundary condition future studies must test rather than smooth over. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary. ### Boundary-Condition Matrix | Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary | |---|---:|---:|---|---| | longevity | 0 | 1 | null | direct interventional hard-endpoint gap | | cardiometabolic | 0 | 3 | null | direct interventional hard-endpoint gap | | immune | 0 | 1 | null | direct interventional hard-endpoint gap | | contextual adjacent evidence | 0 | 30 | mixed, null, positive, unclear | conflict-resolution gap | | dosing and pharmacokinetics | 0 | 10 | null, unclear | direct interventional hard-endpoint gap | | immune and inflammation | 0 | 3 | null, unclear | direct interventional hard-endpoint gap | | safety and comorbidity | 0 | 2 | null, positive | direct interventional hard-endpoint gap | | skeletal, fracture, and bone | 0 | 3 | null, unclear | direct interventional hard-endpoint gap | | mortality and survival | 0 | 1 | null | direct interventional hard-endpoint gap | ### Evidence-Gap Priority | Priority | Gap | Rationale | |---|---|---| | P1 | longevity: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null | | P2 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null | | P3 | immune: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: null | | P4 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 30 indirect sources; direction profile: mixed, null, positive, unclear | | P5 | dosing and pharmacokinetics: direct interventional hard-endpoint gap | 0 direct and 10 indirect sources; direction profile: null, unclear | ### Next-Study Design Recommendation The 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. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating. ## Evidence Snapshot The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement. ### Load-Bearing Included Studies - Additional corpus sources included animal/preclinical evidence; Greilberger 2023; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.01. - Greilberger 2022; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.01. - Greilberger 2021; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.01. - Wu 2022; tier=B2; directness=indirect; endpoint=immune inflammation; direction=unclear; representative statistic=P < 0.05. - Tomaszewska 2020; tier=B2; directness=indirect; endpoint=skeletal fracture bone; direction=null. - Wu 2021; tier=B2; directness=indirect; endpoint=dosing pharmacokinetics; direction=unclear; representative statistic=P < 0.05. - Zhao 2026; tier=B2; directness=indirect; endpoint=immune inflammation; direction=null; representative statistic=P = 0.0008. - Dhat 2023; tier=B2; directness=indirect; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.0001. - Tian 2023; tier=B2; directness=indirect; endpoint=dosing pharmacokinetics; direction=null; representative statistic=P < 0.05. - Chen 2019; tier=B2; directness=indirect; endpoint=dosing pharmacokinetics; direction=null; representative statistic=P < 0.05. ### Source Classification Map Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement. - Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=466. - Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=335. - Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=188. - Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio ): outcome=immune inflammation; directness=indirect; tier=B2; direction=unclear; claims=155. - Alpha-Ketoglutarate: An Effective Feed Supplement in Improving Bone Metabolism and Muscle Quality of Laying Hens: A Preliminary Study: outcome=skeletal fracture bone; directness=indirect; tier=B2; direction=null; claims=80. - 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: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=unclear; claims=79. - Alpha-ketoglutarate accelerates granulocyte-monocyte progenitor differentiation and atherosclerotic plaque inflammation via oxoglutarate receptor 1: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=74. - Epigenetic modifier alpha-ketoglutarate modulates aberrant gene body methylation and hydroxymethylation marks in diabetic heart: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=57. - Dietary Alpha-Ketoglutarate Supplementation Improves Bone Growth, Phosphorus Digestion, and Growth Performance in Piglets: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=54. - 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: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=46. - Effects of Long-Term Cultivation on Medium with Alpha-Ketoglutarate Supplementation on Metabolic Processes of Saccharomyces cerevisiae: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=45. - Alpha-ketoglutarate promotes random-pattern skin flap survival by enhancing angiogenesis via PI3K/Akt/HIF-1α signaling pathway: outcome=mortality survival; directness=indirect; tier=B2; direction=null; claims=44. - Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations: outcome=skeletal fracture bone; directness=indirect; tier=B2; direction=null; claims=44. - Glutaminase 1 regulates the release of extracellular vesicles during neuroinflammation through key metabolic intermediate alpha-ketoglutarate: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=42. - Increased Circulating Levels of Alpha-Ketoglutarate in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=41. - Replication Study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=41. - Alpha-ketoglutarate ameliorates abdominal aortic aneurysm via inhibiting PXDN/HOCL/ERK signaling pathways: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=36. - Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)—intervention study protocol: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=32. - Elevation of Intracellular Alpha-Ketoglutarate Levels Inhibits Osteoclastogenesis by Suppressing the NF-κB Signaling Pathway in a PHD1-Dependent Manner: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=30. - Alpha-ketoglutarate enhances adipose-derived stem cells survival in wound healing by hypoxia-inducible factor 1-alpha-mediated redox homeostasis and glycogen-dependent bioenergetics: outcome=immune; directness=indirect; tier=B2; direction=null; claims=29. - Development and First-in-Human Translation of Hyperpolarized [1- 13 C]Alpha-Ketoglutarate MR Spectroscopy in the Brain: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=26. - Effects of Alpha-Ketoglutarate Supplementation on Growth Performance, Diarrhea Incidence, Plasma Amino Acid, and Nutrient Digestibility in Weaned Piglets: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=25. - Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia: outcome=cardiometabolic; directness=indirect; tier=B2; direction=null; claims=21. - 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: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=18. - Effects of Dietary Alpha-Ketoglutarate Supplementation on Diarrhea Incidence and Nutrient Digestibility in Weaned Piglets Fed Low-Protein Diets: outcome=dosing pharmacokinetics; directness=indirect; tier=B2; direction=null; claims=14. - Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways: outcome=skeletal fracture bone; directness=indirect; tier=B2; direction=unclear; claims=13. - 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: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=13. - Alpha-Ketoglutarate: A Potential Inner Mitochondrial and Cytosolic Protector against Peroxynitrite and Peroxynitrite-Induced Nitration?: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=12. - Lack of association of the alpha-ketoglutarate-dependent dioxygenase (FTO) gene polymorphisms with pulmonary tuberculosis risk: a systematic review and meta-analysis: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=11. - AKT signaling is associated with epigenetic reprogramming via the upregulation of TET and its cofactor, alpha-ketoglutarate during iPSC generation: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=11. - The Role of the Rare Variants in the Genes Encoding the Alpha-Ketoglutarate Dehydrogenase in Alzheimer’s Disease: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=10. - Foliar application of alpha-ketoglutarate plus nitrogen improves drought resistance in soybean ( Glycine max L. Merr. ): outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=9. - Alpha Ketoglutarate Downregulates the Neutral Endopeptidase and Enhances the Growth Inhibitory Activity of Thiorphan in Highly Aggressive Osteosarcoma Cells: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=8. - Repurposing FDA-approved drugs to find a novel inhibitor of alpha-ketoglutarate-dependent dioxygenase FTO to treat esophageal cancer: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=8. - A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=8. - D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=6. - Comparative Study of Various Delivery Methods for the Supply of Alpha-Ketoglutarate to the Neural Cells for Tissue Engineering: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=5. - Alpha-Ketoglutarate Drives an Osteogenic and Extracellular Matrix Gene Program in Periodontal Ligament Fibroblasts via Selective Reduction of H3K27me3: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=2. - Alpha-ketoglutarate utilization in Saccharomyces cerevisiae : transport, compartmentation and catabolism: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=2. - A scoping review regarding reproductive capacity modulation based on alpha-ketoglutarate supplementation: outcome=dosing pharmacokinetics; directness=review; tier=B2; direction=null; claims=1. ### Classification Criteria - **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices. - **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately. - **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else. - **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen. ### Load-Bearing Tensions - Additional corpus sources included animal/preclinical evidence; severity 4 disagreement: Dhat 2023 vs Qiu 2025; Dhat 2023 (null) vs Qiu 2025 (mixed) on contextual other - Severity 4 disagreement: Greilberger 2023 vs Qiu 2025; Greilberger 2023 (null) vs Qiu 2025 (mixed) on contextual other - Severity 4 disagreement: Lamichhane 2023 vs Qiu 2025; Lamichhane 2023 (null) vs Qiu 2025 (mixed) on contextual other - Severity 4 disagreement: Vatashchuk 2023 vs Qiu 2025; Vatashchuk 2023 (null) vs Qiu 2025 (mixed) on contextual other - Severity 4 disagreement: Mohammadi 2025 vs Qiu 2025; Mohammadi 2025 (null) vs Qiu 2025 (mixed) on contextual other - Severity 4 disagreement: Qiu 2025 vs Hasegawa 2026; Qiu 2025 (mixed) vs Hasegawa 2026 (null) on contextual other - Severity 4 disagreement: Qiu 2025 vs Kim 2026; Qiu 2025 (mixed) vs Kim 2026 (null) on contextual other - Severity 4 disagreement: Qiu 2025 vs Vishnoi 2013; Qiu 2025 (mixed) vs Vishnoi 2013 (null) on contextual other ## Methods ### Review type and protocol 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-2026-06-12T11-13-55Z`. ### Information sources Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-12. ### Search strategy The following topic-anchored queries were executed against the information sources listed above: - `alpha-ketoglutarate AND aging AND human` - `calcium alpha-ketoglutarate AND biological age` - `AKG AND longevity AND trial` - `alpha ketoglutarate AND epigenetic clock` - `Ca-AKG AND safety AND human` ### Eligibility criteria - Sources whose primary content addresses alpha ketoglutarate akg. - Sources with extractable quantitative or qualitative findings. - Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable. - Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle). ### Selection of sources of evidence The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 184 records in the receipt-candidate union, 64 were classified as source candidates and 54 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission. ### source admission funnel | Admission bucket | n | |---|---:| | Receipt candidate union | 184 | | Classified source candidates | 64 | | No extractable claims | 31 | | None-only claim binding | 5 | | Mixed partial-or-none claim-binding candidates | 62 | | Partial-only claim-binding candidates | 14 | | Strict high-confidence sources | 8 | | Admitted final sources | 54 | ### Exclusion reasons - Non-traceable findings (claim could not be linked to source text): 0 records. - Wrong population / off-topic sources excluded at screening. - Duplicate records deduplicated by DOI / PMID before screening. ### Data items The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text. ### Risk-of-bias appraisal 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`. ### Synthesis approach 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. ### AI-use disclosure Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified. ### Accountability Accountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. Certification under the `researka_agent_certified` model verifies that the manuscript is internally consistent, provenance-traced, and format-checked against these artifacts; it does not adjudicate domain correctness, corpus fit, or novelty, which remain subject to expert and reader review. Additional corpus sources included animal/preclinical evidence; additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Iwaniak 2022, Takemura 2025, Kaawaj 2020, Su 2019, Huang 2025, Wang 2020, Wu 2018, Showalter 2017, Liu 2022, Dilimulati 2026, Ruiz 2023, Sun 2025c, Mehra 2016, Cai 2016, Greilberger 2021b, Sekita 2021, Csaban 2021, Gai 2022, Stuart 2014, Mizerska-Kowalska 2022, Lin 2015, Alpha-ketoglutarate 2018, Zhang 2020, Doroftei 2024, Fiehn 2016. ## References - **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. - **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. 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