{"publication_id":"eff2808f-cded-4bcd-b7a5-59a823b84f7b","traces":[{"claim_id":"claim_1","claim":"Evidence-honesty note: 46/53 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.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_2","claim":"This paper synthesizes evidence on Alpha-ketoglutarate across 53 accepted source papers and 2847 high-confidence extracted claims.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_3","claim":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 45 adjacent clinical sources, and 8 mechanistic or model-system sources, with 1 cross-study disagreement across the evidence base.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_4","claim":"Positive study-level signals are summarized in the safety and comorbidity outcome class, null signals in the contextual adjacent evidence, cardiometabolic and mechanism outcome classes, and negative signals in no dominant outcome class. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_5","claim":"The conclusion is that Alpha-ketoglutarate remains a bounded geroscience case: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_6","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-2026-06-20T04-00-35Z`.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_7","claim":"The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_8","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).","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_9","claim":"Evidence-tension synthesis: claims grouped by outcome class (cardiometabolic, contextual adjacent evidence, deficiency prevalence, immune and inflammation, immune and inflammation, mechanism, mortality and survival, muscle function, 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":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_10","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":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_11","claim":"| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_12","claim":"| Contextual Adjacent Evidence | n=33; claims=1572 | no extracted directional signal in 31/33 sources | 30 indirect; 1 protocol; 2 review | limited corpus depth in this outcome class |","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_13","claim":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_14","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":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_15","claim":"33 included sources were assigned to this outcome class. Directional coding: null=31, unclear=2. Directness coding: indirect=30, protocol=1, review=2.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_16","claim":"4 included sources were assigned to this outcome class. Directional coding: mixed=1, null=3. Directness coding: mechanistic=4.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_17","claim":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=1, mechanistic=2.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_18","claim":"3 included sources were assigned to this outcome class. Directional coding: null=1, unclear=2. Directness coding: indirect=3.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_19","claim":"1 included source were assigned to this outcome class. Directional coding: null=1. Directness coding: indirect=1.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_20","claim":"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.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","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=2, unclear=1. Directness coding: indirect=3.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_22","claim":"2 included sources were assigned to this outcome class. Directional coding: null=1, positive=1. Directness coding: mechanistic=2.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","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=2. Directness coding: indirect=2.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","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":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","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: indirect=1.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_26","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":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_27","claim":"Additional corpus sources included animal/preclinical evidence; the most consequential scope gap is the near-absence of long-term, hard-outcome randomized evidence in non-diabetic, community-dwelling adults. Consequently, every human claim in this synthesis that is anchored to a clinical event — whether survival in flap surgery (Huang 2025), aneurysm progression (Liu 2022), or diabetic cardiomyopathy (Dhat 2023) — is supported only by indirect, indirect-directness sources, and the headline conclusions cannot be transported to general adult populations without a dedicated long-term mortality RCT, of which the corpus contains none.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_28","claim":"Finally, the corpus contains a mechanism-to-clinic gap for the most clinically relevant claim, namely that αKG influences cardiovascular, skeletal, and longevity outcomes in humans. Mechanistic plausibility is densely documented: PI3K/Akt/HIF-1α angiogenesis in skin flaps (Huang 2025), PHD1-dependent NF-κB suppression in osteoclastogenesis (Tian 2023b), epigenetic H3K27me3 reduction in periodontal regeneration (Hasegawa 2026), histone methylation rescue in age-related osteoporosis (Wang 2020), and Tnfrsf12a/Fn14 histone-modification protection against cancer cachexia (Ruiz 2023). However, each of these sources is either preclinical (An 2021, Iwaniak 2022, Bayliak 2017, Kalawaj 2020), mechanistic-only (Iniguez 2022, Cai 2016, Qiu 2025, Sekita 2021, Wu 2018, Burdyliuk 2017, Showalter 2017, Fiehn 2016), or review/protocol-level (Sandalova 2023, Lamichhane 2023, Doroftei 2024, Wu 2016). 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.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_29","claim":"This synthesis maps 53 included sources on Alpha Ketoglutarate Akg across 10 outcome classes and 1 cross-study disagreement. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]},{"claim_id":"claim_30","claim":"Across 53 curated reference papers, the evidence base for Alpha shows a context-dependent profile. Positive signals appear in: safety comorbidity. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Alpha 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.","candidate_sources":[{"study":"Different RONS Generation in MTC-SK and NSCL Cells Lead to Varying Antitumoral Effects of Alpha-Ketoglutarate + 5-HMF","doi":"10.3390/cimb45080410","url":"https://doi.org/10.3390/cimb45080410"},{"study":"Alpha-Ketoglutarate or 5-HMF: Single Compounds Effectively Eliminate Leukemia Cells via Caspase-3 Apoptosis and Antioxidative Pathways","doi":"10.3390/ijms23169034","url":"https://doi.org/10.3390/ijms23169034"},{"study":"Alpha-ketoglutarate rescues impaired endothelial progenitor cell-mediated angiogenesis in diabetic mice","doi":"10.3389/fphar.2025.1656473","url":"https://doi.org/10.3389/fphar.2025.1656473"},{"study":"Alpha-Ketoglutarate and 5-HMF: A Potential Anti-Tumoral Combination against Leukemia Cells","doi":"10.3390/antiox10111804","url":"https://doi.org/10.3390/antiox10111804"},{"study":"Low Protein Diets Supplemented With Alpha-Ketoglutarate Enhance the Growth Performance, Immune Response, and Intestinal Health in Common Carp ( Cyprinus carpio )","doi":"10.3389/fimmu.2022.915657","url":"https://doi.org/10.3389/fimmu.2022.915657"}]}]}