{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Caloric Restriction → Lifespan Extension", "entry_form": "phenomenon", "gradeable_restatement": "Sustained caloric restriction without malnutrition causally extends lifespan across model organisms and humans.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Species, genotype, baseline disease, diet, dose and timing", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Caloric Restriction → Lifespan Extension", "central_claim": "Sustained caloric restriction without malnutrition causally extends lifespan across model organisms and humans.", "proposed_mechanism": "Sustained caloric restriction without malnutrition causally extends lifespan across model organisms and humans.", "claimed_scope": "animal and human organismal aging", "claimed_level": [ "progression" ], "is_conjunctive": true, "conjunctive_note": "Human-scope central claim is governed by SC3 under the index scope-matched rule. SC2 is evaluated as the indexed candidate mechanism, not added as a necessary clause of the generic lifespan claim. SC4 distinguishes functional benefit from mortality." }, "rubric_routing": { "primary_rubric": "06-metabolism-aging.md", "secondary_rubrics": [], "index_notes_applied": [ "Human-scope central claim is governed by SC3 under the index scope-matched rule. SC2 is evaluated as the indexed candidate mechanism, not added as a necessary clause of the generic lifespan claim. SC4 distinguishes functional benefit from mortality." ], "rubric_fit_note": "Exact archived v5.3 framework. Any stale index empirical framing is rechecked against primary results." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Caloric restriction extends lifespan in multiple model organisms.", "subclaim_type": "mechanism", "scope": "named species, genotype, sex, diet and restriction schedules determined before outcome", "claimed_scope": "named species, genotype, sex, diet and restriction schedules determined before outcome", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Controlled survival outcomes and cross-context replication", "hsef_level": "Ζ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC1 reaches Ζ within named experimental contexts. Controlled survival, adult-onset diverse-mouse restriction, calorie/timing separation and genetic pathway contrasts converge beyond one strain or species [1–4,6–8,35–44,46]. Contextual contradictions and healthspan mismatch prevent Η in this bounded appraisal." }, { "id": "SC2", "statement": "CR lifespan effects are mediated by a unified nutrient-sensing mechanism.", "subclaim_type": "mechanism", "scope": "experimental model organisms", "claimed_scope": "experimental model organisms", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Pathway necessity/rescue separating calories, nutrients and feeding timing", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC2 remains Γ for one unified nutrient-sensing coordinator. Several pathways are causally identified in particular systems, but Sir2, NQO1 and insulin-sensitivity contrasts show that familiar routes are not uniformly necessary [35–44,46–57]. Individual constrained pathways can reach Ε without proving unity." }, { "id": "SC3", "statement": "Caloric restriction extends human lifespan.", "subclaim_type": "generalization", "scope": "adults without malnutrition", "claimed_scope": "adults without malnutrition", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Mortality or validated organismal trajectory endpoints; biomarkers distinguished", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC3 remains Γ for human lifespan extension. Human randomized intervention changes physiological and molecular measures and some function, but no examined study measures extension of human survival or validates those measures as CR-mediated mortality surrogates [16–29,59,60]." }, { "id": "SC4", "statement": "Caloric restriction improves measured human healthspan-related function.", "subclaim_type": "mechanism", "scope": "baseline populations and intervention periods of human CR trials", "claimed_scope": "baseline populations and intervention periods of human CR trials", "governing_rubric": "06-metabolism-aging.md", "key_evidence_anchor": "Randomized functional outcomes alongside safety and adherence", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "SC4 reaches Ε for defined human functional outcomes. Randomized restriction improves selected quality-of-life outcomes, and diet-induced weight loss improves physical performance in older adults with obesity [59,60]. Baseline context, follow-up, masking, lean/bone loss and endpoint distinctions bound the conclusion." } ], "aggregation_rule": "scope-matched", "aggregation_preregistered": true, "aggregation_rationale": "Human-scope central claim is governed by SC3 under the index scope-matched rule. SC2 is evaluated as the indexed candidate mechanism, not added as a necessary clause of the generic lifespan claim. SC4 distinguishes functional benefit from mortality.", "primary_subclaim_id": "SC3", "aggregation_derivation": "The registered scope-matched human-lifespan gate SC3 returns Γ. SC1 animal survival reaches Ζ and SC4 human function reaches Ε; the candidate unified mechanism SC2 is separately Γ and is not an added necessary clause of the generic exposure claim. All preregistered aggregation sensitivities happen to return Γ.", "aggregation_alternatives": { "weakest_link_would_return": "Γ", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M2", "is_nominal": false, "name": "Parallel nutrient-sensing and repair pathways", "core_claim": "Diet alters several partially overlapping pathways and physiological tradeoffs.", "explains_what_nominal_does_not": "Diet alters several partially overlapping pathways and physiological tradeoffs.", "strongest_supporting_evidence": [ "Host genetic, immune, transcriptional and temporal contrasts identify different routes [35,38,43,44,46–57]." ], "strongest_contradictory_evidence": [ "A network description is not a fully identified common pathway; specific mediators remain protocol-dependent." ], "hsef_level_for_this_model": "Ζ", "rationale": "Host genetic, immune, transcriptional and temporal contrasts identify different routes [35,38,43,44,46–57]. A network description is not a fully identified common pathway; specific mediators remain protocol-dependent." }, { "rank_in_tournament": 2, "model_id": "M5", "is_nominal": false, "name": "Meal timing/fasting and dietary composition", "core_claim": "Feeding phase and fasting explain additional effects beyond calorie amount.", "explains_what_nominal_does_not": "Feeding phase and fasting explain additional effects beyond calorie amount.", "strongest_supporting_evidence": [ "Matched-calorie schedules move survival, and 2026 TRF maps sex dependence [2,3,58]." ], "strongest_contradictory_evidence": [ "Spread calorie restriction still extends median survival, so timing alone is insufficient [2]." ], "hsef_level_for_this_model": "Ε", "rationale": "Matched-calorie schedules move survival, and 2026 TRF maps sex dependence [2,3,58]. Spread calorie restriction still extends median survival, so timing alone is insufficient [2]." }, { "rank_in_tournament": 3, "model_id": "M4", "is_nominal": false, "name": "Specific nutrient restriction", "core_claim": "Individual nutrient balance can change longevity independent of generic calorie dose.", "explains_what_nominal_does_not": "Individual nutrient balance can change longevity independent of generic calorie dose.", "strongest_supporting_evidence": [ "Isoleucine and methionine/folate manipulations support specified animal settings [4,57]." ], "strongest_contradictory_evidence": [ "No one nutrient explains all calorie restriction protocols or human survival." ], "hsef_level_for_this_model": "Ε", "rationale": "Isoleucine and methionine/folate manipulations support specified animal settings [4,57]. No one nutrient explains all calorie restriction protocols or human survival." }, { "rank_in_tournament": 4, "model_id": "M3", "is_nominal": false, "name": "Hormetic stress response", "core_claim": "Moderate stress responses support protection under selected protocols.", "explains_what_nominal_does_not": "Moderate stress responses support protection under selected protocols.", "strongest_supporting_evidence": [ "Worm neuronal redox interventions and mouse hormone rescue identify bounded stress routes [49,54]." ], "strongest_contradictory_evidence": [ "Stress resistance is distinct from organismal longevity and does not generalize automatically." ], "hsef_level_for_this_model": "Ε", "rationale": "Worm neuronal redox interventions and mouse hormone rescue identify bounded stress routes [49,54]. Stress resistance is distinct from organismal longevity and does not generalize automatically." }, { "rank_in_tournament": 5, "model_id": "M1", "is_nominal": true, "name": "One unified nutrient-sensing coordinator", "core_claim": "A single conserved node explains all CR lifespan effects.", "explains_what_nominal_does_not": "A single conserved node explains all CR lifespan effects.", "strongest_supporting_evidence": [ "Conserved AMPK, sirtuin, TOR and transcriptional responses make unity plausible." ], "strongest_contradictory_evidence": [ "Necessity differs by protocol, tissue and species; metabolic benefit can dissociate from survival [36,37,40,44,49]." ], "hsef_level_for_this_model": "Γ", "rationale": "Conserved AMPK, sirtuin, TOR and transcriptional responses make unity plausible. Necessity differs by protocol, tissue and species; metabolic benefit can dissociate from survival [36,37,40,44,49]." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. Matched-calorie/timing factorial interventions plus adult-specific loss/rescue of proposed nodes distinguish a single coordinator from parallel nutrient and timing routes.", "study_separating_rank1_from_rank2": "Matched-calorie/timing factorial interventions plus adult-specific loss/rescue of proposed nodes distinguish a single coordinator from parallel nutrient and timing routes.", "nominal_wins_only_by_funding_artifact": false, "level_unchanged_by_tournament": true }, "evidence_inventory": [ { "n": 1, "pmid": "39385029", "title": "Dietary restriction impacts health and lifespan of genetically diverse mice.", "citation": "Di Francesco A, Deighan AG, Litichevskiy L et al. Dietary restriction impacts health and lifespan of genetically diverse mice. Nature. 2024.", "doi": "10.1038/s41586-024-08026-3", "pmcid": "PMC11485257", "url": "https://pubmed.ncbi.nlm.nih.gov/39385029/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39385029/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39385029", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec1, Sec2, Sec6, Sec11, Sec26. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Adult-onset restriction extended survival in genetically diverse female mice; health measures did not uniformly track survival.", "what_it_does_not_show": "Restriction included daily/weekend fasting, and measured-trait path analysis is not selective mediator intervention.", "confounders_present": [ "Restriction included daily/weekend fasting, and measured-trait path analysis is not selective mediator intervention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 2, "pmid": "35511946", "title": "Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice.", "citation": "Acosta-Rodríguez V, Rijo-Ferreira F, Izumo M et al. Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice. Science (New York, N.Y.). 2022.", "doi": "10.1126/science.abk0297", "pmcid": "PMC9262309", "url": "https://pubmed.ncbi.nlm.nih.gov/35511946/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35511946/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID35511946", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: S2. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Equal-calorie regimens separated restriction, fasting and circadian timing; spread feeding still extended median survival.", "what_it_does_not_show": "The single male strain and differing maximum-survival results limit generalization; timing contributes substantially.", "confounders_present": [ "The single male strain and differing maximum-survival results limit generalization; timing contributes substantially." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 3, "pmid": "34663973", "title": "Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice.", "citation": "Pak HH, Haws SA, Green CL et al. Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice. Nature metabolism. 2021.", "doi": "10.1038/s42255-021-00466-9", "pmcid": "PMC8544824", "url": "https://pubmed.ncbi.nlm.nih.gov/34663973/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34663973/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34663973", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Separated feeding regimens attributed key mouse CR benefits to prolonged fasting.", "what_it_does_not_show": "The tested protocols do not establish that all calorie restriction effects in all species are solely fasting effects.", "confounders_present": [ "The tested protocols do not establish that all calorie restriction effects in all species are solely fasting effects." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 4, "pmid": "37939658", "title": "Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice.", "citation": "Green CL, Trautman ME, Chaiyakul K et al. Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice. Cell metabolism. 2023.", "doi": "10.1016/j.cmet.2023.10.005", "pmcid": "PMC10655617", "url": "https://pubmed.ncbi.nlm.nih.gov/37939658/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37939658/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37939658", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Isoleucine restriction improved frailty/metabolism and extended lifespan in genetically heterogeneous mice of both sexes.", "what_it_does_not_show": "Nutrient-specific effects and sex differences distinguish this intervention from pure calorie reduction.", "confounders_present": [ "Nutrient-specific effects and sex differences distinguish this intervention from pure calorie reduction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 5, "pmid": "39433757", "title": "Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice.", "citation": "Dos Santos C, Cambraia A, Shrestha S et al. Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice. Nature communications. 2024.", "doi": "10.1038/s41467-024-53127-2", "pmcid": "PMC11493975", "url": "https://pubmed.ncbi.nlm.nih.gov/39433757/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39433757/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID37790446" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39433757", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "CR preserved beta-cell structure/function and reduced turnover but impaired adaptive proliferation during high-fat feeding.", "what_it_does_not_show": "Cell longevity and beta-cell markers are not a new organismal survival endpoint in this report.", "confounders_present": [ "Cell longevity and beta-cell markers are not a new organismal survival endpoint in this report." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 6, "pmid": "19590001", "title": "Caloric restriction delays disease onset and mortality in rhesus monkeys.", "citation": "Colman RJ, Anderson RM, Johnson SC et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science (New York, N.Y.). 2009.", "doi": "10.1126/science.1173635", "pmcid": "PMC2812811", "url": "https://pubmed.ncbi.nlm.nih.gov/19590001/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19590001/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Wisconsin-rhesus", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Adult-onset Wisconsin rhesus restriction reduced age-associated deaths and disease onset.", "what_it_does_not_show": "Age-related mortality at this report is not identical to an all-cause complete-survival result; human lifespan is not measured.", "confounders_present": [ "Age-related mortality at this report is not identical to an all-cause complete-survival result; human lifespan is not measured." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 7, "pmid": "22932268", "title": "Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study.", "citation": "Mattison JA, Roth GS, Beasley TM et al. Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature. 2012.", "doi": "10.1038/nature11432", "pmcid": "PMC3832985", "url": "https://pubmed.ncbi.nlm.nih.gov/22932268/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22932268/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NIA-rhesus", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "The NIA rhesus CR regimen did not improve survival despite reported health benefits.", "what_it_does_not_show": "Differences in baseline intake, diet and age of initiation limit direct comparison with Wisconsin.", "confounders_present": [ "Differences in baseline intake, diet and age of initiation limit direct comparison with Wisconsin." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 8, "pmid": "28094793", "title": "Caloric restriction improves health and survival of rhesus monkeys.", "citation": "Mattison JA, Colman RJ, Beasley TM et al. Caloric restriction improves health and survival of rhesus monkeys. Nature communications. 2017.", "doi": "10.1038/ncomms14063", "pmcid": "PMC5247583", "url": "https://pubmed.ncbi.nlm.nih.gov/28094793/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28094793/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Wisconsin+NIA-joint", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Joint longitudinal analysis compared the divergent rhesus survival results and conserved health benefits.", "what_it_does_not_show": "These are the same NIA/Wisconsin cohorts, not a third independent primate replication.", "confounders_present": [ "These are the same NIA/Wisconsin cohorts, not a third independent primate replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 9, "pmid": "12634286", "title": "Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction.", "citation": "Bodkin NL, Alexander TM, Ortmeyer HK et al. Mortality and morbidity in laboratory-maintained Rhesus monkeys and effects of long-term dietary restriction. The journals of gerontology. Series A, Biological sciences and medical sciences. 2003.", "doi": "10.1093/gerona/58.3.b212", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12634286/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12634286/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID12634286", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Long-term laboratory rhesus data associated restriction with lower mortality and better insulin sensitivity.", "what_it_does_not_show": "Only eight restricted monkeys and unequal cohort sizes limit causal precision and human inference.", "confounders_present": [ "Only eight restricted monkeys and unequal cohort sizes limit causal precision and human inference." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 10, "pmid": "9226348", "title": "Activity measures in rhesus monkeys on long-term calorie restriction.", "citation": "Weed JL, Lane MA, Roth GS et al. Activity measures in rhesus monkeys on long-term calorie restriction. Physiology & behavior. 1997.", "doi": "10.1016/s0031-9384(97)00147-9", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/9226348/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/9226348/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NIA-rhesus", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Long-term rhesus CR increased selected activity measures in one age group.", "what_it_does_not_show": "Movement, pacing and stereotypies do not by themselves establish lifespan extension or uniformly improved function.", "confounders_present": [ "Movement, pacing and stereotypies do not by themselves establish lifespan extension or uniformly improved function." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 11, "pmid": "20883771", "title": "Caloric restriction delays aging-induced cellular phenotypes in rhesus monkey skeletal muscle.", "citation": "McKiernan SH, Colman RJ, Lopez M et al. Caloric restriction delays aging-induced cellular phenotypes in rhesus monkey skeletal muscle. Experimental gerontology. 2011.", "doi": "10.1016/j.exger.2010.09.011", "pmcid": "PMC2998549", "url": "https://pubmed.ncbi.nlm.nih.gov/20883771/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20883771/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Wisconsin-rhesus", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Rhesus CR preserved upper-leg mass/fiber features during early sarcopenia.", "what_it_does_not_show": "It did not prevent mitochondrial deletion abnormalities; shared Wisconsin animals are not new survival replication.", "confounders_present": [ "It did not prevent mitochondrial deletion abnormalities; shared Wisconsin animals are not new survival replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 12, "pmid": "31982367", "title": "Molecular and Functional Networks Linked to Sarcopenia Prevention by Caloric Restriction in Rhesus Monkeys.", "citation": "Rhoads TW, Clark JP, Gustafson GE et al. Molecular and Functional Networks Linked to Sarcopenia Prevention by Caloric Restriction in Rhesus Monkeys. Cell systems. 2020.", "doi": "10.1016/j.cels.2019.12.002", "pmcid": "PMC7047532", "url": "https://pubmed.ncbi.nlm.nih.gov/31982367/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31982367/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Wisconsin-rhesus", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Rhesus muscle metabolic/tissue profiles linked CR to preserved muscle and physical activity.", "what_it_does_not_show": "Integrated profiling suggests candidate routes without selectively testing their necessity.", "confounders_present": [ "Integrated profiling suggests candidate routes without selectively testing their necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 13, "pmid": "10630589", "title": "Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk.", "citation": "Lane MA, Ingram DK, Roth GS et al. Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk. Toxicological sciences : an official journal of the Society of Toxicology. 1999.", "doi": "10.1093/toxsci/52.2.41", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/10630589/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/10630589/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NIA-rhesus", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC3" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Reported NIA primary measurements showed favorable cardiovascular/metabolic risk changes, including short-term changes in older monkeys.", "what_it_does_not_show": "The report's broader background is not counted as new evidence; risk-factor change is not a human mortality outcome.", "confounders_present": [ "The report's broader background is not counted as new evidence; risk-factor change is not a human mortality outcome." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 14, "pmid": "29514073", "title": "Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys.", "citation": "Rhoads TW, Burhans MS, Chen VB et al. Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys. Cell metabolism. 2018.", "doi": "10.1016/j.cmet.2018.01.014", "pmcid": "PMC5844481", "url": "https://pubmed.ncbi.nlm.nih.gov/29514073/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29514073/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29514073", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Longitudinal rhesus liver profiling showed CR-associated metabolic and RNA-processing changes.", "what_it_does_not_show": "Predictive network analysis does not prove a unified required mediator.", "confounders_present": [ "Predictive network analysis does not prove a unified required mediator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 15, "pmid": "17618073", "title": "Metabolizable energy intake during long-term calorie restriction in rhesus monkeys.", "citation": "Raman A, Baum ST, Colman RJ et al. Metabolizable energy intake during long-term calorie restriction in rhesus monkeys. Experimental gerontology. 2007.", "doi": "10.1016/j.exger.2007.05.008", "pmcid": "PMC2084374", "url": "https://pubmed.ncbi.nlm.nih.gov/17618073/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17618073/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Wisconsin-rhesus", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Bomb calorimetry quantified the actual restricted versus control energy exposure in old rhesus monkeys.", "what_it_does_not_show": "An exposure-measurement report is not a separate lifespan intervention or mechanistic line.", "confounders_present": [ "An exposure-measurement report is not a separate lifespan intervention or mechanistic line." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 16, "pmid": "26187233", "title": "A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity.", "citation": "Ravussin E, Redman LM, Rochon J et al. A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. The journals of gerontology. Series A, Biological sciences and medical sciences. 2015.", "doi": "10.1093/gerona/glv057", "pmcid": "PMC4841173", "url": "https://pubmed.ncbi.nlm.nih.gov/26187233/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26187233/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID27059599" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "CALERIE achieved sustained moderate restriction and favorable risk measures; the primary resting-metabolic residual contrast was significant at twelve but not twenty-four months.", "what_it_does_not_show": "Neither mortality nor extended healthy lifespan was measured; the linked erratum's fine impact remains unresolved.", "confounders_present": [ "Neither mortality nor extended healthy lifespan was measured; the linked erratum's fine impact remains unresolved." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 17, "pmid": "31303390", "title": "2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial.", "citation": "Kraus WE, Bhapkar M, Huffman KM et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. The lancet. Diabetes & endocrinology. 2019.", "doi": "10.1016/S2213-8587(19)30151-2", "pmcid": "PMC6707879", "url": "https://pubmed.ncbi.nlm.nih.gov/31303390/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31303390/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CALERIE exploratory randomized outcomes improved several cardiometabolic risk factors over two years.", "what_it_does_not_show": "Risk factors, including insulin sensitivity, are not validated CR-mediated lifespan surrogates or a new independent cohort.", "confounders_present": [ "Risk factors, including insulin sensitivity, are not validated CR-mediated lifespan surrogates or a new independent cohort." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 18, "pmid": "17341128", "title": "Calorie restriction increases muscle mitochondrial biogenesis in healthy humans.", "citation": "Civitarese AE, Carling S, Heilbronn LK et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS medicine. 2007.", "doi": "10.1371/journal.pmed.0040076", "pmcid": "PMC1808482", "url": "https://pubmed.ncbi.nlm.nih.gov/17341128/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/17341128/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE1-NCT00099151", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Six-month CR changed human muscle mitochondrial DNA and transcripts and reduced DNA damage.", "what_it_does_not_show": "Key mitochondrial enzyme activities were unchanged; molecular markers do not establish lifespan extension.", "confounders_present": [ "Key mitochondrial enzyme activities were unchanged; molecular markers do not establish lifespan extension." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 19, "pmid": "18809812", "title": "Calorie restriction and bone health in young, overweight individuals.", "citation": "Redman LM, Rood J, Anton SD et al. Calorie restriction and bone health in young, overweight individuals. Archives of internal medicine. 2008.", "doi": "10.1001/archinte.168.17.1859", "pmcid": "PMC2748345", "url": "https://pubmed.ncbi.nlm.nih.gov/18809812/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/18809812/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE1-NCT00099151", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Six-month CR changed bone turnover without significant total/hip density loss in young overweight adults.", "what_it_does_not_show": "Short duration and nutrient support do not exclude longer-term bone or fracture harm.", "confounders_present": [ "Short duration and nutrient support do not exclude longer-term bone or fracture harm." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 20, "pmid": "35598698", "title": "Associations between the timing of eating and weight-loss in calorically restricted healthy adults: Findings from the CALERIE study.", "citation": "Fleischer JG, Das SK, Bhapkar M et al. Associations between the timing of eating and weight-loss in calorically restricted healthy adults: Findings from the CALERIE study. Experimental gerontology. 2022.", "doi": "10.1016/j.exger.2022.111837", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/35598698/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35598698/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Secondary CALERIE modeling associated meal timing with weight loss beyond restriction.", "what_it_does_not_show": "Timing was not independently randomized and the analysis does not establish lifespan mediation.", "confounders_present": [ "Timing was not independently randomized and the analysis does not establish lifespan mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 21, "pmid": "32485641", "title": "Caloric restriction, resting metabolic rate and cognitive performance in Non-obese adults: A post-hoc analysis from CALERIE study.", "citation": "Grigolon RB, Brietzke E, Trevizol AP et al. Caloric restriction, resting metabolic rate and cognitive performance in Non-obese adults: A post-hoc analysis from CALERIE study. Journal of psychiatric research. 2020.", "doi": "10.1016/j.jpsychires.2020.05.018", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/32485641/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32485641/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Post hoc CALERIE analysis linked metabolic-rate changes to cognitive performance under CR.", "what_it_does_not_show": "Moderation and component associations are not a prespecified isolated cognitive mechanism trial.", "confounders_present": [ "Moderation and component associations are not a prespecified isolated cognitive mechanism trial." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 22, "pmid": "34543722", "title": "Association between the FTO rs9939609 single nucleotide polymorphism and dietary adherence during a 2-year caloric restriction intervention: Exploratory analyses from CALERIE™ phase 2.", "citation": "Dorling JL, Belsky DW, Racette SB et al. Association between the FTO rs9939609 single nucleotide polymorphism and dietary adherence during a 2-year caloric restriction intervention: Exploratory analyses from CALERIE™ phase 2. Experimental gerontology. 2021.", "doi": "10.1016/j.exger.2021.111555", "pmcid": "PMC8720865", "url": "https://pubmed.ncbi.nlm.nih.gov/34543722/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34543722/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "FTO genotype did not significantly alter restriction adherence or most aging-related biomarker changes.", "what_it_does_not_show": "An exploratory subgroup association is not a Mendelian instrument for lifelong calorie exposure or survival.", "confounders_present": [ "An exploratory subgroup association is not a Mendelian instrument for lifelong calorie exposure or survival." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 23, "pmid": "37961856", "title": "Calorie restriction reduces biomarkers of cellular senescence in humans.", "citation": "Aversa Z, White TA, Heeren AA et al. Calorie restriction reduces biomarkers of cellular senescence in humans. Aging cell. 2024.", "doi": "10.1111/acel.14038", "pmcid": "PMC10861196", "url": "https://pubmed.ncbi.nlm.nih.gov/37961856/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37961856/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC3" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CALERIE samples showed reduced circulating senescence-associated markers and an adipose gene-set signal.", "what_it_does_not_show": "Markers and machine-learning prediction of metabolic change do not establish clinical aging reversal.", "confounders_present": [ "Markers and machine-learning prediction of metabolic change do not establish clinical aging reversal." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 24, "pmid": "35143297", "title": "Caloric restriction in humans reveals immunometabolic regulators of health span.", "citation": "Spadaro O, Youm Y, Shchukina I et al. Caloric restriction in humans reveals immunometabolic regulators of health span. Science (New York, N.Y.). 2022.", "doi": "10.1126/science.abg7292", "pmcid": "PMC10061495", "url": "https://pubmed.ncbi.nlm.nih.gov/35143297/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35143297/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Human CR improved thymopoiesis; mouse Pla2g7 deletion improved inflammation and metabolic phenotypes.", "what_it_does_not_show": "Human correlation plus mouse deletion is not selectively identified human mediator necessity or mortality benefit.", "confounders_present": [ "Human correlation plus mouse deletion is not selectively identified human mediator necessity or mortality benefit." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 25, "pmid": "37781916", "title": "Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity.", "citation": "Ryu S, Spadaro O, Sidorov S et al. Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity. The Journal of clinical investigation. 2023.", "doi": "10.1172/JCI169173", "pmcid": "PMC10541189", "url": "https://pubmed.ncbi.nlm.nih.gov/37781916/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37781916/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Human adipose SPARC reduction motivated inducible adult mouse downregulation and adipocyte deletion with metabolic/inflammatory benefit.", "what_it_does_not_show": "CR-like disease physiology is not a measured general lifespan outcome or uniquely necessary CR coordinator.", "confounders_present": [ "CR-like disease physiology is not a measured general lifespan outcome or uniquely necessary CR coordinator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 26, "pmid": "37823711", "title": "Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study.", "citation": "Das JK, Banskota N, Candia J et al. Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study. Aging cell. 2023.", "doi": "10.1111/acel.13963", "pmcid": "PMC10726900", "url": "https://pubmed.ncbi.nlm.nih.gov/37823711/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37823711/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2", "SC4" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CALERIE muscle biopsies showed transcription/splicing changes with preserved strength despite minor lean loss.", "what_it_does_not_show": "Statistical pathway mediation and muscle quality are not proof of longer human survival.", "confounders_present": [ "Statistical pathway mediation and muscle quality are not proof of longer human survival." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 27, "pmid": "37118425", "title": "Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial.", "citation": "Waziry R, Ryan CP, Corcoran DL et al. Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nature aging. 2023.", "doi": "10.1038/s43587-022-00357-y", "pmcid": "PMC10148951", "url": "https://pubmed.ncbi.nlm.nih.gov/37118425/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37118425/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "ErratumIn: PMID37161091" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec1. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Post hoc CALERIE analysis changed DunedinPACE but not PhenoAge/GrimAge significantly.", "what_it_does_not_show": "The primary discussion explicitly requires clinical endpoint follow-up to validate intervention-surrogate mediation; correction remains attached.", "confounders_present": [ "The primary discussion explicitly requires clinical endpoint follow-up to validate intervention-surrogate mediation; correction remains attached." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 28, "pmid": "24257721", "title": "Energy requirements in nonobese men and women: results from CALERIE.", "citation": "Redman LM, Kraus WE, Bhapkar M et al. Energy requirements in nonobese men and women: results from CALERIE. The American journal of clinical nutrition. 2014.", "doi": "10.3945/ajcn.113.065631", "pmcid": "PMC3862460", "url": "https://pubmed.ncbi.nlm.nih.gov/24257721/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24257721/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Doubly labeled water demonstrated reliable energy requirements and substantial self-report intake underestimation.", "what_it_does_not_show": "Baseline exposure calibration improves trial interpretation but does not add a survival result.", "confounders_present": [ "Baseline exposure calibration improves trial interpretation but does not add a survival result." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 29, "pmid": "35643360", "title": "Nutritional quality of calorie restricted diets in the CALERIE™ 1 trial.", "citation": "Racette SB, Barry VG, Bales CW et al. Nutritional quality of calorie restricted diets in the CALERIE™ 1 trial. Experimental gerontology. 2022.", "doi": "10.1016/j.exger.2022.111840", "pmcid": "PMC9624012", "url": "https://pubmed.ncbi.nlm.nih.gov/35643360/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/35643360/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE1-pooled-three-sites", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3", "SC4" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "CALERIE phase1 food diaries showed nutritional quality maintained or improved under supervised restriction.", "what_it_does_not_show": "Not every nutrient reached adequacy in every participant; nutritional quality is not a mortality endpoint.", "confounders_present": [ "Not every nutrient reached adequacy in every participant; nutritional quality is not a mortality endpoint." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 30, "pmid": "39695227", "title": "Lithocholic acid phenocopies anti-ageing effects of calorie restriction.", "citation": "Qu Q, Chen Y, Wang Y et al. Lithocholic acid phenocopies anti-ageing effects of calorie restriction. Nature. 2025.", "doi": "10.1038/s41586-024-08329-5", "pmcid": "PMC12222012", "url": "https://pubmed.ncbi.nlm.nih.gov/39695227/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39695227/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID39875609" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "LCA-2025-programme", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Lithocholic acid improved aged-mouse function and extended worm/fly lifespan with AMPK dependence.", "what_it_does_not_show": "Mouse functional rescue is distinct from mouse survival; linked correction details were not fully examined.", "confounders_present": [ "Mouse functional rescue is distinct from mouse survival; linked correction details were not fully examined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 31, "pmid": "39695235", "title": "Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing.", "citation": "Qu Q, Chen Y, Wang Y et al. Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing. Nature. 2025.", "doi": "10.1038/s41586-024-08348-2", "pmcid": "PMC12222023", "url": "https://pubmed.ncbi.nlm.nih.gov/39695235/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39695235/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "LCA-2025-programme", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "LCA-TULP3-sirtuin-vATPase signaling and a muscle mutant linked AMPK to aged-mouse function and worm/fly longevity.", "what_it_does_not_show": "Companion work shares the LCA programme and is not an independent lab replication or complete CR necessity test.", "confounders_present": [ "Companion work shares the LCA programme and is not an independent lab replication or complete CR necessity test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 32, "pmid": "39117797", "title": "Spermidine is essential for fasting-mediated autophagy and longevity.", "citation": "Hofer SJ, Daskalaki I, Bergmann M et al. Spermidine is essential for fasting-mediated autophagy and longevity. Nature cell biology. 2024.", "doi": "10.1038/s41556-024-01468-x", "pmcid": "PMC11392816", "url": "https://pubmed.ncbi.nlm.nih.gov/39117797/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39117797/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39117797", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Genetic/pharmacologic polyamine-pathway perturbation abrogated fasting-related autophagy and longevity/health effects in models.", "what_it_does_not_show": "Human metabolite changes are not a human longevity intervention; fasting is not identical to calorie restriction.", "confounders_present": [ "Human metabolite changes are not a human longevity intervention; fasting is not identical to calorie restriction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 33, "pmid": "37046086", "title": "Ageing-associated changes in transcriptional elongation influence longevity.", "citation": "Debès C, Papadakis A, Grönke S et al. Ageing-associated changes in transcriptional elongation influence longevity. Nature. 2023.", "doi": "10.1038/s41586-023-05922-y", "pmcid": "PMC10132977", "url": "https://pubmed.ncbi.nlm.nih.gov/37046086/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37046086/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID37046086", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Slower RNA polymerase variants extended worm/fly lifespan while restriction reversed age-linked elongation changes.", "what_it_does_not_show": "Human cell division capacity is not organismal human lifespan; the complete CR pathway is not isolated.", "confounders_present": [ "Human cell division capacity is not organismal human lifespan; the complete CR pathway is not isolated." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 34, "pmid": "23900241", "title": "Metformin improves healthspan and lifespan in mice.", "citation": "Martin-Montalvo A, Mercken EM, Mitchell SJ et al. Metformin improves healthspan and lifespan in mice. Nature communications. 2013.", "doi": "10.1038/ncomms3192", "pmcid": "PMC3736576", "url": "https://pubmed.ncbi.nlm.nih.gov/23900241/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/23900241/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID23900241", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Middle-age low-dose metformin improved male-mouse survival/function; high dose was toxic without calorie reduction.", "what_it_does_not_show": "A partial CR mimetic is a comparator, not evidence that one conserved CR coordinator is sufficient across humans.", "confounders_present": [ "A partial CR mimetic is a comparator, not evidence that one conserved CR coordinator is sufficient across humans." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 35, "pmid": "19461873", "title": "HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans.", "citation": "Chen D, Thomas EL, Kapahi P et al. HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans. PLoS genetics. 2009.", "doi": "10.1371/journal.pgen.1000486", "pmcid": "PMC2676694", "url": "https://pubmed.ncbi.nlm.nih.gov/19461873/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19461873/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID19461873", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "HIF-1/egl-9 perturbation and tissue rescue linked nutrient-dependent worm longevity to IRE-1.", "what_it_does_not_show": "Nutrient context and tissue-specificity constrain the pathway; cross-species unity is not shown.", "confounders_present": [ "Nutrient context and tissue-specificity constrain the pathway; cross-species unity is not shown." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 36, "pmid": "25633578", "title": "Calorie restriction-mediated replicative lifespan extension in yeast is non-cell autonomous.", "citation": "Mei SC, Brenner C et al. Calorie restriction-mediated replicative lifespan extension in yeast is non-cell autonomous. PLoS biology. 2015.", "doi": "10.1371/journal.pbio.1002048", "pmcid": "PMC4310591", "url": "https://pubmed.ncbi.nlm.nih.gov/25633578/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25633578/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID25633578", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Moving yeast mothers removed CR replicative longevity, restored by supplements or conditioned medium; the transferable factor was Sir2-independent.", "what_it_does_not_show": "Replicative cell aging and media ecology differ from adult animal or human aging.", "confounders_present": [ "Replicative cell aging and media ecology differ from adult animal or human aging." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 37, "pmid": "16051752", "title": "HST2 mediates SIR2-independent life-span extension by calorie restriction.", "citation": "Lamming DW, Latorre-Esteves M, Medvedik O et al. HST2 mediates SIR2-independent life-span extension by calorie restriction. Science (New York, N.Y.). 2005.", "doi": "10.1126/science.1113611", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16051752/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16051752/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID16051752", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Yeast Hst2 mediated Sir2-independent lifespan extension under restriction.", "what_it_does_not_show": "Redundant sirtuin routes challenge single-Sir2 necessity and do not establish a human longevity mechanism.", "confounders_present": [ "Redundant sirtuin routes challenge single-Sir2 necessity and do not establish a human longevity mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 38, "pmid": "30905669", "title": "Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity.", "citation": "Wu Z, Isik M, Moroz N et al. Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity. Cell metabolism. 2019.", "doi": "10.1016/j.cmet.2019.02.013", "pmcid": "PMC6506407", "url": "https://pubmed.ncbi.nlm.nih.gov/30905669/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30905669/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID34614410" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID30905669", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Worm p38-ATF7 immune signaling had to be intact but downregulated for dietary longevity.", "what_it_does_not_show": "Immune and nutrient pathways are context dependent; correction-body details remain unexamined.", "confounders_present": [ "Immune and nutrient pathways are context dependent; correction-body details remain unexamined." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 39, "pmid": "7540704", "title": "Dietary calorie restriction in the Emory mouse: effects on lifespan, eye lens cataract prevalence and progression, levels of ascorbate, glutathione, glucose, and glycohemoglobin, tail collagen breaktime, DNA and RNA oxidation, skin integrity, fecundity, and cancer.", "citation": "Taylor A, Lipman RD, Jahngen-Hodge J et al. Dietary calorie restriction in the Emory mouse: effects on lifespan, eye lens cataract prevalence and progression, levels of ascorbate, glutathione, glucose, and glycohemoglobin, tail collagen breaktime, DNA and RNA oxidation, skin integrity, fecundity, and cancer. Mechanisms of ageing and development. 1995.", "doi": "10.1016/0047-6374(94)01541-s", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/7540704/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/7540704/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID7540704", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Emory-mouse restriction extended median survival and reduced cataract/cancer measures.", "what_it_does_not_show": "Single-background findings and some adverse tissue signs limit universal healthspan alignment.", "confounders_present": [ "Single-background findings and some adverse tissue signs limit universal healthspan alignment." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 40, "pmid": "29733330", "title": "Benefits of Caloric Restriction in Longevity and Chemical-Induced Tumorigenesis Are Transmitted Independent of NQO1.", "citation": "Diaz-Ruiz A, Di Francesco A, Carboneau BA et al. Benefits of Caloric Restriction in Longevity and Chemical-Induced Tumorigenesis Are Transmitted Independent of NQO1. The journals of gerontology. Series A, Biological sciences and medical sciences. 2019.", "doi": "10.1093/gerona/gly112", "pmcid": "PMC6599277", "url": "https://pubmed.ncbi.nlm.nih.gov/29733330/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29733330/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29733330", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "NQO1 knockout retained CR benefits for lifespan, metabolic function and carcinogen outcomes.", "what_it_does_not_show": "NQO1 upregulation is not necessary for these tested benefits; retained pathways do not identify a unified alternative.", "confounders_present": [ "NQO1 upregulation is not necessary for these tested benefits; retained pathways do not identify a unified alternative." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 41, "pmid": "33975472", "title": "Transgenerational fitness effects of lifespan extension by dietary restriction in Caenorhabditis elegans.", "citation": "Ivimey-Cook ER, Sales K, Carlsson H et al. Transgenerational fitness effects of lifespan extension by dietary restriction in Caenorhabditis elegans. Proceedings. Biological sciences. 2021.", "doi": "10.1098/rspb.2021.0701", "pmcid": "PMC8113902", "url": "https://pubmed.ncbi.nlm.nih.gov/33975472/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33975472/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID33975472", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Temporary fasting reduced parental worm mortality but produced adverse multigenerational fitness/survival tradeoffs.", "what_it_does_not_show": "Generation and exposure schedules limit a universal benefit claim.", "confounders_present": [ "Generation and exposure schedules limit a universal benefit claim." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 42, "pmid": "12124627", "title": "Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration.", "citation": "Lin SJ, Kaeberlein M, Andalis AA et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature. 2002.", "doi": "10.1038/nature00829", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/12124627/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/12124627/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID12124627", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Yeast glucose restriction/PKA perturbation linked respiration and Sir2/NAD to replicative lifespan.", "what_it_does_not_show": "Strain and replicative-aging conditions do not establish the same necessary route in other species.", "confounders_present": [ "Strain and replicative-aging conditions do not establish the same necessary route in other species." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 43, "pmid": "30872315", "title": "A microRNA switch controls dietary restriction-induced longevity through Wnt signaling.", "citation": "Xu Y, He Z, Song M et al. A microRNA switch controls dietary restriction-induced longevity through Wnt signaling. EMBO reports. 2019.", "doi": "10.15252/embr.201846888", "pmcid": "PMC6500965", "url": "https://pubmed.ncbi.nlm.nih.gov/30872315/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30872315/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID30872315", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Adult-onset microRNA/Wnt switching was required for worm dietary longevity.", "what_it_does_not_show": "The temporal switch helps separate development, but the specific route remains a worm context.", "confounders_present": [ "The temporal switch helps separate development, but the specific route remains a worm context." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 44, "pmid": "31577953", "title": "Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension.", "citation": "Yu D, Tomasiewicz JL, Yang SE et al. Calorie-Restriction-Induced Insulin Sensitivity Is Mediated by Adipose mTORC2 and Not Required for Lifespan Extension. Cell reports. 2019.", "doi": "10.1016/j.celrep.2019.08.084", "pmcid": "PMC6820997", "url": "https://pubmed.ncbi.nlm.nih.gov/31577953/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31577953/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID31577953", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "mixed", "what_it_shows": "Adipose Rictor deletion blocked CR insulin sensitization while preserving fitness and lifespan extension.", "what_it_does_not_show": "This directly separates a familiar metabolic marker from the required survival mediator.", "confounders_present": [ "This directly separates a familiar metabolic marker from the required survival mediator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 45, "pmid": "31253655", "title": "Dietary restriction induces posttranscriptional regulation of longevity genes.", "citation": "Rollins JA, Shaffer D, Snow SS et al. Dietary restriction induces posttranscriptional regulation of longevity genes. Life science alliance. 2019.", "doi": "10.26508/lsa.201800281", "pmcid": "PMC6600014", "url": "https://pubmed.ncbi.nlm.nih.gov/31253655/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31253655/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID31253655", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "RNAi tests identified nonsense-mediated-decay genes required for worm dietary longevity.", "what_it_does_not_show": "Transcript/translatome associations alone are not mediator proof; RNAi survival tests retain their specific scope.", "confounders_present": [ "Transcript/translatome associations alone are not mediator proof; RNAi survival tests retain their specific scope." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 46, "pmid": "25808402", "title": "The life-extending effect of dietary restriction requires Foxo3 in mice.", "citation": "Shimokawa I, Komatsu T, Hayashi N et al. The life-extending effect of dietary restriction requires Foxo3 in mice. Aging cell. 2015.", "doi": "10.1111/acel.12340", "pmcid": "PMC4531086", "url": "https://pubmed.ncbi.nlm.nih.gov/25808402/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25808402/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID25808402", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Foxo3-deficient mice failed to show significant CR lifespan extension while cancer suppression persisted.", "what_it_does_not_show": "The reported absence of significance and one genetic setting do not establish universal Foxo3 necessity across all CR protocols.", "confounders_present": [ "The reported absence of significance and one genetic setting do not establish universal Foxo3 necessity across all CR protocols." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 47, "pmid": "34383046", "title": "Lamin regulates the dietary restriction response via the mTOR pathway in Caenorhabditis elegans.", "citation": "Charar C, Metsuyanim-Cohen S, Bar DZ et al. Lamin regulates the dietary restriction response via the mTOR pathway in Caenorhabditis elegans. Journal of cell science. 2021.", "doi": "10.1242/jcs.258428", "pmcid": "PMC8445603", "url": "https://pubmed.ncbi.nlm.nih.gov/34383046/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34383046/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID34383046", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Lamin downregulation altered dietary-restriction size/fat phenotypes via RAGC/mTOR localization in worms.", "what_it_does_not_show": "This report does not supply a new organismal lifespan rescue result in the examined abstract.", "confounders_present": [ "This report does not supply a new organismal lifespan rescue result in the examined abstract." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 48, "pmid": "25542313", "title": "Endogenous hydrogen sulfide production is essential for dietary restriction benefits.", "citation": "Hine C, Harputlugil E, Zhang Y et al. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell. 2015.", "doi": "10.1016/j.cell.2014.11.048", "pmcid": "PMC4297538", "url": "https://pubmed.ncbi.nlm.nih.gov/25542313/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/25542313/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID25542313", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Sulfur-amino-acid/CGL perturbations blocked DR hepatic stress protection; transsulfuration changes appeared across longevity models.", "what_it_does_not_show": "Injury resistance and across-model pathway occurrence do not alone prove a common lifespan mediator.", "confounders_present": [ "Injury resistance and across-model pathway occurrence do not alone prove a common lifespan mediator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 49, "pmid": "24199155", "title": "Neuronal ROS signaling rather than AMPK/sirtuin-mediated energy sensing links dietary restriction to lifespan extension.", "citation": "Schmeisser S, Priebe S, Groth M et al. Neuronal ROS signaling rather than AMPK/sirtuin-mediated energy sensing links dietary restriction to lifespan extension. Molecular metabolism. 2013.", "doi": "10.1016/j.molmet.2013.02.002", "pmcid": "PMC3817383", "url": "https://pubmed.ncbi.nlm.nih.gov/24199155/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24199155/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID24199155", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Complex-I inhibition extended worm lifespan without reduced intake; neuronal ROS/PMK/SKN perturbations blocked the effect despite AMPK/sirtuin independence.", "what_it_does_not_show": "A DR-like pharmacological route is not proof that every dietary protocol uses that mechanism.", "confounders_present": [ "A DR-like pharmacological route is not proof that every dietary protocol uses that mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 50, "pmid": "33796867", "title": "Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal.", "citation": "Zhang B, Jun H, Wu J et al. Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to-gut signal. Nature aging. 2021.", "doi": "10.1038/s43587-021-00039-1", "pmcid": "PMC8009090", "url": "https://pubmed.ncbi.nlm.nih.gov/33796867/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33796867/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID33796867", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Food odors shortened DR worm lifespan through an olfactory brain-gut octopamine/AMPK route.", "what_it_does_not_show": "Perceived food cues modify dietary longevity; mouse primary-cell signaling is not mouse or human lifespan.", "confounders_present": [ "Perceived food cues modify dietary longevity; mouse primary-cell signaling is not mouse or human lifespan." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 51, "pmid": "29107506", "title": "Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling.", "citation": "Weir HJ, Yao P, Huynh FK et al. Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell metabolism. 2017.", "doi": "10.1016/j.cmet.2017.09.024", "pmcid": "PMC5718936", "url": "https://pubmed.ncbi.nlm.nih.gov/29107506/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/29107506/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29107506", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "Fusion/fission, fatty-acid oxidation and peroxisomal perturbations separated DR/AMPK/fasting worm longevity requirements.", "what_it_does_not_show": "Different dynamic versus stabilized network requirements constrain a unified explanation.", "confounders_present": [ "Different dynamic versus stabilized network requirements constrain a unified explanation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 52, "pmid": "24655420", "title": "A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans.", "citation": "Chamoli M, Singh A, Malik Y et al. A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans. Aging cell. 2014.", "doi": "10.1111/acel.12218", "pmcid": "PMC4326946", "url": "https://pubmed.ncbi.nlm.nih.gov/24655420/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24655420/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID24655420", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "mekk-3 knockdown induced a dietary-like longevity state without compromised food intake in worms.", "what_it_does_not_show": "A genetic mimetic distinguishes sensing from calorie dose but does not establish human extension.", "confounders_present": [ "A genetic mimetic distinguishes sensing from calorie dose but does not establish human extension." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 53, "pmid": "33180887", "title": "The genetic paradigms of dietary restriction fail to extend life span in cep-1(gk138) mutant of C. elegans p53 due to possible background mutations.", "citation": "Goyala A, Baruah A, Mukhopadhyay A et al. The genetic paradigms of dietary restriction fail to extend life span in cep-1(gk138) mutant of C. elegans p53 due to possible background mutations. PloS one. 2020.", "doi": "10.1371/journal.pone.0241478", "pmcid": "PMC7660490", "url": "https://pubmed.ncbi.nlm.nih.gov/33180887/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/33180887/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID33180887", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "A cep-1 strain blocked genetic but not nongenetic dietary longevity; authors implicated background mutations.", "what_it_does_not_show": "The result cannot be attributed specifically to p53 without resolving linked genetic background.", "confounders_present": [ "The result cannot be attributed specifically to p53 without resolving linked genetic background." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 54, "pmid": "30938024", "title": "Hyperadrenocorticism of calorie restriction contributes to its anti-inflammatory action in mice.", "citation": "Allen BD, Liao CY, Shu J et al. Hyperadrenocorticism of calorie restriction contributes to its anti-inflammatory action in mice. Aging cell. 2019.", "doi": "10.1111/acel.12944", "pmcid": "PMC6516174", "url": "https://pubmed.ncbi.nlm.nih.gov/30938024/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30938024/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID30938024", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Corticosterone replacement restored CR attenuation of edema in hormone-insufficient mice.", "what_it_does_not_show": "Anti-inflammatory challenge response is not directly measured lifespan mediation.", "confounders_present": [ "Anti-inflammatory challenge response is not directly measured lifespan mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 55, "pmid": "16959573", "title": "SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.", "citation": "Haigis MC, Mostoslavsky R, Haigis KM et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 2006.", "doi": "10.1016/j.cell.2006.06.057", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/16959573/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/16959573/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID16959573", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "supports", "what_it_shows": "SIRT4 loss and CR altered beta-cell GDH/insulin regulation through NAD-dependent modification.", "what_it_does_not_show": "This cell/tissue metabolic result does not establish organismal lifespan necessity or a uniform sirtuin activation rule.", "confounders_present": [ "This cell/tissue metabolic result does not establish organismal lifespan necessity or a uniform sirtuin activation rule." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 56, "pmid": "26541492", "title": "Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice.", "citation": "Thompson AC, Bruss MD, Price JC et al. Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice. Aging cell. 2016.", "doi": "10.1111/acel.12414", "pmcid": "PMC4717272", "url": "https://pubmed.ncbi.nlm.nih.gov/26541492/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26541492/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID26541492", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [ "M1" ], "evidence_class": "Weak", "system": "animal", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Hepatic protein replacement rates associated with lifespan extension across mouse interventions.", "what_it_does_not_show": "Cross-model biomarker correlation is not causal mediation or another independent survival test.", "confounders_present": [ "Cross-model biomarker correlation is not causal mediation or another independent survival test." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 57, "pmid": "39060538", "title": "Separation of reproductive decline from lifespan extension during methionine restriction.", "citation": "Wei F, Liu S, Liu J et al. Separation of reproductive decline from lifespan extension during methionine restriction. Nature aging. 2024.", "doi": "10.1038/s43587-024-00674-4", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39060538/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39060538/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID39060538", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Folate supplementation preserved methionine-restriction fly longevity while restoring reproductive capacity.", "what_it_does_not_show": "Defined nutrient balance can separate tradeoffs; this is not pure calorie restriction or human lifespan.", "confounders_present": [ "Defined nutrient balance can separate tradeoffs; this is not pure calorie restriction or human lifespan." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 58, "pmid": "42230994", "title": "Time-restricted feeding extends healthspan in both sexes and lifespan in male C57BL/6 J mice.", "citation": "Iiams SE, Skinner NJ, Wight-Carter M et al. Time-restricted feeding extends healthspan in both sexes and lifespan in male C57BL/6 J mice. Nature aging. 2026.", "doi": "10.1038/s43587-026-01129-8", "pmcid": "PMC13303084", "url": "https://pubmed.ncbi.nlm.nih.gov/42230994/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/42230994/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "UpdateOf: PMID41280091" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID42230994", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "animal", "decisive_perturbation": true, "endogenous": false, "direction": "mixed", "what_it_shows": "Nightly time-restricted feeding improved both-sex health measures, while survival extended only in male mice under the shorter window.", "what_it_does_not_show": "The strongest group also voluntarily restricted calories; sex and calorie/time factors remain material.", "confounders_present": [ "The strongest group also voluntarily restricted calories; sex and calorie/time factors remain material." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 59, "pmid": "27136347", "title": "Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and Sexual Function in Healthy Nonobese Adults: The CALERIE 2 Randomized Clinical Trial.", "citation": "Martin CK, Bhapkar M, Pittas AG et al. Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and Sexual Function in Healthy Nonobese Adults: The CALERIE 2 Randomized Clinical Trial. JAMA internal medicine. 2016.", "doi": "10.1001/jamainternmed.2016.1189", "pmcid": "PMC4905696", "url": "https://pubmed.ncbi.nlm.nih.gov/27136347/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/27136347/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [ "M1" ], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "CALERIE randomized restriction improved selected mood, general-health and sexual-function questionnaire outcomes.", "what_it_does_not_show": "Self-report and unblinded diet intervention limit interpretation; benefits are not durable disease-free survival.", "confounders_present": [ "Self-report and unblinded diet intervention limit interpretation; benefits are not durable disease-free survival." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } }, { "n": 60, "pmid": "21449785", "title": "Weight loss, exercise, or both and physical function in obese older adults.", "citation": "Villareal DT, Chode S, Parimi N et al. Weight loss, exercise, or both and physical function in obese older adults. The New England journal of medicine. 2011.", "doi": "10.1056/NEJMoa1008234", "pmcid": "PMC3114602", "url": "https://pubmed.ncbi.nlm.nih.gov/21449785/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/21449785/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NCT00146107", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC4" ], "favors_models": [ "M1" ], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized diet-induced weight loss improved physical performance in older obese adults; exercise combination produced larger gains.", "what_it_does_not_show": "Diet alone also reduced lean mass and hip density; the obesity-treatment context does not establish nonobese human lifespan extension.", "confounders_present": [ "Diet alone also reduced lean mass and hip density; the obesity-treatment context does not establish nonobese human lifespan extension." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] } } ], "verification_summary": { "load_bearing_claims_checked": 65, "verified": 65, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC3", "cap": "Γ", "cap_source": "rubric", "triggered": true, "trigger_text_quoted": "Biomarker-only improvement without organismal benefit", "specific_trigger": "SC3 remains Γ for human lifespan extension. Human randomized intervention changes physiological and molecular measures and some function, but no examined study measures extension of human survival or validates those measures as CR-mediated mortality surrogates [16–29,59,60].", "resulting_ceiling": "Γ" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Sustained caloric restriction without malnutrition causally extends lifespan across model organisms and humans.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "Animal dietary and genetic interventions cross thresholds within their tested organism, background and schedule. Multispecies survival evidence is assessed as a set, without re-capping it as a single-strain experiment. Human functional intervention earns SC4 causality, whereas a marker that predicts mortality is not yet a validated mediator/surrogate of CR-caused mortality reduction. The same generic mechanism is not silently substituted for the registered human-lifespan claim.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID39385029, PMID35511946, PMID34663973, PMID37939658, PMID19590001, PMID22932268, PMID28094793, PMID12634286, PMID9226348, PMID20883771, PMID31982367, PMID10630589, PMID39695227, PMID39695235, PMID39117797, PMID37046086, PMID23900241, PMID19461873, PMID25633578, PMID16051752, PMID30905669, PMID7540704, PMID29733330, PMID33975472, PMID12124627, PMID30872315, PMID31577953, PMID31253655, PMID25808402, PMID24199155, PMID33796867, PMID29107506, PMID24655420, PMID33180887, PMID39060538, PMID42230994", "gamma_hard_rules_triggered": [ "“ROS change measurements alone”, “NAD level change measurements alone”, “Mitochondrial metrics alone” and “Senescence marker changes alone” constrain isolated marker inferences.", "“Single-species or single-strain evidence” does not describe the assembled SC1 set, but limits individual model legs.", "“Biomarker-only improvement without organismal benefit” constrains human lifespan inference; functional SC4 outcomes are retained separately." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "SC1 reaches Ζ within named experimental contexts. Controlled survival, adult-onset diverse-mouse restriction, calorie/timing separation and genetic pathway contrasts converge beyond one strain or species [1–4,6–8,35–44,46]. Contextual contradictions and healthspan mismatch prevent Η in this bounded appraisal.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "unclear", "qualifying_evidence_citation": "PMID39385029, PMID35511946, PMID34663973, PMID37939658, PMID39433757, PMID31982367, PMID29514073, PMID17341128, PMID37961856, PMID35143297, PMID37781916, PMID37823711, PMID39695227, PMID39695235, PMID39117797, PMID37046086, PMID23900241, PMID19461873, PMID25633578, PMID16051752, PMID30905669, PMID29733330, PMID33975472, PMID12124627, PMID30872315, PMID31577953, PMID31253655, PMID25808402, PMID34383046, PMID25542313, PMID24199155, PMID33796867, PMID29107506, PMID24655420, PMID33180887, PMID30938024, PMID16959573, PMID39060538, PMID42230994", "gamma_hard_rules_triggered": [ "“ROS change measurements alone”, “NAD level change measurements alone”, “Mitochondrial metrics alone” and “Senescence marker changes alone” constrain isolated marker inferences.", "“Single-species or single-strain evidence” does not describe the assembled SC1 set, but limits individual model legs.", "“Biomarker-only improvement without organismal benefit” constrains human lifespan inference; functional SC4 outcomes are retained separately." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "SC2 remains Γ for one unified nutrient-sensing coordinator. Several pathways are causally identified in particular systems, but Sir2, NQO1 and insulin-sensitivity contrasts show that familiar routes are not uniformly necessary [35–44,46–57]. Individual constrained pathways can reach Ε without proving unity.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "unclear", "qualifying_evidence_citation": "PMID19590001, PMID22932268, PMID28094793, PMID12634286, PMID10630589, PMID26187233, PMID31303390, PMID17341128, PMID37961856, PMID37118425", "gamma_hard_rules_triggered": [ "“ROS change measurements alone”, “NAD level change measurements alone”, “Mitochondrial metrics alone” and “Senescence marker changes alone” constrain isolated marker inferences.", "“Single-species or single-strain evidence” does not describe the assembled SC1 set, but limits individual model legs.", "“Biomarker-only improvement without organismal benefit” constrains human lifespan inference; functional SC4 outcomes are retained separately." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "SC3 remains Γ for human lifespan extension. Human randomized intervention changes physiological and molecular measures and some function, but no examined study measures extension of human survival or validates those measures as CR-mediated mortality surrogates [16–29,59,60].", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC4", "field_valid_perturbation_quote": "\n- Genetic or pharmacologic intervention producing reproducible lifespan/healthspan extension\n- Must separate developmental effects from true aging effects\n- Biomarker change alone does NOT satisfy this threshold", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID26187233, PMID31303390, PMID18809812, PMID35143297, PMID37823711, PMID27136347, PMID21449785", "gamma_hard_rules_triggered": [ "“ROS change measurements alone”, “NAD level change measurements alone”, “Mitochondrial metrics alone” and “Senescence marker changes alone” constrain isolated marker inferences.", "“Single-species or single-strain evidence” does not describe the assembled SC1 set, but limits individual model legs.", "“Biomarker-only improvement without organismal benefit” constrains human lifespan inference; functional SC4 outcomes are retained separately." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "SC4 reaches Ε for defined human functional outcomes. Randomized restriction improves selected quality-of-life outcomes, and diet-induced weight loss improves physical performance in older adults with obesity [59,60]. Baseline context, follow-up, masking, lean/bone loss and endpoint distinctions bound the conclusion.", "ceiling_from_boundary_check": "Δ or higher" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "yes", "supporting_evidence": [ "[1] Adult-onset restriction extended survival in genetically diverse female mice; health measures did not uniformly track survival.", "[2] Equal-calorie regimens separated restriction, fasting and circadian timing; spread feeding still extended median survival.", "[3] Separated feeding regimens attributed key mouse CR benefits to prolonged fasting.", "[4] Isoleucine restriction improved frailty/metabolism and extended lifespan in genetically heterogeneous mice of both sexes.", "[6] Adult-onset Wisconsin rhesus restriction reduced age-associated deaths and disease onset.", "[7] The NIA rhesus CR regimen did not improve survival despite reported health benefits.", "[8] Joint longitudinal analysis compared the divergent rhesus survival results and conserved health benefits.", "[9] Long-term laboratory rhesus data associated restriction with lower mortality and better insulin sensitivity.", "[10] Long-term rhesus CR increased selected activity measures in one age group.", "[11] Rhesus CR preserved upper-leg mass/fiber features during early sarcopenia.", "[12] Rhesus muscle metabolic/tissue profiles linked CR to preserved muscle and physical activity.", "[13] Reported NIA primary measurements showed favorable cardiovascular/metabolic risk changes, including short-term changes in older monkeys.", "[30] Lithocholic acid improved aged-mouse function and extended worm/fly lifespan with AMPK dependence.", "[31] LCA-TULP3-sirtuin-vATPase signaling and a muscle mutant linked AMPK to aged-mouse function and worm/fly longevity.", "[32] Genetic/pharmacologic polyamine-pathway perturbation abrogated fasting-related autophagy and longevity/health effects in models.", "[33] Slower RNA polymerase variants extended worm/fly lifespan while restriction reversed age-linked elongation changes.", "[34] Middle-age low-dose metformin improved male-mouse survival/function; high dose was toxic without calorie reduction.", "[35] HIF-1/egl-9 perturbation and tissue rescue linked nutrient-dependent worm longevity to IRE-1.", "[36] Moving yeast mothers removed CR replicative longevity, restored by supplements or conditioned medium; the transferable factor was Sir2-independent.", "[37] Yeast Hst2 mediated Sir2-independent lifespan extension under restriction.", "[38] Worm p38-ATF7 immune signaling had to be intact but downregulated for dietary longevity.", "[39] Emory-mouse restriction extended median survival and reduced cataract/cancer measures.", "[40] NQO1 knockout retained CR benefits for lifespan, metabolic function and carcinogen outcomes.", "[41] Temporary fasting reduced parental worm mortality but produced adverse multigenerational fitness/survival tradeoffs.", "[42] Yeast glucose restriction/PKA perturbation linked respiration and Sir2/NAD to replicative lifespan.", "[43] Adult-onset microRNA/Wnt switching was required for worm dietary longevity.", "[44] Adipose Rictor deletion blocked CR insulin sensitization while preserving fitness and lifespan extension.", "[45] RNAi tests identified nonsense-mediated-decay genes required for worm dietary longevity.", "[46] Foxo3-deficient mice failed to show significant CR lifespan extension while cancer suppression persisted.", "[49] Complex-I inhibition extended worm lifespan without reduced intake; neuronal ROS/PMK/SKN perturbations blocked the effect despite AMPK/sirtuin independence.", "[50] Food odors shortened DR worm lifespan through an olfactory brain-gut octopamine/AMPK route.", "[51] Fusion/fission, fatty-acid oxidation and peroxisomal perturbations separated DR/AMPK/fasting worm longevity requirements.", "[52] mekk-3 knockdown induced a dietary-like longevity state without compromised food intake in worms.", "[53] A cep-1 strain blocked genetic but not nongenetic dietary longevity; authors implicated background mutations.", "[57] Folate supplementation preserved methionine-restriction fly longevity while restoring reproductive capacity.", "[58] Nightly time-restricted feeding improved both-sex health measures, while survival extended only in male mice under the shorter window." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ε", "requirement_quoted": "Requires causal effect in constrained contexts, backgrounds, or species.", "satisfied": "yes", "supporting_evidence": [ "[1] Adult-onset restriction extended survival in genetically diverse female mice; health measures did not uniformly track survival.", "[2] Equal-calorie regimens separated restriction, fasting and circadian timing; spread feeding still extended median survival.", "[3] Separated feeding regimens attributed key mouse CR benefits to prolonged fasting.", "[4] Isoleucine restriction improved frailty/metabolism and extended lifespan in genetically heterogeneous mice of both sexes.", "[6] Adult-onset Wisconsin rhesus restriction reduced age-associated deaths and disease onset.", "[7] The NIA rhesus CR regimen did not improve survival despite reported health benefits.", "[8] Joint longitudinal analysis compared the divergent rhesus survival results and conserved health benefits.", "[9] Long-term laboratory rhesus data associated restriction with lower mortality and better insulin sensitivity.", "[10] Long-term rhesus CR increased selected activity measures in one age group.", "[11] Rhesus CR preserved upper-leg mass/fiber features during early sarcopenia.", "[12] Rhesus muscle metabolic/tissue profiles linked CR to preserved muscle and physical activity.", "[13] Reported NIA primary measurements showed favorable cardiovascular/metabolic risk changes, including short-term changes in older monkeys.", "[30] Lithocholic acid improved aged-mouse function and extended worm/fly lifespan with AMPK dependence.", "[31] LCA-TULP3-sirtuin-vATPase signaling and a muscle mutant linked AMPK to aged-mouse function and worm/fly longevity.", "[32] Genetic/pharmacologic polyamine-pathway perturbation abrogated fasting-related autophagy and longevity/health effects in models.", "[33] Slower RNA polymerase variants extended worm/fly lifespan while restriction reversed age-linked elongation changes.", "[34] Middle-age low-dose metformin improved male-mouse survival/function; high dose was toxic without calorie reduction.", "[35] HIF-1/egl-9 perturbation and tissue rescue linked nutrient-dependent worm longevity to IRE-1.", "[36] Moving yeast mothers removed CR replicative longevity, restored by supplements or conditioned medium; the transferable factor was Sir2-independent.", "[37] Yeast Hst2 mediated Sir2-independent lifespan extension under restriction.", "[38] Worm p38-ATF7 immune signaling had to be intact but downregulated for dietary longevity.", "[39] Emory-mouse restriction extended median survival and reduced cataract/cancer measures.", "[40] NQO1 knockout retained CR benefits for lifespan, metabolic function and carcinogen outcomes.", "[41] Temporary fasting reduced parental worm mortality but produced adverse multigenerational fitness/survival tradeoffs.", "[42] Yeast glucose restriction/PKA perturbation linked respiration and Sir2/NAD to replicative lifespan.", "[43] Adult-onset microRNA/Wnt switching was required for worm dietary longevity.", "[44] Adipose Rictor deletion blocked CR insulin sensitization while preserving fitness and lifespan extension.", "[45] RNAi tests identified nonsense-mediated-decay genes required for worm dietary longevity.", "[46] Foxo3-deficient mice failed to show significant CR lifespan extension while cancer suppression persisted.", "[49] Complex-I inhibition extended worm lifespan without reduced intake; neuronal ROS/PMK/SKN perturbations blocked the effect despite AMPK/sirtuin independence.", "[50] Food odors shortened DR worm lifespan through an olfactory brain-gut octopamine/AMPK route.", "[51] Fusion/fission, fatty-acid oxidation and peroxisomal perturbations separated DR/AMPK/fasting worm longevity requirements.", "[52] mekk-3 knockdown induced a dietary-like longevity state without compromised food intake in worms.", "[53] A cep-1 strain blocked genetic but not nongenetic dietary longevity; authors implicated background mutations.", "[57] Folate supplementation preserved methionine-restriction fly longevity while restoring reproductive capacity.", "[58] Nightly time-restricted feeding improved both-sex health measures, while survival extended only in male mice under the shorter window." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Reproducible intervention effects\n- Mechanistic narrowing\n- Evidence not reducible to general sickness, caloric reduction, or developmental artifacts", "satisfied": "yes", "supporting_evidence": [ "[1] Adult-onset restriction extended survival in genetically diverse female mice; health measures did not uniformly track survival.", "[2] Equal-calorie regimens separated restriction, fasting and circadian timing; spread feeding still extended median survival.", "[3] Separated feeding regimens attributed key mouse CR benefits to prolonged fasting.", "[4] Isoleucine restriction improved frailty/metabolism and extended lifespan in genetically heterogeneous mice of both sexes.", "[6] Adult-onset Wisconsin rhesus restriction reduced age-associated deaths and disease onset.", "[7] The NIA rhesus CR regimen did not improve survival despite reported health benefits.", "[8] Joint longitudinal analysis compared the divergent rhesus survival results and conserved health benefits.", "[9] Long-term laboratory rhesus data associated restriction with lower mortality and better insulin sensitivity.", "[10] Long-term rhesus CR increased selected activity measures in one age group.", "[11] Rhesus CR preserved upper-leg mass/fiber features during early sarcopenia.", "[12] Rhesus muscle metabolic/tissue profiles linked CR to preserved muscle and physical activity.", "[13] Reported NIA primary measurements showed favorable cardiovascular/metabolic risk changes, including short-term changes in older monkeys.", "[30] Lithocholic acid improved aged-mouse function and extended worm/fly lifespan with AMPK dependence.", "[31] LCA-TULP3-sirtuin-vATPase signaling and a muscle mutant linked AMPK to aged-mouse function and worm/fly longevity.", "[32] Genetic/pharmacologic polyamine-pathway perturbation abrogated fasting-related autophagy and longevity/health effects in models.", "[33] Slower RNA polymerase variants extended worm/fly lifespan while restriction reversed age-linked elongation changes.", "[34] Middle-age low-dose metformin improved male-mouse survival/function; high dose was toxic without calorie reduction.", "[35] HIF-1/egl-9 perturbation and tissue rescue linked nutrient-dependent worm longevity to IRE-1.", "[36] Moving yeast mothers removed CR replicative longevity, restored by supplements or conditioned medium; the transferable factor was Sir2-independent.", "[37] Yeast Hst2 mediated Sir2-independent lifespan extension under restriction.", "[38] Worm p38-ATF7 immune signaling had to be intact but downregulated for dietary longevity.", "[39] Emory-mouse restriction extended median survival and reduced cataract/cancer measures.", "[40] NQO1 knockout retained CR benefits for lifespan, metabolic function and carcinogen outcomes.", "[41] Temporary fasting reduced parental worm mortality but produced adverse multigenerational fitness/survival tradeoffs.", "[42] Yeast glucose restriction/PKA perturbation linked respiration and Sir2/NAD to replicative lifespan.", "[43] Adult-onset microRNA/Wnt switching was required for worm dietary longevity.", "[44] Adipose Rictor deletion blocked CR insulin sensitization while preserving fitness and lifespan extension.", "[45] RNAi tests identified nonsense-mediated-decay genes required for worm dietary longevity.", "[46] Foxo3-deficient mice failed to show significant CR lifespan extension while cancer suppression persisted.", "[49] Complex-I inhibition extended worm lifespan without reduced intake; neuronal ROS/PMK/SKN perturbations blocked the effect despite AMPK/sirtuin independence.", "[50] Food odors shortened DR worm lifespan through an olfactory brain-gut octopamine/AMPK route.", "[51] Fusion/fission, fatty-acid oxidation and peroxisomal perturbations separated DR/AMPK/fasting worm longevity requirements.", "[52] mekk-3 knockdown induced a dietary-like longevity state without compromised food intake in worms.", "[53] A cep-1 strain blocked genetic but not nongenetic dietary longevity; authors implicated background mutations.", "[57] Folate supplementation preserved methionine-restriction fly longevity while restoring reproductive capacity.", "[58] Nightly time-restricted feeding improved both-sex health measures, while survival extended only in male mice under the shorter window." ], "what_would_cross_it": "" }, { "subclaim_id": "SC1", "threshold": "Η", "requirement_quoted": "Requires:\n- Robust cross-context intervention evidence\n- Mechanistic specificity\n- Strong alignment of lifespan/healthspan outcomes", "satisfied": "no", "supporting_evidence": [ "[1] Adult-onset restriction extended survival in genetically diverse female mice; health measures did not uniformly track survival.", "[2] Equal-calorie regimens separated restriction, fasting and circadian timing; spread feeding still extended median survival.", "[3] Separated feeding regimens attributed key mouse CR benefits to prolonged fasting.", "[4] Isoleucine restriction improved frailty/metabolism and extended lifespan in genetically heterogeneous mice of both sexes.", "[6] Adult-onset Wisconsin rhesus restriction reduced age-associated deaths and disease onset.", "[7] The NIA rhesus CR regimen did not improve survival despite reported health benefits.", "[8] Joint longitudinal analysis compared the divergent rhesus survival results and conserved health benefits.", "[9] Long-term laboratory rhesus data associated restriction with lower mortality and better insulin sensitivity.", "[10] Long-term rhesus CR increased selected activity measures in one age group.", "[11] Rhesus CR preserved upper-leg mass/fiber features during early sarcopenia.", "[12] Rhesus muscle metabolic/tissue profiles linked CR to preserved muscle and physical activity.", "[13] Reported NIA primary measurements showed favorable cardiovascular/metabolic risk changes, including short-term changes in older monkeys.", "[30] Lithocholic acid improved aged-mouse function and extended worm/fly lifespan with AMPK dependence.", "[31] LCA-TULP3-sirtuin-vATPase signaling and a muscle mutant linked AMPK to aged-mouse function and worm/fly longevity.", "[32] Genetic/pharmacologic polyamine-pathway perturbation abrogated fasting-related autophagy and longevity/health effects in models.", "[33] Slower RNA polymerase variants extended worm/fly lifespan while restriction reversed age-linked elongation changes.", "[34] Middle-age low-dose metformin improved male-mouse survival/function; high dose was toxic without calorie reduction.", "[35] HIF-1/egl-9 perturbation and tissue rescue linked nutrient-dependent worm longevity to IRE-1.", "[36] Moving yeast mothers removed CR replicative longevity, restored by supplements or conditioned medium; the transferable factor was Sir2-independent.", "[37] Yeast Hst2 mediated Sir2-independent lifespan extension under restriction.", "[38] Worm p38-ATF7 immune signaling had to be intact but downregulated for dietary longevity.", "[39] Emory-mouse restriction extended median survival and reduced cataract/cancer measures.", "[40] NQO1 knockout retained CR benefits for lifespan, metabolic function and carcinogen outcomes.", "[41] Temporary fasting reduced parental worm mortality but produced adverse multigenerational fitness/survival tradeoffs.", "[42] Yeast glucose restriction/PKA perturbation linked respiration and Sir2/NAD to replicative lifespan.", "[43] Adult-onset microRNA/Wnt switching was required for worm dietary longevity.", "[44] Adipose Rictor deletion blocked CR insulin sensitization while preserving fitness and lifespan extension.", "[45] RNAi tests identified nonsense-mediated-decay genes required for worm dietary longevity.", "[46] Foxo3-deficient mice failed to show significant CR lifespan extension while cancer suppression persisted.", "[49] Complex-I inhibition extended worm lifespan without reduced intake; neuronal ROS/PMK/SKN perturbations blocked the effect despite AMPK/sirtuin independence.", "[50] Food odors shortened DR worm lifespan through an olfactory brain-gut octopamine/AMPK route.", "[51] Fusion/fission, fatty-acid oxidation and peroxisomal perturbations separated DR/AMPK/fasting worm longevity requirements.", "[52] mekk-3 knockdown induced a dietary-like longevity state without compromised food intake in worms.", "[53] A cep-1 strain blocked genetic but not nongenetic dietary longevity; authors implicated background mutations.", "[57] Folate supplementation preserved methionine-restriction fly longevity while restoring reproductive capacity.", "[58] Nightly time-restricted feeding improved both-sex health measures, while survival extended only in male mice under the shorter window." ], "what_would_cross_it": "For Η, align survival and functional aging across independently controlled species/backgrounds with narrowed exposure/pathway attribution and tradeoff assessment." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [ "[1] Adult-onset restriction extended survival in genetically diverse female mice; health measures did not uniformly track survival.", "[2] Equal-calorie regimens separated restriction, fasting and circadian timing; spread feeding still extended median survival.", "[3] Separated feeding regimens attributed key mouse CR benefits to prolonged fasting.", "[4] Isoleucine restriction improved frailty/metabolism and extended lifespan in genetically heterogeneous mice of both sexes.", "[5] CR preserved beta-cell structure/function and reduced turnover but impaired adaptive proliferation during high-fat feeding.", "[12] Rhesus muscle metabolic/tissue profiles linked CR to preserved muscle and physical activity.", "[14] Longitudinal rhesus liver profiling showed CR-associated metabolic and RNA-processing changes.", "[18] Six-month CR changed human muscle mitochondrial DNA and transcripts and reduced DNA damage.", "[23] CALERIE samples showed reduced circulating senescence-associated markers and an adipose gene-set signal.", "[24] Human CR improved thymopoiesis; mouse Pla2g7 deletion improved inflammation and metabolic phenotypes.", "[25] Human adipose SPARC reduction motivated inducible adult mouse downregulation and adipocyte deletion with metabolic/inflammatory benefit.", "[26] CALERIE muscle biopsies showed transcription/splicing changes with preserved strength despite minor lean loss.", "[30] Lithocholic acid improved aged-mouse function and extended worm/fly lifespan with AMPK dependence.", "[31] LCA-TULP3-sirtuin-vATPase signaling and a muscle mutant linked AMPK to aged-mouse function and worm/fly longevity.", "[32] Genetic/pharmacologic polyamine-pathway perturbation abrogated fasting-related autophagy and longevity/health effects in models.", "[33] Slower RNA polymerase variants extended worm/fly lifespan while restriction reversed age-linked elongation changes.", "[34] Middle-age low-dose metformin improved male-mouse survival/function; high dose was toxic without calorie reduction.", "[35] HIF-1/egl-9 perturbation and tissue rescue linked nutrient-dependent worm longevity to IRE-1.", "[36] Moving yeast mothers removed CR replicative longevity, restored by supplements or conditioned medium; the transferable factor was Sir2-independent.", "[37] Yeast Hst2 mediated Sir2-independent lifespan extension under restriction.", "[38] Worm p38-ATF7 immune signaling had to be intact but downregulated for dietary longevity.", "[40] NQO1 knockout retained CR benefits for lifespan, metabolic function and carcinogen outcomes.", "[41] Temporary fasting reduced parental worm mortality but produced adverse multigenerational fitness/survival tradeoffs.", "[42] Yeast glucose restriction/PKA perturbation linked respiration and Sir2/NAD to replicative lifespan.", "[43] Adult-onset microRNA/Wnt switching was required for worm dietary longevity.", "[44] Adipose Rictor deletion blocked CR insulin sensitization while preserving fitness and lifespan extension.", "[45] RNAi tests identified nonsense-mediated-decay genes required for worm dietary longevity.", "[46] Foxo3-deficient mice failed to show significant CR lifespan extension while cancer suppression persisted.", "[47] Lamin downregulation altered dietary-restriction size/fat phenotypes via RAGC/mTOR localization in worms.", "[48] Sulfur-amino-acid/CGL perturbations blocked DR hepatic stress protection; transsulfuration changes appeared across longevity models.", "[49] Complex-I inhibition extended worm lifespan without reduced intake; neuronal ROS/PMK/SKN perturbations blocked the effect despite AMPK/sirtuin independence.", "[50] Food odors shortened DR worm lifespan through an olfactory brain-gut octopamine/AMPK route.", "[51] Fusion/fission, fatty-acid oxidation and peroxisomal perturbations separated DR/AMPK/fasting worm longevity requirements.", "[52] mekk-3 knockdown induced a dietary-like longevity state without compromised food intake in worms.", "[53] A cep-1 strain blocked genetic but not nongenetic dietary longevity; authors implicated background mutations.", "[54] Corticosterone replacement restored CR attenuation of edema in hormone-insufficient mice.", "[55] SIRT4 loss and CR altered beta-cell GDH/insulin regulation through NAD-dependent modification.", "[57] Folate supplementation preserved methionine-restriction fly longevity while restoring reproductive capacity.", "[58] Nightly time-restricted feeding improved both-sex health measures, while survival extended only in male mice under the shorter window." ], "what_would_cross_it": "Show adult-specific loss and rescue of a common proposed node consistently mediating CR survival across predeclared organisms and feeding/nutrient protocols." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "no", "supporting_evidence": [ "[6] Adult-onset Wisconsin rhesus restriction reduced age-associated deaths and disease onset.", "[7] The NIA rhesus CR regimen did not improve survival despite reported health benefits.", "[8] Joint longitudinal analysis compared the divergent rhesus survival results and conserved health benefits.", "[9] Long-term laboratory rhesus data associated restriction with lower mortality and better insulin sensitivity.", "[13] Reported NIA primary measurements showed favorable cardiovascular/metabolic risk changes, including short-term changes in older monkeys.", "[16] CALERIE achieved sustained moderate restriction and favorable risk measures; the primary resting-metabolic residual contrast was significant at twelve but not twenty-four months.", "[17] CALERIE exploratory randomized outcomes improved several cardiometabolic risk factors over two years.", "[18] Six-month CR changed human muscle mitochondrial DNA and transcripts and reduced DNA damage.", "[23] CALERIE samples showed reduced circulating senescence-associated markers and an adipose gene-set signal.", "[27] Post hoc CALERIE analysis changed DunedinPACE but not PhenoAge/GrimAge significantly." ], "what_would_cross_it": "Measure human clinical survival or validate intervention-mediated changes in a surrogate against chronic disease, disability and mortality; natural experiments or defensible exposure instruments are eligible equivalents." }, { "subclaim_id": "SC4", "threshold": "Δ", "requirement_quoted": "Requires at least one intervention changing lifespan or healthspan in a way consistent with the hypothesis.", "satisfied": "yes", "supporting_evidence": [ "[16] CALERIE achieved sustained moderate restriction and favorable risk measures; the primary resting-metabolic residual contrast was significant at twelve but not twenty-four months.", "[17] CALERIE exploratory randomized outcomes improved several cardiometabolic risk factors over two years.", "[19] Six-month CR changed bone turnover without significant total/hip density loss in young overweight adults.", "[24] Human CR improved thymopoiesis; mouse Pla2g7 deletion improved inflammation and metabolic phenotypes.", "[26] CALERIE muscle biopsies showed transcription/splicing changes with preserved strength despite minor lean loss.", "[59] CALERIE randomized restriction improved selected mood, general-health and sexual-function questionnaire outcomes.", "[60] Randomized diet-induced weight loss improved physical performance in older obese adults; exercise combination produced larger gains." ], "what_would_cross_it": "" }, { "subclaim_id": "SC4", "threshold": "Ε", "requirement_quoted": "Requires causal effect in constrained contexts, backgrounds, or species.", "satisfied": "yes", "supporting_evidence": [ "[16] CALERIE achieved sustained moderate restriction and favorable risk measures; the primary resting-metabolic residual contrast was significant at twelve but not twenty-four months.", "[17] CALERIE exploratory randomized outcomes improved several cardiometabolic risk factors over two years.", "[19] Six-month CR changed bone turnover without significant total/hip density loss in young overweight adults.", "[24] Human CR improved thymopoiesis; mouse Pla2g7 deletion improved inflammation and metabolic phenotypes.", "[26] CALERIE muscle biopsies showed transcription/splicing changes with preserved strength despite minor lean loss.", "[59] CALERIE randomized restriction improved selected mood, general-health and sexual-function questionnaire outcomes.", "[60] Randomized diet-induced weight loss improved physical performance in older obese adults; exercise combination produced larger gains." ], "what_would_cross_it": "" }, { "subclaim_id": "SC4", "threshold": "Ζ", "requirement_quoted": "Requires:\n- Reproducible intervention effects\n- Mechanistic narrowing\n- Evidence not reducible to general sickness, caloric reduction, or developmental artifacts", "satisfied": "no", "supporting_evidence": [ "[16] CALERIE achieved sustained moderate restriction and favorable risk measures; the primary resting-metabolic residual contrast was significant at twelve but not twenty-four months.", "[17] CALERIE exploratory randomized outcomes improved several cardiometabolic risk factors over two years.", "[19] Six-month CR changed bone turnover without significant total/hip density loss in young overweight adults.", "[24] Human CR improved thymopoiesis; mouse Pla2g7 deletion improved inflammation and metabolic phenotypes.", "[26] CALERIE muscle biopsies showed transcription/splicing changes with preserved strength despite minor lean loss.", "[59] CALERIE randomized restriction improved selected mood, general-health and sexual-function questionnaire outcomes.", "[60] Randomized diet-induced weight loss improved physical performance in older obese adults; exercise combination produced larger gains." ], "what_would_cross_it": "For Ζ, independent functional clinical effects with narrowed mechanism, replicated beyond one trial family and excluding weight-loss-only or nonspecific care explanations." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "NIA primate survival did not improve under its protocol [7].", "Insulin sensitization was blocked without removing CR lifespan/fitness benefit [44].", "Human methylation clocks differed in response [27].", "The recent time-restricted feeding study improved health in both sexes but extended lifespan only in males [58]." ], "note": "Diet, timing, sex, genetic background, age of onset and outcome type define experimentally mapped contexts. These limits retain narrow causal levels, but animal survival cannot replace the human SC3 outcome." }, "falsification_patterns_met": [ { "subclaim_id": "SC2", "pattern": "Necessity fails when the proposed pathway is removed", "evidence": "Sir2-independent routes, NQO1-null retention and Rictor-mediated insulin-resistance retention challenge uniform coordinator claims [36,37,40,44].", "downgrade_applied": false }, { "subclaim_id": "SC1", "pattern": "Effects disappear across strains or species", "evidence": "Primate and sex/protocol heterogeneity map limits; these do not erase independently positive experimental contexts [7,58].", "downgrade_applied": false }, { "subclaim_id": "SC3", "pattern": "Pathway manipulation changes biomarkers but not lifespan/healthspan", "evidence": "Human mortality was not measured; it is incorrect to label missing survival data a demonstrated negative survival effect [16–29].", "downgrade_applied": false } ], "pitfalls_flagged": [ { "subclaim_id": "SC3", "pitfall": "13. Therapeutic effect misread as mechanistic proof", "where": "Risk improvement and weight-loss benefit are not proof of human aging reversal." }, { "subclaim_id": "SC1", "pitfall": "16. Untested generalization confused with mapped boundaries", "where": "Animal genotype, sex and dietary limits are retained without denying causal effects." }, { "subclaim_id": "SC3", "pitfall": "21. A universal cap re-applied to a convergent evidence set", "where": "The strong model evidence is not dragged down by an associative human clock leg; the human outcome remains a separate question." }, { "subclaim_id": "SC1", "pitfall": "22. Scope fitted to the result", "where": "Species, genotype and diet are defined before outcome; long-lived responders do not define success." } ], "causal_tally_audit": { "tally_claimed_by_document": 53, "tally_after_audit": 53, "items_rejected": [ "Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines.", "Diet, genetic, drug-mimetic and negative contrasts are counted as discriminators, not all as positive CR longevity tests.", "No human mortality-extension test is claimed; single-cell longevity, stress protection and molecular profiles are distinct endpoints." ] }, "steelman": { "case_one_rung_higher": "The strongest Δ case for human lifespan is the reproducible animal effect combined with randomized human physiological, immune and functional benefits. The convergence supports translation plausibility. The missing identifying experiment is a human aging/survival trajectory result, or a genuinely validated intervention surrogate; a prognostic clock is insufficient.", "case_one_rung_lower": "The strongest Β case is that human longevity has no direct outcome and its putative markers may merely follow weight loss. It understates controlled animal survival and mechanistically narrowed routes plus functional human effects. The assembled case supplies mechanistic plausibility beyond pure aging association, supporting Γ without replacing SC3 with SC1 or SC4.", "which_rejected": "Reject Δ at the human lifespan gate because the clinical trajectory/surrogate-validation experiment is missing; reject Β because mechanistic/functional intervention support is present. The separate animal Ζ and functional human Ε remain intact.", "blocking_cap_threshold_or_missing_experiment": "Missing experiment: Follow a predeclared human restriction contrast long enough for adjudicated incident disease, disability and mortality, with measured intake, nutrient adequacy, adherence and competing harms. In parallel, validate whether intervention-induced changes in candidate aging measures mediate those outcomes across independent exposure contrasts; lifelong natural experiments or defensible exposure instruments can complement randomized follow-up." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "60 primary reports with 3 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The registered scope-matched human-lifespan gate SC3 returns Γ. SC1 animal survival reaches Ζ and SC4 human function reaches Ε; the candidate unified mechanism SC2 is separately Γ and is not an added necessary clause of the generic exposure claim. All preregistered aggregation sensitivities happen to return Γ." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": "5", "derivation": "Direction procedure: controlled diet assignments precede outcome, excluding a solely downstream label (step 1); functional and survival perturbations exclude epiphenomenon (step 2). One necessary, sufficient, rate-limiting human aging initiator is not identified (step 3), and restriction is not a uniformly necessary prerequisite for longevity (step 4). Nutrient and timing signals modify/stabilize aging-related trajectories in defined settings, matching step 5 for the mechanism at the broad claimed scope. This role label does not deny that assigned restriction causes animal survival differences.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Mechanistic only", "artifact": "Named primary programmes include LCA/TULP3-sirtuin-AMPK experiments [30,31], polyamine-hypusination work [32] and meal-timing survival contrasts [2,58]. This search verified their completed results, not an ongoing next-boundary human mortality trial.", "justification": "Named primary programmes include LCA/TULP3-sirtuin-AMPK experiments [30,31], polyamine-hypusination work [32] and meal-timing survival contrasts [2,58]. This search verified their completed results, not an ongoing next-boundary human mortality trial." }, "stability": { "value": "Stable", "trigger": "No specifically verified pending CR clinical survival or validated-surrogate result was identified in this bounded search; completed CALERIE reports are not pending triggers.", "justification": "No specifically verified pending CR clinical survival or validated-surrogate result was identified in this bounded search; completed CALERIE reports are not pending triggers." }, "divergence": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "Ranking categorical verdict visible; no prior letter used as a target", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": false, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "experiment": "Follow a predeclared human restriction contrast long enough for adjudicated incident disease, disability and mortality, with measured intake, nutrient adequacy, adherence and competing harms. In parallel, validate whether intervention-induced changes in candidate aging measures mediate those outcomes across independent exposure contrasts; lifelong natural experiments or defensible exposure instruments can complement randomized follow-up.", "readout": "Adjudicated survival, multimorbidity, disability, physical function and fractures, with candidate surrogate mediation", "critical_control": "Baseline age/BMI/sex and nutrient adequacy; distinguish feeding timing and composition; account for adherence without selecting post-outcome responders", "supporting_result": "Reproducible favorable human clinical aging trajectories attributable to restriction, with independently validated mediator or exposure specificity", "falsifying_result": "Adequate sustained exposure without clinical benefit, harms offsetting benefit, or marker changes failing to mediate hard outcomes" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "Does restriction extend human survival independent of baseline obesity treatment?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Which model mechanisms are required under which calorie, nutrient and timing protocols?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "What is the net human balance of function, lean mass, bone and immune effects?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Can aging algorithms become validated intervention surrogates rather than merely prognostic measures?", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "How do dose, sex, age of onset and sustainable adherence modify benefit?", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-04", "reviewer": "Codex", "evidence_base_note": "60 primary reports; cutoff 2026-10-04; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/PMC; SciSpace and authenticated Consensus discovery; primary-source verification. No API credential handled.", "skill_version": "5.3", "validator_run": "Archived validator run; receipt and logs accompany this pair.", "validator_warnings_addressed": "Claim-form warning is justified: the popularity-list topic is explicitly restated as a causal proposition. The steelman specifies the missing experiment.", "consensus_consistency_audit": "2026-10-09; supplementary provenance/source reconciliation; original grading retained; prior grades visible." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": false, "why_not_sufficient": "Controlled multispecies survival, dose/timing comparisons, adult-onset interventions and gene loss/rescue are eligible equivalents, carrying animal SC1 to Ζ. Human exposure genetics, lifelong natural experiments or validated clinical mediation could also qualify without waiting for a deliberate lifespan RCT. The examined FTO adherence analysis is not such an exposure instrument, and CALERIE's prognostic measures do not establish intervention-mediated mortality. No observational leg is re-capped over the entire animal set." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "Controlled multispecies survival, dose/timing comparisons, adult-onset interventions and gene loss/rescue are eligible equivalents, carrying animal SC1 to Ζ. Human exposure genetics, lifelong natural experiments or validated clinical mediation could also qualify without waiting for a deliberate lifespan RCT. The examined FTO adherence analysis is not such an exposure instrument, and CALERIE's prognostic measures do not establish intervention-mediated mortality. No observational leg is re-capped over the entire animal set." }, { "kind": "dose_response_across_populations", "available": true, "why_not_sufficient": "Controlled multispecies survival, dose/timing comparisons, adult-onset interventions and gene loss/rescue are eligible equivalents, carrying animal SC1 to Ζ. Human exposure genetics, lifelong natural experiments or validated clinical mediation could also qualify without waiting for a deliberate lifespan RCT. The examined FTO adherence analysis is not such an exposure instrument, and CALERIE's prognostic measures do not establish intervention-mediated mortality. No observational leg is re-capped over the entire animal set." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "Controlled multispecies survival, dose/timing comparisons, adult-onset interventions and gene loss/rescue are eligible equivalents, carrying animal SC1 to Ζ. Human exposure genetics, lifelong natural experiments or validated clinical mediation could also qualify without waiting for a deliberate lifespan RCT. The examined FTO adherence analysis is not such an exposure instrument, and CALERIE's prognostic measures do not establish intervention-mediated mortality. No observational leg is re-capped over the entire animal set." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": true, "why_not_sufficient": "Controlled multispecies survival, dose/timing comparisons, adult-onset interventions and gene loss/rescue are eligible equivalents, carrying animal SC1 to Ζ. Human exposure genetics, lifelong natural experiments or validated clinical mediation could also qualify without waiting for a deliberate lifespan RCT. The examined FTO adherence analysis is not such an exposure instrument, and CALERIE's prognostic measures do not establish intervention-mediated mortality. No observational leg is re-capped over the entire animal set." } ], "convergence_present": true, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 60, "claims_total": 65, "claims_verified": 65, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 60, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "Adult-onset restriction extended survival in genetically diverse female mice; health measures did not uniformly track survival. Restriction included daily/weekend fasting, and measured-trait path analysis is not selective mediator intervention.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec1, Sec2, Sec6, Sec11, Sec26. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C2", "text": "Equal-calorie regimens separated restriction, fasting and circadian timing; spread feeding still extended median survival. The single male strain and differing maximum-survival results limit generalization; timing contributes substantially.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: S2. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C3", "text": "Separated feeding regimens attributed key mouse CR benefits to prolonged fasting. The tested protocols do not establish that all calorie restriction effects in all species are solely fasting effects.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C4", "text": "Isoleucine restriction improved frailty/metabolism and extended lifespan in genetically heterogeneous mice of both sexes. Nutrient-specific effects and sex differences distinguish this intervention from pure calorie reduction.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C5", "text": "CR preserved beta-cell structure/function and reduced turnover but impaired adaptive proliferation during high-fat feeding. Cell longevity and beta-cell markers are not a new organismal survival endpoint in this report.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C6", "text": "Adult-onset Wisconsin rhesus restriction reduced age-associated deaths and disease onset. Age-related mortality at this report is not identical to an all-cause complete-survival result; human lifespan is not measured.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C7", "text": "The NIA rhesus CR regimen did not improve survival despite reported health benefits. Differences in baseline intake, diet and age of initiation limit direct comparison with Wisconsin.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C8", "text": "Joint longitudinal analysis compared the divergent rhesus survival results and conserved health benefits. These are the same NIA/Wisconsin cohorts, not a third independent primate replication.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C9", "text": "Long-term laboratory rhesus data associated restriction with lower mortality and better insulin sensitivity. Only eight restricted monkeys and unequal cohort sizes limit causal precision and human inference.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C10", "text": "Long-term rhesus CR increased selected activity measures in one age group. Movement, pacing and stereotypies do not by themselves establish lifespan extension or uniformly improved function.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C11", "text": "Rhesus CR preserved upper-leg mass/fiber features during early sarcopenia. It did not prevent mitochondrial deletion abnormalities; shared Wisconsin animals are not new survival replication.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C12", "text": "Rhesus muscle metabolic/tissue profiles linked CR to preserved muscle and physical activity. Integrated profiling suggests candidate routes without selectively testing their necessity.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C13", "text": "Reported NIA primary measurements showed favorable cardiovascular/metabolic risk changes, including short-term changes in older monkeys. The report's broader background is not counted as new evidence; risk-factor change is not a human mortality outcome.", "carries_number": false, "load_bearing_for": [ "SC1", "SC3" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C14", "text": "Longitudinal rhesus liver profiling showed CR-associated metabolic and RNA-processing changes. Predictive network analysis does not prove a unified required mediator.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C15", "text": "Bomb calorimetry quantified the actual restricted versus control energy exposure in old rhesus monkeys. An exposure-measurement report is not a separate lifespan intervention or mechanistic line.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C16", "text": "CALERIE achieved sustained moderate restriction and favorable risk measures; the primary resting-metabolic residual contrast was significant at twelve but not twenty-four months. Neither mortality nor extended healthy lifespan was measured; the linked erratum's fine impact remains unresolved.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C17", "text": "CALERIE exploratory randomized outcomes improved several cardiometabolic risk factors over two years. Risk factors, including insulin sensitivity, are not validated CR-mediated lifespan surrogates or a new independent cohort.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C18", "text": "Six-month CR changed human muscle mitochondrial DNA and transcripts and reduced DNA damage. Key mitochondrial enzyme activities were unchanged; molecular markers do not establish lifespan extension.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C19", "text": "Six-month CR changed bone turnover without significant total/hip density loss in young overweight adults. Short duration and nutrient support do not exclude longer-term bone or fracture harm.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C20", "text": "Secondary CALERIE modeling associated meal timing with weight loss beyond restriction. Timing was not independently randomized and the analysis does not establish lifespan mediation.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C21", "text": "Post hoc CALERIE analysis linked metabolic-rate changes to cognitive performance under CR. Moderation and component associations are not a prespecified isolated cognitive mechanism trial.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C22", "text": "FTO genotype did not significantly alter restriction adherence or most aging-related biomarker changes. An exploratory subgroup association is not a Mendelian instrument for lifelong calorie exposure or survival.", "carries_number": false, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C23", "text": "CALERIE samples showed reduced circulating senescence-associated markers and an adipose gene-set signal. Markers and machine-learning prediction of metabolic change do not establish clinical aging reversal.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C24", "text": "Human CR improved thymopoiesis; mouse Pla2g7 deletion improved inflammation and metabolic phenotypes. Human correlation plus mouse deletion is not selectively identified human mediator necessity or mortality benefit.", "carries_number": true, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C25", "text": "Human adipose SPARC reduction motivated inducible adult mouse downregulation and adipocyte deletion with metabolic/inflammatory benefit. CR-like disease physiology is not a measured general lifespan outcome or uniquely necessary CR coordinator.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C26", "text": "CALERIE muscle biopsies showed transcription/splicing changes with preserved strength despite minor lean loss. Statistical pathway mediation and muscle quality are not proof of longer human survival.", "carries_number": false, "load_bearing_for": [ "SC2", "SC4" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C27", "text": "Post hoc CALERIE analysis changed DunedinPACE but not PhenoAge/GrimAge significantly. The primary discussion explicitly requires clinical endpoint follow-up to validate intervention-surrogate mediation; correction remains attached.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec1. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C28", "text": "Doubly labeled water demonstrated reliable energy requirements and substantial self-report intake underestimation. Baseline exposure calibration improves trial interpretation but does not add a survival result.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C29", "text": "CALERIE phase1 food diaries showed nutritional quality maintained or improved under supervised restriction. Not every nutrient reached adequacy in every participant; nutritional quality is not a mortality endpoint.", "carries_number": true, "load_bearing_for": [ "SC3", "SC4" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C30", "text": "Lithocholic acid improved aged-mouse function and extended worm/fly lifespan with AMPK dependence. Mouse functional rescue is distinct from mouse survival; linked correction details were not fully examined.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C31", "text": "LCA-TULP3-sirtuin-vATPase signaling and a muscle mutant linked AMPK to aged-mouse function and worm/fly longevity. Companion work shares the LCA programme and is not an independent lab replication or complete CR necessity test.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C32", "text": "Genetic/pharmacologic polyamine-pathway perturbation abrogated fasting-related autophagy and longevity/health effects in models. Human metabolite changes are not a human longevity intervention; fasting is not identical to calorie restriction.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C33", "text": "Slower RNA polymerase variants extended worm/fly lifespan while restriction reversed age-linked elongation changes. Human cell division capacity is not organismal human lifespan; the complete CR pathway is not isolated.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C34", "text": "Middle-age low-dose metformin improved male-mouse survival/function; high dose was toxic without calorie reduction. A partial CR mimetic is a comparator, not evidence that one conserved CR coordinator is sufficient across humans.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C35", "text": "HIF-1/egl-9 perturbation and tissue rescue linked nutrient-dependent worm longevity to IRE-1. Nutrient context and tissue-specificity constrain the pathway; cross-species unity is not shown.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C36", "text": "Moving yeast mothers removed CR replicative longevity, restored by supplements or conditioned medium; the transferable factor was Sir2-independent. Replicative cell aging and media ecology differ from adult animal or human aging.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C37", "text": "Yeast Hst2 mediated Sir2-independent lifespan extension under restriction. Redundant sirtuin routes challenge single-Sir2 necessity and do not establish a human longevity mechanism.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C38", "text": "Worm p38-ATF7 immune signaling had to be intact but downregulated for dietary longevity. Immune and nutrient pathways are context dependent; correction-body details remain unexamined.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C39", "text": "Emory-mouse restriction extended median survival and reduced cataract/cancer measures. Single-background findings and some adverse tissue signs limit universal healthspan alignment.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C40", "text": "NQO1 knockout retained CR benefits for lifespan, metabolic function and carcinogen outcomes. NQO1 upregulation is not necessary for these tested benefits; retained pathways do not identify a unified alternative.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C41", "text": "Temporary fasting reduced parental worm mortality but produced adverse multigenerational fitness/survival tradeoffs. Generation and exposure schedules limit a universal benefit claim.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C42", "text": "Yeast glucose restriction/PKA perturbation linked respiration and Sir2/NAD to replicative lifespan. Strain and replicative-aging conditions do not establish the same necessary route in other species.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C43", "text": "Adult-onset microRNA/Wnt switching was required for worm dietary longevity. The temporal switch helps separate development, but the specific route remains a worm context.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C44", "text": "Adipose Rictor deletion blocked CR insulin sensitization while preserving fitness and lifespan extension. This directly separates a familiar metabolic marker from the required survival mediator.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C45", "text": "RNAi tests identified nonsense-mediated-decay genes required for worm dietary longevity. Transcript/translatome associations alone are not mediator proof; RNAi survival tests retain their specific scope.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C46", "text": "Foxo3-deficient mice failed to show significant CR lifespan extension while cancer suppression persisted. The reported absence of significance and one genetic setting do not establish universal Foxo3 necessity across all CR protocols.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C47", "text": "Lamin downregulation altered dietary-restriction size/fat phenotypes via RAGC/mTOR localization in worms. This report does not supply a new organismal lifespan rescue result in the examined abstract.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C48", "text": "Sulfur-amino-acid/CGL perturbations blocked DR hepatic stress protection; transsulfuration changes appeared across longevity models. Injury resistance and across-model pathway occurrence do not alone prove a common lifespan mediator.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C49", "text": "Complex-I inhibition extended worm lifespan without reduced intake; neuronal ROS/PMK/SKN perturbations blocked the effect despite AMPK/sirtuin independence. A DR-like pharmacological route is not proof that every dietary protocol uses that mechanism.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C50", "text": "Food odors shortened DR worm lifespan through an olfactory brain-gut octopamine/AMPK route. Perceived food cues modify dietary longevity; mouse primary-cell signaling is not mouse or human lifespan.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C51", "text": "Fusion/fission, fatty-acid oxidation and peroxisomal perturbations separated DR/AMPK/fasting worm longevity requirements. Different dynamic versus stabilized network requirements constrain a unified explanation.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C52", "text": "mekk-3 knockdown induced a dietary-like longevity state without compromised food intake in worms. A genetic mimetic distinguishes sensing from calorie dose but does not establish human extension.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C53", "text": "A cep-1 strain blocked genetic but not nongenetic dietary longevity; authors implicated background mutations. The result cannot be attributed specifically to p53 without resolving linked genetic background.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C54", "text": "Corticosterone replacement restored CR attenuation of edema in hormone-insufficient mice. Anti-inflammatory challenge response is not directly measured lifespan mediation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C55", "text": "SIRT4 loss and CR altered beta-cell GDH/insulin regulation through NAD-dependent modification. This cell/tissue metabolic result does not establish organismal lifespan necessity or a uniform sirtuin activation rule.", "carries_number": true, "load_bearing_for": [ "SC2" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C56", "text": "Hepatic protein replacement rates associated with lifespan extension across mouse interventions. Cross-model biomarker correlation is not causal mediation or another independent survival test.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C57", "text": "Folate supplementation preserved methionine-restriction fly longevity while restoring reproductive capacity. Defined nutrient balance can separate tradeoffs; this is not pure calorie restriction or human lifespan.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 57 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C58", "text": "Nightly time-restricted feeding improved both-sex health measures, while survival extended only in male mice under the shorter window. The strongest group also voluntarily restricted calories; sex and calorie/time factors remain material.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 58 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C59", "text": "CALERIE randomized restriction improved selected mood, general-health and sexual-function questionnaire outcomes. Self-report and unblinded diet intervention limit interpretation; benefits are not durable disease-free survival.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 59 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "C60", "text": "Randomized diet-induced weight loss improved physical performance in older obese adults; exercise combination produced larger gains. Diet alone also reduced lean mass and hip density; the obesity-treatment context does not establish nonobese human lifespan extension.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 60 ], "verification": "verified", "verified_against": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC1", "text": "SC1 reaches Ζ within named experimental contexts. Controlled survival, adult-onset diverse-mouse restriction, calorie/timing separation and genetic pathway contrasts converge beyond one strain or species [1–4,6–8,35–44,46]. Contextual contradictions and healthspan mismatch prevent Η in this bounded appraisal.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 15, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 49, 50, 51, 52, 53, 57, 58 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC2", "text": "SC2 remains Γ for one unified nutrient-sensing coordinator. Several pathways are causally identified in particular systems, but Sir2, NQO1 and insulin-sensitivity contrasts show that familiar routes are not uniformly necessary [35–44,46–57]. Individual constrained pathways can reach Ε without proving unity.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 1, 2, 3, 4, 5, 12, 14, 18, 20, 23, 24, 25, 26, 30, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC3", "text": "SC3 remains Γ for human lifespan extension. Human randomized intervention changes physiological and molecular measures and some function, but no examined study measures extension of human survival or validates those measures as CR-mediated mortality surrogates [16–29,59,60].", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 6, 7, 8, 9, 13, 16, 17, 18, 22, 23, 27, 28, 29 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CSC4", "text": "SC4 reaches Ε for defined human functional outcomes. Randomized restriction improves selected quality-of-life outcomes, and diet-induced weight loss improves physical performance in older adults with obesity [59,60]. Baseline context, follow-up, masking, lean/bone loss and endpoint distinctions bound the conclusion.", "carries_number": false, "load_bearing_for": [ "SC4" ], "source_ns": [ 16, 17, 19, 20, 21, 22, 24, 26, 29, 59, 60 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-04", "note": "" }, { "id": "CH", "text": "Caloric restriction causally extends lifespan in defined animal settings (Ζ) and improves some human functional outcomes (Ε); extending human lifespan remains Γ.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 7, 16, 27, 59, 60 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-04", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Di Francesco A, Deighan AG, Litichevskiy L et al. 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Nature. 2012.", "tier": "A", "kind": "primary", "pmid": "22932268", "doi": "10.1038/nature11432", "url": "https://pubmed.ncbi.nlm.nih.gov/22932268/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NIA-rhesus", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C7", "CSC1", "CSC3", "CH" ] }, { "n": 8, "citation": "Mattison JA, Colman RJ, Beasley TM et al. Caloric restriction improves health and survival of rhesus monkeys. 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Series A, Biological sciences and medical sciences. 2003.", "tier": "A", "kind": "primary", "pmid": "12634286", "doi": "10.1093/gerona/58.3.b212", "url": "https://pubmed.ncbi.nlm.nih.gov/12634286/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID12634286", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C9", "CSC1", "CSC3" ] }, { "n": 10, "citation": "Weed JL, Lane MA, Roth GS et al. Activity measures in rhesus monkeys on long-term calorie restriction. 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Cell systems. 2020.", "tier": "A", "kind": "primary", "pmid": "31982367", "doi": "10.1016/j.cels.2019.12.002", "url": "https://pubmed.ncbi.nlm.nih.gov/31982367/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Wisconsin-rhesus", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C12", "CSC1", "CSC2" ] }, { "n": 13, "citation": "Lane MA, Ingram DK, Roth GS et al. Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk. Toxicological sciences : an official journal of the Society of Toxicology. 1999.", "tier": "A", "kind": "primary", "pmid": "10630589", "doi": "10.1093/toxsci/52.2.41", "url": "https://pubmed.ncbi.nlm.nih.gov/10630589/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "NIA-rhesus", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C13", "CSC1", "CSC3" ] }, { "n": 14, "citation": "Rhoads TW, Burhans MS, Chen VB et al. Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys. Cell metabolism. 2018.", "tier": "A", "kind": "primary", "pmid": "29514073", "doi": "10.1016/j.cmet.2018.01.014", "url": "https://pubmed.ncbi.nlm.nih.gov/29514073/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "PMID29514073", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C14", "CSC2" ] }, { "n": 15, "citation": "Raman A, Baum ST, Colman RJ et al. Metabolizable energy intake during long-term calorie restriction in rhesus monkeys. Experimental gerontology. 2007.", "tier": "A", "kind": "primary", "pmid": "17618073", "doi": "10.1016/j.exger.2007.05.008", "url": "https://pubmed.ncbi.nlm.nih.gov/17618073/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "Wisconsin-rhesus", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C15", "CSC1" ] }, { "n": 16, "citation": "Ravussin E, Redman LM, Rochon J et al. A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. The journals of gerontology. 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PLoS medicine. 2007.", "tier": "A", "kind": "rct", "pmid": "17341128", "doi": "10.1371/journal.pmed.0040076", "url": "https://pubmed.ncbi.nlm.nih.gov/17341128/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE1-NCT00099151", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C18", "CSC2", "CSC3" ] }, { "n": 19, "citation": "Redman LM, Rood J, Anton SD et al. Calorie restriction and bone health in young, overweight individuals. Archives of internal medicine. 2008.", "tier": "A", "kind": "rct", "pmid": "18809812", "doi": "10.1001/archinte.168.17.1859", "url": "https://pubmed.ncbi.nlm.nih.gov/18809812/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE1-NCT00099151", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C19", "CSC4" ] }, { "n": 20, "citation": "Fleischer JG, Das SK, Bhapkar M et al. Associations between the timing of eating and weight-loss in calorically restricted healthy adults: Findings from the CALERIE study. 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Journal of psychiatric research. 2020.", "tier": "A", "kind": "rct", "pmid": "32485641", "doi": "10.1016/j.jpsychires.2020.05.018", "url": "https://pubmed.ncbi.nlm.nih.gov/32485641/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C21", "CSC4" ] }, { "n": 22, "citation": "Dorling JL, Belsky DW, Racette SB et al. Association between the FTO rs9939609 single nucleotide polymorphism and dietary adherence during a 2-year caloric restriction intervention: Exploratory analyses from CALERIE™ phase 2. 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Aging cell. 2024.", "tier": "A", "kind": "primary", "pmid": "37961856", "doi": "10.1111/acel.14038", "url": "https://pubmed.ncbi.nlm.nih.gov/37961856/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C23", "CSC2", "CSC3" ] }, { "n": 24, "citation": "Spadaro O, Youm Y, Shchukina I et al. Caloric restriction in humans reveals immunometabolic regulators of health span. Science (New York, N.Y.). 2022.", "tier": "A", "kind": "primary", "pmid": "35143297", "doi": "10.1126/science.abg7292", "url": "https://pubmed.ncbi.nlm.nih.gov/35143297/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C24", "CSC2", "CSC4" ] }, { "n": 25, "citation": "Ryu S, Spadaro O, Sidorov S et al. Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity. The Journal of clinical investigation. 2023.", "tier": "A", "kind": "primary", "pmid": "37781916", "doi": "10.1172/JCI169173", "url": "https://pubmed.ncbi.nlm.nih.gov/37781916/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C25", "CSC2" ] }, { "n": 26, "citation": "Das JK, Banskota N, Candia J et al. Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study. Aging cell. 2023.", "tier": "A", "kind": "rct", "pmid": "37823711", "doi": "10.1111/acel.13963", "url": "https://pubmed.ncbi.nlm.nih.gov/37823711/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "abstract_metadata", "access_note": "Complete primary abstract and linked-status metadata examined. No complete-paper or supplement audit claimed.", "carries_claims": [ "C26", "CSC2", "CSC4" ] }, { "n": 27, "citation": "Waziry R, Ryan CP, Corcoran DL et al. Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nature aging. 2023.", "tier": "A", "kind": "rct", "pmid": "37118425", "doi": "10.1038/s43587-022-00357-y", "url": "https://pubmed.ncbi.nlm.nih.gov/37118425/", "status_flags": [ "ErratumIn: PMID37161091" ], "opened": true, "opened_on": "2026-10-04", "status_checked_on": "2026-10-04", "study_id": "CALERIE2-NCT00427193", "access_depth": "full_text_partial", "access_note": "Complete primary abstract and linked-status metadata examined. Selected body sections: Sec1. No complete-paper or supplement audit claimed.", "carries_claims": [ "C27", "CSC3", "CH" ] }, { "n": 28, "citation": "Redman LM, Kraus WE, Bhapkar M et al. Energy requirements in nonobese men and women: results from CALERIE. 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These are one exposure intervention family, not two independent lines by paper count." }, { "label": "Genetic necessity and dissociation", "sources": [ 46, 44, 40, 43 ], "excludes_error": "Loss-of-function contrasts identify or reject specific required routes and separate insulin sensitization, cancer suppression and developmental Wnt effects from survival. A generic metabolic biomarker explanation cannot generate these discriminating results." }, { "label": "Long-lived primate protocol comparison", "sources": [ 6, 7 ], "excludes_error": "A long-lived primate setting challenges a mouse-only tumor/husbandry account and independently maps diet/onset limits. The two primate cohorts and their combined report are not counted again as independent reports." } ], "shared_failure_mode_checked": true, "note": "Ζ refers to the narrow animal survival subclaim and the parallel-pathway model's actually demonstrated settings. Independence rests on intervention assignment/feeding control, genotype-specific mechanistic discrimination and the long-lived primate context excluding different errors; repeated cohorts do not add lines. CALERIE phase2 reports share NCT00427193, phase1 pooled nutritional data overlap phase1 mitochondrial/bone work, and the 2017 primate analysis reuses Wisconsin/NIA cohorts. LCA companion papers share one programme. No human survival convergence is asserted." }, "consensus_validation": { "slug": "caloric-restriction", "completed": true, "provider_mode": "Consensus Pro browser response (preserved exact provider output) plus Consensus MCP keyword search and record fetch; source comparison against frozen review inventory and PubMed abstracts", "cutoff": "2026-10-04 (frozen review cutoff)", "queries": [ "exact calorie restriction longevity human CALERIE randomized trial oxidative stress insulin IGF-1 rhesus macaque lifespan comparison", "Preserved Pro browser query: https://consensus.app/search/caloric-restriction-mice-human-calorie-restriction-survival/hf_Mm4R0QXm5_QF3UMqz0A/" ], "raw_paths": [ "checks/caloric-restriction/browser-thread.json", "checks/caloric-restriction/consensus-browser-response.md", "checks/caloric-restriction/mcp-consensus-search-01.json", "checks/caloric-restriction/mcp-consensus-fetch-d1a0f0d388b956c2ab17bde425cdc829.json", "checks/caloric-restriction/mcp-consensus-fetch-e396a4dee95450f0bfa15f9f523b0fd5.json" ], "source_counts_preserved": { "primary_reports": 60, "claims": 65 }, "primary_comparisons": [ { "pmid": "19590001", "doi": "10.1126/science.1173635", "review_source_n": 6, "source_type": "primary animal study", "access_depth": "PubMed abstract and linked-status metadata; no complete-paper/supplement audit", "result_comparison": "Wisconsin rhesus survival benefit in studied setting supports animal lifespan, not human lifespan; existing frozen source.", "already_present": true }, { "pmid": "22932268", "doi": "10.1038/nature11432", "review_source_n": 7, "source_type": "primary animal study", "access_depth": "PubMed abstract and linked-status metadata; no complete-paper/supplement audit", "result_comparison": "NIA rhesus cohort had health benefits without improved survival; constrains universal primate survival claim; existing frozen source.", "already_present": true }, { "pmid": "28094793", "doi": "10.1038/ncomms14063", "review_source_n": 8, "source_type": "primary animal cohort comparison", "access_depth": "PubMed abstract and linked-status metadata; no complete-paper/supplement audit", "result_comparison": "Compares the same two rhesus cohorts; divergent survival, shared health effects; not an independent replication; existing frozen source.", "already_present": true }, { "pmid": "27136347", "doi": "10.1001/jamainternmed.2016.1189", "review_source_n": 59, "source_type": "primary human randomized trial", "access_depth": "PubMed abstract and linked-status metadata; no complete-paper/supplement audit", "result_comparison": "CALERIE 2 randomized 220 non-obese adults for two years; function-related outcomes, not lifespan/mortality; existing frozen source.", "already_present": true } ], "score_before": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "60 primary reports with 3 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The registered scope-matched human-lifespan gate SC3 returns Γ. SC1 animal survival reaches Ζ and SC4 human function reaches Ε; the candidate unified mechanism SC2 is separately Γ and is not an added necessary clause of the generic exposure claim. All preregistered aggregation sensitivities happen to return Γ." }, "score_after": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "60 primary reports with 3 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness.", "rests_on_non_peer_reviewed_work": false, "rationale": "The registered scope-matched human-lifespan gate SC3 returns Γ. SC1 animal survival reaches Ζ and SC4 human function reaches Ε; the candidate unified mechanism SC2 is separately Γ and is not an added necessary clause of the generic exposure claim. All preregistered aggregation sensitivities happen to return Γ." }, "grade_changed": false, "conclusion": "Human lifespan extension remains Γ because animal survival and human physiological/function outcomes do not substitute for human mortality or a validated mortality surrogate. 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