source · application/json
source_73c7a976a52e4f21
sha256 c03584258f7875ea5b2f6852751af6eedf8eaa09884035619bcc04a6fd9dc141
by researka:v2 · 2026-06-22 08:30:13.360822+04:00
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Source-bundle reconciliation note: Directional coding is conservative claim-level coding from extracted claim records, not a statement that the source texts contain no directional findings; source-level positive, negative, or unclear findings should be interpreted through the coded outcome class, directness, and claim-count fields. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims.", "type": "claim"}, {"id": "claim_2", "text": "This paper synthesizes evidence on Growth differentiation factor 11 across 48 included source papers and 2684 high-confidence extracted claims.", "type": "claim"}, {"id": "claim_3", "text": "The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 39 adjacent clinical sources, and 9 mechanistic or model-system sources, with 152 cross-study disagreements across the evidence base.", "type": "claim"}, {"id": "claim_4", "text": "Positive study-level signals are not the dominant direction in any outcome class; null signals are summarized in the contextual adjacent evidence, cardiometabolic, and muscle function outcome classes; negative signals are not the dominant direction in any outcome class; mixed or heterogeneous signals are summarized in the mechanism, mortality and survival, frailty, and immune and inflammation outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.", "type": "claim"}, {"id": "claim_5", "text": "The conclusion is that Growth differentiation factor 11 should be treated as a bounded geroscience hypothesis: the retained clinical and adjacent evidence profile defines the scope for targeted testing, while mixed and null findings limit any unqualified anti-aging claim.", "type": "claim"}, {"id": "claim_6", "text": "| Evidence domain | Corpus slice | Strongest signal | Directness | Main limitation |", "type": "claim"}, {"id": "claim_7", "text": "| Contextual Adjacent Evidence | n=31; claims=1456 | no extracted directional signal in 22/31 sources | 31 indirect | limited corpus depth in this outcome class |", "type": "claim"}, {"id": "claim_8", "text": "Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.", "type": "claim"}, {"id": "claim_9", "text": "This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.", "type": "claim"}, {"id": "claim_10", "text": "31 included sources were assigned to this outcome class. Directional coding: mixed=1, negative=4, null=22, positive=2, unclear=2. Directness coding: indirect=31.", "type": "claim"}, {"id": "claim_11", "text": "6 included sources were assigned to this outcome class. Directional coding: negative=2, null=2, unclear=2. Directness coding: mechanistic=6.", "type": "claim"}, {"id": "claim_12", "text": "4 included sources were assigned to this outcome class. Directional coding: null=4. Directness coding: indirect=3, mechanistic=1.", "type": "claim"}, {"id": "claim_13", "text": "3 included sources were assigned to this outcome class. Directional coding: null=2, unclear=1. Directness coding: indirect=1, mechanistic=1, review=1.", "type": "claim"}, {"id": "claim_14", "text": "2 included sources were assigned to this outcome class. Directional coding: mixed=1, null=1. Directness coding: indirect=2.", "type": "claim"}, {"id": "claim_15", "text": "Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.", "type": "claim"}, {"id": "claim_16", "text": "In animal/preclinical evidence, several clinically relevant endpoints were not measured at all. Gait speed — a canonical functional marker with reference values such as 0.8 m/s (Studenski 2011) and a 0.1 m/s meaningful change (Perera 2006) — does not appear in any source. Incident diabetes, glycemic control against the 7% HbA1c target (ADA 2024), and BMI-stratified obesity outcomes (WHO 2000: 25 kg/m² overweight, 30 kg/m² obesity) appear only as mechanistic context (Lu 2019; Walker 2020) and not as adjudicated trial endpoints. The corpus therefore cannot speak to whether GDF11 modification would shift any of the standard geriatric or metabolic endpoints used in clinical practice.", "type": "claim"}, {"id": "claim_17", "text": "Several clinically relevant claims are supported only by mechanistic evidence, leaving a documented mechanism-to-clinic gap. Pending further trials that resolve the 152 surfaced tensions, the responsible clinical posture is to treat GDF11 as a hypothesis-generating biomarker and a promising but unproven therapeutic target.", "type": "claim"}, {"id": "claim_18", "text": "This synthesis maps 48 included sources on GDF11 across 7 outcome classes and 152 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.", "type": "claim"}, {"id": "claim_19", "text": "Across 48 curated reference papers, the evidence base for GDF11 shows a context-dependent profile. Positive signals appear in: contextual other. Negative signals appear in: contextual other, mechanism. Null findings dominate: contextual other, cardiometabolic. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The GDF11 anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.", "type": "claim"}, {"id": "claim_20", "text": "The strongest unresolved contrast is the disagreement between Elliott 2017 and Frohlich 2020 on contextual adjacent evidence (severity 5/5), which defines the boundary condition future studies must test rather than smooth over.", "type": "claim"}, {"id": "claim_21", "text": "In animal/preclinical evidence, prior reviews in the corpus (Smith 2015) emphasize convergent signals on GDF11. This synthesis adds a design-level evidence-weighting layer and an explicit cross-study disagreement map, keeping boundary conditions visible instead of averaging them away in narrative summary.", "type": "claim"}, {"id": "claim_22", "text": "| Evidence domain | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |", "type": "claim"}, {"id": "claim_23", "text": "| muscle function | 0 | 3 | null, unclear | direct interventional hard-endpoint gap |", "type": "claim"}, {"id": "claim_24", "text": "| contextual adjacent evidence | 0 | 31 | mixed, negative, null, positive, unclear | conflict-resolution gap |", "type": "claim"}, {"id": "claim_25", "text": "| mortality and survival | 0 | 2 | mixed, null | direct interventional hard-endpoint gap |", "type": "claim"}, {"id": "claim_26", "text": "| P1 | cardiometabolic: direct interventional hard-endpoint gap | 0 direct and 4 indirect sources; direction profile: null |", "type": "claim"}, {"id": "claim_27", "text": "| P3 | mechanism: conflict-resolution gap | 0 direct and 6 indirect sources; direction profile: negative, null, unclear |", "type": "claim"}, {"id": "claim_28", "text": "| P4 | muscle function: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null, unclear |", "type": "claim"}, {"id": "claim_29", "text": "The next high-yield study for GDF11 should target the **cardiometabolic** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.", "type": "claim"}, {"id": "claim_30", "text": "The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.", "type": "claim"}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s41467-023-43292-1", "effect": "not extracted", "endpoint": "not extracted", "id": "source_1", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21", "type": "source", "url": "https://doi.org/10.1038/s41467-023-43292-1", "year": 2023}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1007/s10522-022-09967-w", "effect": "not extracted", "endpoint": "not extracted", "id": "source_2", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Dietary intake of GDF11 delays the onset of several biomarkers of aging in male mice through anti-oxidant system via Smad2/3 pathway", "type": "source", "url": "https://doi.org/10.1007/s10522-022-09967-w", "year": 2022}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s41467-025-61815-w", "effect": "not extracted", "endpoint": "not extracted", "id": "source_3", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Activated GDF11/8 subforms predict cardiovascular events and mortality in humans", "type": "source", "url": "https://doi.org/10.1038/s41467-025-61815-w", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s43587-022-00352-3", "effect": "not extracted", "endpoint": "not extracted", "id": "source_4", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Systemic GDF11 attenuates depression-like phenotype in aged mice via stimulation of neuronal autophagy", "type": "source", "url": "https://doi.org/10.1038/s43587-022-00352-3", "year": 2023}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3389/fendo.2023.1137048", "effect": "not extracted", "endpoint": "not extracted", "id": "source_5", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Acute endurance exercise modulates growth differentiation factor 11 in cerebrospinal fluid of healthy young adults", "type": "source", "url": "https://doi.org/10.3389/fendo.2023.1137048", "year": 2023}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s42003-024-07342-8", "effect": "not extracted", "endpoint": "not extracted", "id": "source_6", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Protogenin facilitates trunk-to-tail HOX code transition via modulating GDF11/SMAD2 signaling in mammalian embryos", "type": "source", "url": "https://doi.org/10.1038/s42003-024-07342-8", "year": 2024}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3389/fphys.2021.726345", "effect": "not extracted", "endpoint": "not extracted", "id": "source_7", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity", "type": "source", "url": "https://doi.org/10.3389/fphys.2021.726345", "year": 2021}, {"comparator": "not extracted", "directness": "primary", "doi": "10.7554/eLife.83806", "effect": "not extracted", "endpoint": "not extracted", "id": "source_8", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "MeCP2 regulates Gdf11 , a dosage-sensitive gene critical for neurological function", "type": "source", "url": "https://doi.org/10.7554/eLife.83806", "year": 2023}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1016/j.ymthe.2025.07.003", "effect": "not extracted", "endpoint": "not extracted", "id": "source_9", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "GDF11-secreting cell transplant efficiently ameliorates age-related pulmonary fibrosis", "type": "source", "url": "https://doi.org/10.1016/j.ymthe.2025.07.003", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1186/s12860-023-00478-1", "effect": "not extracted", "endpoint": "not extracted", "id": "source_10", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Myogenic differentiation of human myoblasts and Mesenchymal stromal cells under GDF11 on Poly-ɛ-caprolactone-collagen I-Polyethylene-nanofibers", "type": "source", "url": "https://doi.org/10.1186/s12860-023-00478-1", "year": 2023}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s41598-020-61443-y", "effect": "not extracted", "endpoint": "not extracted", "id": "source_11", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice", "type": "source", "url": "https://doi.org/10.1038/s41598-020-61443-y", "year": 2020}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1093/cvr/cvad153", "effect": "not extracted", "endpoint": "not extracted", "id": "source_12", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Circulating GDF11 exacerbates myocardial injury in mice and associates with increased infarct size in humans", "type": "source", "url": "https://doi.org/10.1093/cvr/cvad153", "year": 2023}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1111/cpr.13310", "effect": "not extracted", "endpoint": "not extracted", "id": "source_13", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "GDF11 inhibits adipogenesis and improves mature adipocytes metabolic function via WNT/β‐catenin and ALK5/SMAD2/3 pathways", "type": "source", "url": "https://doi.org/10.1111/cpr.13310", "year": 2022}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s42003-025-09078-5", "effect": "not extracted", "endpoint": "not extracted", "id": "source_14", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "GDF11 alleviates glucocorticoid-induced osteonecrosis of the femoral head by regulating angiogenesis via the PI3K-AKT-eNOS pathway", "type": "source", "url": "https://doi.org/10.1038/s42003-025-09078-5", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.18632/aging.104182", "effect": "not extracted", "endpoint": "not extracted", "id": "source_15", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "GDF11 induces mild hepatic fibrosis independent of metabolic health", "type": "source", "url": "https://doi.org/10.18632/aging.104182", "year": 2020}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1038/s41419-021-03954-8", "effect": "not extracted", "endpoint": "not extracted", "id": "source_16", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity", "type": "source", "url": "https://doi.org/10.1038/s41419-021-03954-8", "year": 2021}, {"comparator": "not extracted", "directness": "primary", "doi": "10.3389/fragi.2026.1736069", "effect": "not extracted", "endpoint": "not extracted", "id": "source_17", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Elevated circulating GDF11 and its role in age-related sarcopenia: insights from clinical, transcriptomic, and in vitro analyses", "type": "source", "url": "https://doi.org/10.3389/fragi.2026.1736069", "year": 2026}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1016/j.jare.2024.08.001", "effect": "not extracted", "endpoint": "not extracted", "id": "source_18", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "GDF11 protects against mitochondrial-dysfunction-dependent NLRP3 inflammasome activation to attenuate osteoarthritis", "type": "source", "url": "https://doi.org/10.1016/j.jare.2024.08.001", "year": 2024}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1136/gutjnl-2019-318812", "effect": "not extracted", "endpoint": "not extracted", "id": "source_19", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells", "type": "source", "url": "https://doi.org/10.1136/gutjnl-2019-318812", "year": 2020}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1073/pnas.1916034117", "effect": "not extracted", "endpoint": "not extracted", "id": "source_20", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone", "type": "source", "url": "https://doi.org/10.1073/pnas.1916034117", "year": 2020}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1016/j.xhgg.2025.100559", "effect": "not extracted", "endpoint": "not extracted", "id": "source_21", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Investigating and correcting a rare pathogenic mutation in GDF11", "type": "source", "url": "https://doi.org/10.1016/j.xhgg.2025.100559", "year": 2025}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1016/j.jpha.2023.09.013", "effect": "not extracted", "endpoint": "not extracted", "id": "source_22", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Hapln1 promotes dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping", "type": "source", "url": "https://doi.org/10.1016/j.jpha.2023.09.013", "year": 2024}, {"comparator": "not extracted", "directness": "primary", "doi": "10.2147/COPD.S301690", "effect": "not extracted", "endpoint": "not extracted", "id": "source_23", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Longitudinal Relationship Between Growth Differentiation Factor 11 and Physical Activity in Chronic Obstructive Pulmonary Disease", "type": "source", "url": "https://doi.org/10.2147/COPD.S301690", "year": 2021}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1007/s10522-023-10054-x", "effect": "not extracted", "endpoint": "not extracted", "id": "source_24", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Evaluation of potential aging biomarkers in healthy individuals: telomerase, AGEs, GDF11/15, sirtuin 1, NAD+, NLRP3, DNA/RNA damage, and klotho", "type": "source", "url": "https://doi.org/10.1007/s10522-023-10054-x", "year": 2023}, {"comparator": "not extracted", "directness": "primary", "doi": "10.1111/acel.13532", "effect": "not extracted", "endpoint": "not extracted", "id": "source_25", "intervention_or_exposure": "not extracted", "population": "not extracted", "risk_of_bias": "not appraised in public sidecar", "study": "Growth differentiation factor 11 accelerates liver senescence through the inhibition of autophagy", "type": 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