{"@context":"https://w3id.org/ro/crate/1.1/context","@type":"Dataset","id":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","name":"Research Synthesis: Epigenetic Clocks — full paper","doi":"10.17605/OSF.IO/K3XRA","doi_status":"minted","osf_url":"https://osf.io/k3xra/","dw_chain_url":"https://provenance.researka.org/artifacts/claim_9278650ba6ab48b5/chain","content_hash":"sha256:4124c2c10671fcbe63a4da878db0e3246a1dacc9cca58c9d161df154c76fc3b7","provenance_passport":{"publication_id":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","submission_id":"c3970068-614b-437f-8ae9-14771ee32227","artifact_type":"research_paper","decision":"accept","content_hash":"sha256:4124c2c10671fcbe63a4da878db0e3246a1dacc9cca58c9d161df154c76fc3b7","persistent_identifiers":{"doi":"10.17605/OSF.IO/K3XRA","osf_url":"https://osf.io/k3xra/","orcid":null,"ror_id":null,"raid_id":null},"persistent_identifier_status":{"doi":"supplied","osf_url":"supplied","orcid":"not_supplied","ror_id":"not_supplied","raid_id":"not_supplied"},"institution":{"name":null,"ror_id":null,"status":"not_supplied"},"integrity":null,"provenance":{"dw_artifact_id":"claim_9278650ba6ab48b5","dw_chain_url":"https://provenance.researka.org/artifacts/claim_9278650ba6ab48b5/chain"},"timeline":["submission_intake","autonomous_review","autonomous_editorial_decision","autonomous_publish"]},"publication":{"id":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","object_type":"publication","parent_object_id":"c3970068-614b-437f-8ae9-14771ee32227","title":"Research Synthesis: Epigenetic Clocks — full paper","body_markdown":"# Research Synthesis: Epigenetic Clocks — full paper\n\n## Abstract\n\nEvidence-honesty note: 35/44 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. 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.\n\nThis paper synthesizes epigenetic clocks as an aging-related intervention across 44 included source papers and 1357 high-confidence extracted claims.\n\nThe evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 38 adjacent clinical sources, and 4 mechanistic or model-system sources, with 509 cross-study disagreements across the evidence base.\n\nNo single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals cluster in the contextual adjacent evidence and longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.\n\nThe conclusion is that epigenetic clocks 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.\n\n## Results\n\n**Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.\n\n| Outcome class | Corpus slice | Strongest signal | Directness | Main limitation |\n|---|---|---|---|---|\n| Contextual Adjacent Evidence | n=32; claims=1073 | no extracted directional signal in 28/32 sources | 28 indirect; 3 mechanistic; 1 review | limited corpus depth in this outcome class |\n| Longevity | n=5; claims=83 | no extracted directional signal in 3/5 sources | 5 indirect | limited corpus depth in this outcome class |\n| Immune and Inflammation | n=3; claims=59 | no extracted directional signal in 3/3 sources | 3 indirect | limited corpus depth in this outcome class |\n| Mortality and Survival | n=3; claims=39 | unclear signal in 2/3 sources | 1 indirect; 2 review | limited corpus depth in this outcome class |\n| Frailty | n=1; claims=103 | mixed signal in 1/1 sources | 1 indirect | single-source slice; hypothesis-generating |\n\nThis evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.\n\n### Contextual Adjacent Evidence Outcomes\n\n32 included sources were assigned to this outcome class. Directional coding: mixed=1, negative=1, null=28, unclear=2. Directness coding: indirect=28, mechanistic=3, review=1.\n\n### Longevity Outcomes\n\n5 included sources were assigned to this outcome class. Directional coding: negative=1, null=3, unclear=1. Directness coding: indirect=5.\n\n### Immune Inflammation Outcomes\n\n3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3.\n\n### Mortality Survival Outcomes\n\n3 included sources were assigned to this outcome class. Directional coding: null=1, unclear=2. Directness coding: indirect=1, review=2.\n\n### Frailty Outcomes\n\n1 included source were assigned to this outcome class. Directional coding: mixed=1. Directness coding: indirect=1.\n\n## Limitations\n\n**Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.\n\nThe curated corpus is dominated by observational cohort designs; no large, long-term randomized controlled trial testing whether modulating epigenetic clocks extends human lifespan or reduces hard clinical endpoints such as incident dementia or cardiovascular death was represented. Consequently, the headline conclusion that accelerated epigenetic aging predicts adverse outcomes cannot be interpreted as causal, and the specific question of whether therapeutic epigenetic age reversal improves survival remains unanswered by this evidence base.\n\nSeveral clinically relevant findings rest on a single contributing study, precluding internal replication within the corpus. Because no other corpus study examined these same exposure–outcome pairs, effect sizes for mortality prediction, reproductive aging, and neuropsychiatric genetic burden cannot be cross-validated within the current synthesis, and the stability of these estimates across independent samples is unknown.\n\nEnrolled populations skew heavily toward adults of European ancestry sampled from high-income settings, limiting generalizability. No study in the corpus focused specifically on children, adolescents, or populations from sub-Saharan Africa, South Asia, or Latin America.\n\nThe corpus provides limited evidence for mechanism-to-clinic translation because preclinical and mechanistic findings were not corroborated by matched human intervention data. Marinello 2025 demonstrated in a preclinical ovary model that epigenetic age tracked with ovarian reserve markers, yet no human trial in the corpus tested whether pharmacological rescue of ovarian aging alters clock readings. Pending further randomized trials, the use of epigenetic clocks as primary endpoints to guide anti-aging interventions or to market a proven standalone geroprotective intervention is not currently supported.\n\n## Conclusion\n\nFor epigenetic clocks, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.\n\n## What This Synthesis Adds\n\nThis synthesis maps 44 included sources on Epigenetic clock across 5 outcome classes and 509 cross-study disagreements. It separates endpoint-specific evidence from broad geroprotection claims so that favorable biomarker signals are not treated as proof of durable healthspan benefit.\n\nAcross 44 curated reference papers, the evidence base for Epigenetic clock shows a context-dependent profile. Negative signals appear in: contextual other, longevity. Null findings dominate: contextual other, immune inflammation. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Epigenetic clock anti-aging case as currently constituted is incomplete: mechanistic plausibility coexists with mixed or sparse human-RCT evidence, and the boundary conditions remain to be established.\n\nThe strongest unresolved contrast is the disagreement between Bozack 2023 and Corley 2023 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.\n\nPrior reviews in the corpus (Fransquet 2019) emphasize convergent signals on Epigenetic clock. 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.\n\n### Boundary-Condition Matrix\n\n| Outcome class | Direct sources | Indirect / mechanism sources | Direction profile | Interpretation boundary |\n|---|---:|---:|---|---|\n| longevity | 0 | 5 | negative, null, unclear | direct interventional hard-endpoint gap |\n| frailty | 0 | 1 | mixed | direct interventional hard-endpoint gap |\n| contextual adjacent evidence | 0 | 32 | mixed, negative, null, unclear | conflict-resolution gap |\n| mortality and survival | 0 | 3 | null, unclear | direct interventional hard-endpoint gap |\n| immune and inflammation | 0 | 3 | null | direct interventional hard-endpoint gap |\n\n### Evidence-Gap Priority\n\n| Priority | Gap | Rationale |\n|---|---|---|\n| P1 | longevity: direct interventional hard-endpoint gap | 0 direct and 5 indirect sources; direction profile: negative, null, unclear |\n| P2 | frailty: direct interventional hard-endpoint gap | 0 direct and 1 indirect source; direction profile: mixed |\n| P3 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 32 indirect sources; direction profile: mixed, negative, null, unclear |\n| P4 | mortality and survival: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null, unclear |\n| P5 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null |\n\n### Next-Study Design Recommendation\n\nThe next high-yield study for Epigenetic clock should target the **longevity** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.\n\n## Evidence Snapshot\n\nThe manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.\n\n### Classification Criteria\n\n- **Outcome class** is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.\n- **Directness** is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.\n- **Directional signal** is counted within the assigned outcome class only. A `no extracted directional signal` cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.\n- **Evidence tier** follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.\n\n### Source Classification Map\n\nEach retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.\n\n- The epigenetic clock as a predictor of disease and mortality risk: a systematic review and meta-analysis: outcome=mortality survival; directness=review; tier=B1; direction=unclear; claims=22.\n- DNA methylation age at birth and childhood: performance of epigenetic clocks and characteristics associated with epigenetic age acceleration in the Project Viva cohort: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=142.\n- A combination nutritional supplement reduces DNA methylation age only in older adults with a raised epigenetic age: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=123.\n- Weight management intervention identifies association of decreased DNA methylation age with improved functional age measures in older adults with obesity: outcome=frailty; directness=indirect; tier=B2; direction=mixed; claims=103.\n- ADHD genetic burden associates with older epigenetic age: mediating roles of education, behavioral and sociodemographic factors among older adults: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=91.\n- Epigenetic Clocks of Biological Aging and Risk of Incident Mild Cognitive Impairment and Dementia: The Women's Health Initiative Memory Study: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=negative; claims=83.\n- Effects of a natural ingredients-based intervention targeting the hallmarks of aging on epigenetic clocks, physical function, and body composition: a single-arm clinical trial: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=76.\n- Sociodemographic and Lifestyle Factors and Epigenetic Aging in US Young Adults: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=50.\n- Genetic association of the gut microbiota with epigenetic clocks mediated by inflammatory cytokines: a Mendelian randomization analysis: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=46.\n- Cell‐type specific impact of metformin on monocyte epigenetic age reversal in virally suppressed older people living with HIV: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=mixed; claims=43.\n- GrimAge and GrimAge2 Age Acceleration effectively predict mortality risk: a retrospective cohort study: outcome=longevity; directness=indirect; tier=B2; direction=negative; claims=40.\n- Universal DNA methylation age across mammalian tissues: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=36.\n- Multi‐Omics Analysis Reveals Biomarkers That Contribute to Biological Age Rejuvenation in Response to Single‐Blinded Randomized Placebo‐Controlled Therapeutic Plasma Exchange: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=32.\n- Alcohol and aging: Next‐generation epigenetic clocks predict biological age acceleration in individuals with alcohol use disorder: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=32.\n- An Epigenetic Clock for Accurate Age Prediction in Atlantic Cod Populations for Improved Fisheries Management: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=31.\n- Association of a pace of aging epigenetic clock with rate of cognitive decline in the Framingham Heart Study Offspring Cohort: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=27.\n- Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=23.\n- Frailty is associated with the epigenetic clock but not with telomere length in a German cohort: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=22.\n- Does the epigenetic clock GrimAge predict mortality independent of genetic influences: an 18 year follow-up study in older female twin pairs: outcome=longevity; directness=indirect; tier=B2; direction=unclear; claims=18.\n- Epigenetic Clock Analysis of Sex Chromosome Aneuploidies: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=17.\n- Associations of Age, Sex, Race/Ethnicity, and Education With 13 Epigenetic Clocks in a Nationally Representative U.S. Sample: The Health and Retirement Study: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=16.\n- A blood-based epigenetic clock for intrinsic capacity predicts mortality and is associated with clinical, immunological and lifestyle factors: outcome=mortality survival; directness=indirect; tier=B2; direction=unclear; claims=16.\n- Development of an epigenetic clock to predict visual age progression of human skin: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=15.\n- Epigenetic Clocks Relate to 4 Age-related Health Outcomes Similarly Across 3 Countries: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=14.\n- Epigenetic Clock in Bears: A Simple Cost‐Effective Blood DNA Methylation‐Based Age Estimation Method Applicable to Multiple Bear Species: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=14.\n- DNA methylation age analysis of rapamycin in common marmosets: outcome=longevity; directness=indirect; tier=B2; direction=null; claims=13.\n- Cell-type specific epigenetic clocks to quantify biological age at cell-type resolution: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=12.\n- A pan-tissue DNA-methylation epigenetic clock based on deep learning: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=10.\n- Epigenetic Clocks and Their Prospective Application in the Complex Landscape of Aging and Alzheimer’s Disease: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=10.\n- Epigenetic clock and DNA methylation analysis of porcine models of aging and obesity: outcome=longevity; directness=indirect; tier=B2; direction=null; claims=9.\n- HIV-1 Infection Accelerates Age According to the Epigenetic Clock: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=8.\n- A Targeted Epigenetic Clock for the Prediction of Biological Age: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=7.\n- An ELOVL2-Based Epigenetic Clock for Forensic Age Prediction: A Systematic Review: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=6.\n- Faster DunedinPACE, an epigenetic clock for pace of biological aging, is associated with accelerated cognitive aging among older adults in the Framingham Heart Study: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=6.\n- Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=6.\n- Deciphering the role of immune cell composition in epigenetic age acceleration: Insights from cell‐type deconvolution applied to human blood epigenetic clocks: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=5.\n- Systematic underestimation of the epigenetic clock and age acceleration in older subjects: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=4.\n- An epigenetic clock to estimate the age of living beluga whales: outcome=longevity; directness=indirect; tier=B2; direction=null; claims=3.\n- Epigenetic clock and methylation study of oocytes from a bovine model of reproductive aging: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=1.\n- DNA methylation age is accelerated in alcohol dependence: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=1.\n\n### Load-Bearing Included Studies\n\n- Fransquet 2019; Review / meta-analysis; tier=B1; directness=review; N=—; population=—; endpoint=mortality survival; direction=unclear; representative statistic=P = 0.008.\n- Bozack 2023; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.001.\n- McGee 2024; Observational; tier=B2; directness=indirect; N=—; population=older adults; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.0058.\n- Petersen 2021; Observational; tier=B2; directness=indirect; N=—; population=older adults; endpoint=frailty; direction=mixed; representative statistic=P < 0.01.\n- Arpawong 2023; Observational; tier=B2; directness=indirect; N=—; population=older adults; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.0001.\n- Nguyen 2026; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=negative; representative statistic=P = 0.01.\n- Carreras-Gallo 2025; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.0038.\n- Harris 2024; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=null.\n- Tian 2024; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=immune inflammation; direction=null; representative statistic=P = 0.0002.\n- Corley 2023; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=mixed; representative statistic=P = 0.01.\n\n### Load-Bearing Tensions\n\nAdditional corpus sources included animal/preclinical evidence; - Severity 4 disagreement: Bozack 2023 vs Corley 2023; Bozack 2023 (null) vs Corley 2023 (mixed) on contextual other\n- Severity 4 disagreement: Arpawong 2023 vs Corley 2023; Arpawong 2023 (null) vs Corley 2023 (mixed) on contextual other\n- Severity 4 disagreement: Lu 2023 vs Corley 2023; Lu 2023 (unclear) vs Corley 2023 (mixed) on contextual other\n- Severity 4 disagreement: Corley 2023 vs Bienkowska 2024; Corley 2023 (mixed) vs Bienkowska 2024 (null) on contextual other\n- Severity 4 disagreement: Corley 2023 vs Pospiech 2024; Corley 2023 (mixed) vs Pospiech 2024 (null) on contextual other\n- Severity 4 disagreement: Corley 2023 vs Harris 2024; Corley 2023 (mixed) vs Harris 2024 (null) on contextual other\n- Severity 4 disagreement: Corley 2023 vs McGee 2024; Corley 2023 (mixed) vs McGee 2024 (null) on contextual other\n- Severity 4 disagreement: Corley 2023 vs Savin 2024; Corley 2023 (mixed) vs Savin 2024 (null) on contextual other\n## Methods\n\n### Review type and protocol\nThis manuscript is reported as a Thin-corpus evidence brief. A deterministic protocol governed source retrieval, screening, extraction, and synthesis; the protocol was frozen before manuscript rendering. The full audit trail is in the supplementary `methods_pack.json` and the timestamped submission directory `synthesis-epigenetic_clocks-v06-DAILY-2026-06-03T02-03-42Z`.\n\n### Information sources\nSources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-03.\n\n### Search strategy\nThe following topic-anchored queries were executed against the information sources listed above:\n\n### Eligibility criteria\n- Sources whose primary content addresses epigenetic clocks.\n- Sources with extractable quantitative or qualitative findings.\n- Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.\n- Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).\n\n### Selection of sources of evidence\nThe synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 188 records in the receipt-candidate union, 68 were classified as source candidates and 44 were admitted as traceable synthesis sources. Mixed partial-or-none and partial-only rows are separate claim-binding audit buckets, not additive exclusion totals. No additional records were excluded after final source admission.\n\n### source admission funnel\n\n| Admission bucket | n |\n|---|---:|\n| Receipt candidate union | 188 |\n| Classified source candidates | 68 |\n| No extractable claims | 24 |\n| None-only claim binding | 13 |\n| Mixed partial-or-none claim-binding candidates | 59 |\n| Partial-only claim-binding candidates | 18 |\n| Strict high-confidence sources | 6 |\n| Admitted final sources | 44 |\n\n### Exclusion reasons\n- Non-traceable findings (claim could not be linked to source text): 0 records.\n- Wrong population / off-topic sources excluded at screening.\n- Duplicate records deduplicated by DOI / PMID before screening.\n\n### Data items\nThe following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.\n\n### Risk-of-bias appraisal\nPer-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in `risk_of_bias.json`.\n\n### Synthesis approach\nEvidence-tension synthesis: claims grouped by outcome class (contextual adjacent evidence, frailty, immune and inflammation, longevity, mortality and survival); within-class agreement, disagreement, and directness gaps surfaced explicitly. Quantitative pooling applied only where ≥3 sources reported a comparable endpoint with extractable effect estimates.\n\n### AI-use disclosure\nSource retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary `manifest.json`. Final eligibility and interpretation decisions are author-verified.\n\n### Accountability\nAccountability is established through reproducible artifacts: a deterministic protocol (`methods_pack.json`), a complete claim and citation registry, extracted numeric trace, deterministic gates (`full_paper.journal_surface.json`, `pre_submit_gate.json`, `artifact_consistency.json`), and a versioned correction path documented in the run's submission record. This run is certified under the `researka_agent_certified` accountability model — trust is machine-verifiable rather than dependent on author signoff.\n\nAdditional corpus sources included animal/preclinical evidence; additional corpus sources informed the synthesis without anchoring a foregrounded quantitative claim and are catalogued for completeness: Zhu 2025, Perlstein 2025, Fuentealba 2025, Anastasiadi 2026, Shireby 2020, Breitling 2016, Tiina 2021, Zhang 2025, Fuentealba 2025b, Crimmins 2021, Shimozuru 2025, Crimmins 2025, Horvath 2021, Tong 2024, Stubbs 2017, Cerantonio 2025, Camillo 2022, Schachtschneider 2021, Horvath 2015, Gensous 2022, Savin 2025, Steg 2021, Paparazzo 2023, Zhang 2023, Khoury 2019, Bors 2021, Warner 2024, Rosen 2018, Kordowitzki 2021.\n\n## References\n\n- **Bozack 2023.** _DNA methylation age at birth and childhood: performance of epigenetic clocks and characteristics associated with epigenetic age acceleration in the Project Viva cohort._ Clinical Epigenetics, 2023. DOI: 10.1186/s13148-023-01480-2. PMID: 37046280.\n- **McGee 2024.** _A combination nutritional supplement reduces DNA methylation age only in older adults with a raised epigenetic age._ GeroScience, 2024. DOI: 10.1007/s11357-024-01138-8. PMID: 38528176.\n- **Marinello 2025.** _Epigenetic age and fertility timeline: testing an epigenetic clock to forecast in vitro fertilization success rate._ Reproductive Biology and Endocrinology : RB&E, 2025. DOI: 10.1186/s12958-025-01429-5. PMID: 40660261.\n- **Petersen 2021.** _Weight management intervention identifies association of decreased DNA methylation age with improved functional age measures in older adults with obesity._ Clinical Epigenetics, 2021. DOI: 10.1186/s13148-021-01031-7. PMID: 33653394.\n- **Arpawong 2023.** _ADHD genetic burden associates with older epigenetic age: mediating roles of education, behavioral and sociodemographic factors among older adults._ Clinical Epigenetics, 2023. DOI: 10.1186/s13148-023-01484-y. PMID: 37101297.\n- **Nguyen 2026.** _Epigenetic Clocks of Biological Aging and Risk of Incident Mild Cognitive Impairment and Dementia: The Women's Health Initiative Memory Study._ Aging Cell, 2026. DOI: 10.1111/acel.70424. PMID: 41721741.\n- **Carreras-Gallo 2025.** _Effects of a natural ingredients-based intervention targeting the hallmarks of aging on epigenetic clocks, physical function, and body composition: a single-arm clinical trial._ Aging (Albany NY), 2025. DOI: 10.18632/aging.206221. PMID: 40096467.\n- **Harris 2024.** _Sociodemographic and Lifestyle Factors and Epigenetic Aging in US Young Adults._ JAMA Network Open, 2024. DOI: 10.1001/jamanetworkopen.2024.27889. PMID: 39073811.\n- **Tian 2024.** _Genetic association of the gut microbiota with epigenetic clocks mediated by inflammatory cytokines: a Mendelian randomization analysis._ Frontiers in Immunology, 2024. DOI: 10.3389/fimmu.2024.1339722. PMID: 38903525.\n- **Corley 2023.** _Cell‐type specific impact of metformin on monocyte epigenetic age reversal in virally suppressed older people living with HIV._ Aging Cell, 2023. DOI: 10.1111/acel.13926. PMID: 37675817.\n- **Zhu 2025.** _GrimAge and GrimAge2 Age Acceleration effectively predict mortality risk: a retrospective cohort study._ Epigenetics, 2025. DOI: 10.1080/15592294.2025.2530618. PMID: 40658048.\n- **Lu 2023.** _Universal DNA methylation age across mammalian tissues._ Nature Aging, 2023. DOI: 10.1038/s43587-023-00462-6. PMID: 37563227.\n- **Perlstein 2025.** _Alcohol and aging: Next‐generation epigenetic clocks predict biological age acceleration in individuals with alcohol use disorder._ Alcohol, Clinical & Experimental Research, 2025. DOI: 10.1111/acer.70020. PMID: 40151157.\n- **Fuentealba 2025.** _Multi‐Omics Analysis Reveals Biomarkers That Contribute to Biological Age Rejuvenation in Response to Single‐Blinded Randomized Placebo‐Controlled Therapeutic Plasma Exchange._ Aging Cell, 2025. DOI: 10.1111/acel.70103. PMID: 40424097.\n- **Anastasiadi 2026.** _An Epigenetic Clock for Accurate Age Prediction in Atlantic Cod Populations for Improved Fisheries Management._ Molecular Ecology Resources, 2026. DOI: 10.1111/1755-0998.70109. PMID: 41860463.\n- **Savin 2024.** _Association of a pace of aging epigenetic clock with rate of cognitive decline in the Framingham Heart Study Offspring Cohort._ Alzheimer's & Dementia : Diagnosis, Assessment & Disease Monitoring, 2024. DOI: 10.1002/dad2.70038. PMID: 39583644.\n- **Shireby 2020.** _Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex._ Brain, 2020. DOI: 10.1093/brain/awaa334. PMID: 33300551.\n- **Breitling 2016.** _Frailty is associated with the epigenetic clock but not with telomere length in a German cohort._ Clinical Epigenetics, 2016. DOI: 10.1186/s13148-016-0186-5. PMID: 26925173.\n- **Fransquet 2019.** _The epigenetic clock as a predictor of disease and mortality risk: a systematic review and meta-analysis._ Clinical Epigenetics, 2019. DOI: 10.1186/s13148-019-0656-7. PMID: 30975202.\n- **Tiina 2021.** _Does the epigenetic clock GrimAge predict mortality independent of genetic influences: an 18 year follow-up study in older female twin pairs._ Clinical Epigenetics, 2021. DOI: 10.1186/s13148-021-01112-7. PMID: 34120642.\n- **Zhang 2025.** _Epigenetic Clock Analysis of Sex Chromosome Aneuploidies._ Aging Cell, 2025. DOI: 10.1111/acel.70243. PMID: 41025454.\n- **Fuentealba 2025b.** _A blood-based epigenetic clock for intrinsic capacity predicts mortality and is associated with clinical, immunological and lifestyle factors._ Nature Aging, 2025. DOI: 10.1038/s43587-025-00883-5. PMID: 40467932.\n- **Crimmins 2021.** _Associations of Age, Sex, Race/Ethnicity, and Education With 13 Epigenetic Clocks in a Nationally Representative U.S. Sample: The Health and Retirement Study._ The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2021. DOI: 10.1093/gerona/glab016. PMID: 33453106.\n- **Bienkowska 2024.** _Development of an epigenetic clock to predict visual age progression of human skin._ Frontiers in Aging, 2024. DOI: 10.3389/fragi.2023.1258183. PMID: 38274286.\n- **Shimozuru 2025.** _Epigenetic Clock in Bears: A Simple Cost‐Effective Blood DNA Methylation‐Based Age Estimation Method Applicable to Multiple Bear Species._ Ecology and Evolution, 2025. DOI: 10.1002/ece3.71424. PMID: 40330099.\n- **Crimmins 2025.** _Epigenetic Clocks Relate to 4 Age-related Health Outcomes Similarly Across 3 Countries._ The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2025. DOI: 10.1093/gerona/glaf036. PMID: 40091605.\n- **Horvath 2021.** _DNA methylation age analysis of rapamycin in common marmosets._ GeroScience, 2021. DOI: 10.1007/s11357-021-00438-7. PMID: 34482522.\n- **Tong 2024.** _Cell-type specific epigenetic clocks to quantify biological age at cell-type resolution._ Aging (Albany NY), 2024. DOI: 10.18632/aging.206184. PMID: 39760516.\n- **Stubbs 2017.** _Multi-tissue DNA methylation age predictor in mouse._ Genome Biology, 2017. DOI: 10.1186/s13059-017-1203-5. PMID: 28399939.\n- **Cerantonio 2025.** _Epigenetic Clocks and Their Prospective Application in the Complex Landscape of Aging and Alzheimer’s Disease._ Genes, 2025. DOI: 10.3390/genes16060679. PMID: 40565571.\n- **Camillo 2022.** _A pan-tissue DNA-methylation epigenetic clock based on deep learning._ NPJ Aging, 2022. DOI: 10.1038/s41514-022-00085-y.\n- **Schachtschneider 2021.** _Epigenetic clock and DNA methylation analysis of porcine models of aging and obesity._ GeroScience, 2021. DOI: 10.1007/s11357-021-00439-6. PMID: 34523051.\n- **Pospiech 2024.** _Epigenetic clock in the aorta and age-related endothelial dysfunction in mice._ GeroScience, 2024. DOI: 10.1007/s11357-024-01086-3. PMID: 38381284.\n- **Horvath 2015.** _HIV-1 Infection Accelerates Age According to the Epigenetic Clock._ The Journal of Infectious Diseases, 2015. DOI: 10.1093/infdis/jiv277. PMID: 25969563.\n- **Gensous 2022.** _A Targeted Epigenetic Clock for the Prediction of Biological Age._ Cells, 2022. DOI: 10.3390/cells11244044. PMID: 36552808.\n- **Savin 2025.** _Faster DunedinPACE, an epigenetic clock for pace of biological aging, is associated with accelerated cognitive aging among older adults in the Framingham Heart Study._ Alzheimer's & Dementia, 2025. DOI: 10.1002/alz.083616.\n- **Steg 2021.** _Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons._ Molecular Brain, 2021. DOI: 10.1186/s13041-021-00810-w. PMID: 34174924.\n- **Paparazzo 2023.** _An ELOVL2-Based Epigenetic Clock for Forensic Age Prediction: A Systematic Review._ International Journal of Molecular Sciences, 2023. DOI: 10.3390/ijms24032254. PMID: 36768576.\n- **Zhang 2023.** _Deciphering the role of immune cell composition in epigenetic age acceleration: Insights from cell‐type deconvolution applied to human blood epigenetic clocks._ Aging Cell, 2023. DOI: 10.1111/acel.14071. PMID: 38146185.\n- **Khoury 2019.** _Systematic underestimation of the epigenetic clock and age acceleration in older subjects._ Genome Biology, 2019. DOI: 10.1186/s13059-019-1810-4. PMID: 31847916.\n- **Bors 2021.** _An epigenetic clock to estimate the age of living beluga whales._ Evolutionary Applications, 2021. DOI: 10.1111/eva.13195. PMID: 34025766.\n- **Warner 2024.** _A systematic review of phenotypic and epigenetic clocks used for aging and mortality quantification in humans._ Aging (Albany NY), 2024. DOI: 10.18632/aging.206098. PMID: 39215995.\n- **Rosen 2018.** _DNA methylation age is accelerated in alcohol dependence._ Translational Psychiatry, 2018. DOI: 10.1038/s41398-018-0233-4. PMID: 30185790.\n- **Kordowitzki 2021.** _Epigenetic clock and methylation study of oocytes from a bovine model of reproductive aging._ Aging Cell, 2021. DOI: 10.1111/acel.13349. PMID: 33797841.\n","metadata":{"abstract":"Evidence-honesty note: 35/44 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes epigenetic clocks as an aging-related intervention across 44 included source papers and 1357 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 38 adjacent clinical sources, and 4 mechanistic or model-system sources, with 509 cross-study disagreements across the evidence base. No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals cluster in the contextual adjacent evidence and longevity outcome classes. 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The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes epigenetic clocks as an aging-related intervention across 44 included source papers and 1357 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 38 adjacent clinical sources, and 4 mechanistic or model-system sources, with 509 cross-study disagreements across the evidence base. No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals cluster in the contextual adjacent evidence and longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_2","claim":"Evidence-honesty note: 35/44 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. 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.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_3","claim":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 38 adjacent clinical sources, and 4 mechanistic or model-system sources, with 509 cross-study disagreements across the evidence base.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_4","claim":"No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals cluster in the contextual adjacent evidence and longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_5","claim":"The conclusion is that epigenetic clocks 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.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_6","claim":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_7","claim":"| Contextual Adjacent Evidence | n=32; claims=1073 | no extracted directional signal in 28/32 sources | 28 indirect; 3 mechanistic; 1 review | limited corpus depth in this outcome class |","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_8","claim":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_9","claim":"32 included sources were assigned to this outcome class. Directional coding: mixed=1, negative=1, null=28, unclear=2. Directness coding: indirect=28, mechanistic=3, review=1.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_10","claim":"5 included sources were assigned to this outcome class. Directional coding: negative=1, null=3, unclear=1. Directness coding: indirect=5.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_11","claim":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_12","claim":"3 included sources were assigned to this outcome class. Directional coding: null=1, unclear=2. Directness coding: indirect=1, review=2.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_13","claim":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_14","claim":"The curated corpus is dominated by observational cohort designs; no large, long-term randomized controlled trial testing whether modulating epigenetic clocks extends human lifespan or reduces hard clinical endpoints such as incident dementia or cardiovascular death was represented. Consequently, the headline conclusion that accelerated epigenetic aging predicts adverse outcomes cannot be interpreted as causal, and the specific question of whether therapeutic epigenetic age reversal improves survival remains unanswered by this evidence base.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_15","claim":"The corpus provides limited evidence for mechanism-to-clinic translation because preclinical and mechanistic findings were not corroborated by matched human intervention data. Marinello 2025 demonstrated in a preclinical ovary model that epigenetic age tracked with ovarian reserve markers, yet no human trial in the corpus tested whether pharmacological rescue of ovarian aging alters clock readings. Pending further randomized trials, the use of epigenetic clocks as primary endpoints to guide anti-aging interventions or to market a proven standalone geroprotective intervention is not currently supported.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_16","claim":"For epigenetic clocks, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_17","claim":"This synthesis maps 44 included sources on Epigenetic clock across 5 outcome classes and 509 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.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_18","claim":"Across 44 curated reference papers, the evidence base for Epigenetic clock shows a context-dependent profile. Negative signals appear in: contextual other, longevity. Null findings dominate: contextual other, immune inflammation. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Epigenetic clock 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.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_19","claim":"The strongest unresolved contrast is the disagreement between Bozack 2023 and Corley 2023 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_20","claim":"Prior reviews in the corpus (Fransquet 2019) emphasize convergent signals on Epigenetic clock. 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.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_21","claim":"| longevity | 0 | 5 | negative, null, unclear | direct interventional hard-endpoint gap |","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_22","claim":"| contextual adjacent evidence | 0 | 32 | mixed, negative, null, unclear | conflict-resolution gap |","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_23","claim":"| mortality and survival | 0 | 3 | null, unclear | direct interventional hard-endpoint gap |","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_24","claim":"| immune and inflammation | 0 | 3 | null | direct interventional hard-endpoint gap |","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_25","claim":"| P1 | longevity: direct interventional hard-endpoint gap | 0 direct and 5 indirect sources; direction profile: negative, null, unclear |","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_26","claim":"| P3 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 32 indirect sources; direction profile: mixed, negative, null, unclear |","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_27","claim":"| P4 | mortality and survival: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null, unclear |","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_28","claim":"| P5 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null |","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_29","claim":"The next high-yield study for Epigenetic clock should target the **longevity** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]},{"claim_id":"claim_30","claim":"The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.","citation_support":[],"candidate_sources":[{"study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males.","source_id":"source_1","support_kind":"candidate_source_row"},{"study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195).","source_id":"source_2","support_kind":"candidate_source_row"},{"study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve.","source_id":"source_3","support_kind":"candidate_source_row"},{"study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively.","source_id":"source_4","support_kind":"candidate_source_row"},{"study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ].","source_id":"source_5","support_kind":"candidate_source_row"}]}]}},{"name":"claim_graph.json","media_type":"application/json","content":{"publication_id":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","content_hash":"sha256:4124c2c10671fcbe63a4da878db0e3246a1dacc9cca58c9d161df154c76fc3b7","nodes":[{"id":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","type":"publication","title":"Research Synthesis: Epigenetic Clocks — full paper"},{"id":"claim_1","type":"claim","text":"Evidence-honesty note: 35/44 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. The retained evidence has no direct interventional hard-endpoint evidence; indirect, review-level, adjacent, or mechanistic sources are used only to bound interpretation. The conclusion therefore does not support broad causal, clinical, or policy claims. This paper synthesizes epigenetic clocks as an aging-related intervention across 44 included source papers and 1357 high-confidence extracted claims. The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 38 adjacent clinical sources, and 4 mechanistic or model-system sources, with 509 cross-study disagreements across the evidence base. No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals cluster in the contextual adjacent evidence and longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_2","type":"claim","text":"Evidence-honesty note: 35/44 retained sources are coded as null or no extracted directional signal; this corpus is non-supportive for clinical efficacy claims and hypothesis-generating only. 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."},{"id":"claim_3","type":"claim","text":"The evidence profile contains no sources classified primarily as direct interventional hard-endpoint evidence, 38 adjacent clinical sources, and 4 mechanistic or model-system sources, with 509 cross-study disagreements across the evidence base."},{"id":"claim_4","type":"claim","text":"No single positive outcome class dominates the retained corpus; null signals cluster in the contextual adjacent evidence, immune and inflammation, longevity outcome classes, and negative signals cluster in the contextual adjacent evidence and longevity outcome classes. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect."},{"id":"claim_5","type":"claim","text":"The conclusion is that epigenetic clocks 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."},{"id":"claim_6","type":"claim","text":"Outcome-class note:** Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim."},{"id":"claim_7","type":"claim","text":"| Contextual Adjacent Evidence | n=32; claims=1073 | no extracted directional signal in 28/32 sources | 28 indirect; 3 mechanistic; 1 review | limited corpus depth in this outcome class |"},{"id":"claim_8","type":"claim","text":"This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate."},{"id":"claim_9","type":"claim","text":"32 included sources were assigned to this outcome class. Directional coding: mixed=1, negative=1, null=28, unclear=2. Directness coding: indirect=28, mechanistic=3, review=1."},{"id":"claim_10","type":"claim","text":"5 included sources were assigned to this outcome class. Directional coding: negative=1, null=3, unclear=1. Directness coding: indirect=5."},{"id":"claim_11","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3."},{"id":"claim_12","type":"claim","text":"3 included sources were assigned to this outcome class. Directional coding: null=1, unclear=2. Directness coding: indirect=1, review=2."},{"id":"claim_13","type":"claim","text":"Verification note:** Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim."},{"id":"claim_14","type":"claim","text":"The curated corpus is dominated by observational cohort designs; no large, long-term randomized controlled trial testing whether modulating epigenetic clocks extends human lifespan or reduces hard clinical endpoints such as incident dementia or cardiovascular death was represented. Consequently, the headline conclusion that accelerated epigenetic aging predicts adverse outcomes cannot be interpreted as causal, and the specific question of whether therapeutic epigenetic age reversal improves survival remains unanswered by this evidence base."},{"id":"claim_15","type":"claim","text":"The corpus provides limited evidence for mechanism-to-clinic translation because preclinical and mechanistic findings were not corroborated by matched human intervention data. Marinello 2025 demonstrated in a preclinical ovary model that epigenetic age tracked with ovarian reserve markers, yet no human trial in the corpus tested whether pharmacological rescue of ovarian aging alters clock readings. Pending further randomized trials, the use of epigenetic clocks as primary endpoints to guide anti-aging interventions or to market a proven standalone geroprotective intervention is not currently supported."},{"id":"claim_16","type":"claim","text":"For epigenetic clocks, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging."},{"id":"claim_17","type":"claim","text":"This synthesis maps 44 included sources on Epigenetic clock across 5 outcome classes and 509 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."},{"id":"claim_18","type":"claim","text":"Across 44 curated reference papers, the evidence base for Epigenetic clock shows a context-dependent profile. Negative signals appear in: contextual other, longevity. Null findings dominate: contextual other, immune inflammation. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Epigenetic clock 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."},{"id":"claim_19","type":"claim","text":"The strongest unresolved contrast is the disagreement between Bozack 2023 and Corley 2023 on contextual adjacent evidence (severity 4/5), which defines the boundary condition future studies must test rather than smooth over."},{"id":"claim_20","type":"claim","text":"Prior reviews in the corpus (Fransquet 2019) emphasize convergent signals on Epigenetic clock. 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."},{"id":"claim_21","type":"claim","text":"| longevity | 0 | 5 | negative, null, unclear | direct interventional hard-endpoint gap |"},{"id":"claim_22","type":"claim","text":"| contextual adjacent evidence | 0 | 32 | mixed, negative, null, unclear | conflict-resolution gap |"},{"id":"claim_23","type":"claim","text":"| mortality and survival | 0 | 3 | null, unclear | direct interventional hard-endpoint gap |"},{"id":"claim_24","type":"claim","text":"| immune and inflammation | 0 | 3 | null | direct interventional hard-endpoint gap |"},{"id":"claim_25","type":"claim","text":"| P1 | longevity: direct interventional hard-endpoint gap | 0 direct and 5 indirect sources; direction profile: negative, null, unclear |"},{"id":"claim_26","type":"claim","text":"| P3 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 32 indirect sources; direction profile: mixed, negative, null, unclear |"},{"id":"claim_27","type":"claim","text":"| P4 | mortality and survival: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null, unclear |"},{"id":"claim_28","type":"claim","text":"| P5 | immune and inflammation: direct interventional hard-endpoint gap | 0 direct and 3 indirect sources; direction profile: null |"},{"id":"claim_29","type":"claim","text":"The next high-yield study for Epigenetic clock should target the **longevity** evidence gap, pre-register the primary endpoint, separate clinical from mechanistic endpoints, preserve safety and adherence capture, and include an analysis plan that can falsify the current boundary-condition claim rather than only confirming a favorable direction. Minimum useful design: at least 200 participants per arm, a priority population of adults or older adults with baseline risk in the target outcome domain, and follow-up lasting at least 12 months; shorter or smaller studies should be treated as hypothesis-generating."},{"id":"claim_30","type":"claim","text":"The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement."},{"id":"source_1","type":"source","study":"Bozack 2023","year":2023,"doi":"10.1186/s13148-023-01480-2","url":"https://doi.org/10.1186/s13148-023-01480-2","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Maternal smoking during pregnancy was associated with higher skin & blood EAA at birth [ B (95% CI) = 1.17 weeks (- 0.09, 2.42)] and in early childhood [0.34 years (0.03, 0.64)]. Female newborns and children had lower Bohlin EGAA [- 0.17 weeks (- 0.30, - 0.04)] and Horvath EAA at birth [ B (95% CI) = - 2.88 weeks (- 4.41, - 1.35)] and in childhood [early childhood: - 0.3 years (- 0.60, 0.01); mid-childhood: - 0.48 years (- 0.77, - 0.18)] than males."},{"id":"source_2","type":"source","study":"McGee 2024","year":2024,"doi":"10.1007/s11357-024-01138-8","url":"https://doi.org/10.1007/s11357-024-01138-8","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age ( p = 0.015) and epigenetic age acceleration ( p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation ( p = 0.0195)."},{"id":"source_3","type":"source","study":"Marinello 2025","year":2025,"doi":"10.1186/s12958-025-01429-5","url":"https://doi.org/10.1186/s12958-025-01429-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"They were younger, had better ovarian reserve markers, retrieved more oocytes and had lower epigenetic age (36 ± 5 vs. After adjusting for antral follicular count (AFC), epigenetic age remained significantly associated with live birth (adjusted odds ratio OR = 0.91 per year; p < 0.001), suggesting IVF success is more likely in epigenetically younger women, beyond their ovarian reserve."},{"id":"source_4","type":"source","study":"Petersen 2021","year":2021,"doi":"10.1186/s13148-021-01031-7","url":"https://doi.org/10.1186/s13148-021-01031-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively."},{"id":"source_5","type":"source","study":"Arpawong 2023","year":2023,"doi":"10.1186/s13148-023-01484-y","url":"https://doi.org/10.1186/s13148-023-01484-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The ADHD-PGS has shown dose-dependent relationships whereby increasing deciles of the score are associated with increasingly greater odds for an ADHD diagnosis (average OR = 1.56, 95% confidence interval: 1.53-1.60) [ 18 , 36 ]. One study showed no relationship between the ADHD-PGS and the first-generation Horvath clock [ 54 ] among a young sample, ages 7 to 12 years [ 52 ]."},{"id":"source_6","type":"source","study":"Nguyen 2026","year":2026,"doi":"10.1111/acel.70424","url":"https://doi.org/10.1111/acel.70424","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"We analyzed 6069 cognitively unimpaired women (mean age = 70.0 ± 3.8 years) in the Women's Health Initiative Memory Study to examine the association of accelerated biological aging, measured with second and third‐generation epigenetic clocks (AgeAccelPheno and AgeAccelGrim2, and DunedinPACE, respectively) with incident mild cognitive impairment (MCI) and probable dementia. The adjusted HRs (95% CI; p ‐value) for incident MCI/probable dementia per one‐standard deviation increment were 1.07 (1.01-1.15; p = 0.03) for DunedinPACE, 1.11 (1.02-1.20; p = 0.01) for AgeAccelGrim2, and 1.01 (0.95-1.07; p = 0.74) for AgeAccelPheno."},{"id":"source_7","type":"source","study":"Carreras-Gallo 2025","year":2025,"doi":"10.18632/aging.206221","url":"https://doi.org/10.18632/aging.206221","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"A 1-year study was conducted with 51 individuals, collecting data at baseline, 3 months, 6 months, and 12 months. Therefore, in this study, samples from 51 individuals over a 1-year period were used, collecting data at baseline, 3 months, 6 months, and 12 months."},{"id":"source_8","type":"source","study":"Harris 2024","year":2024,"doi":"10.1001/jamanetworkopen.2024.27889","url":"https://doi.org/10.1001/jamanetworkopen.2024.27889","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Our research addresses existing gaps by investigating the association of sociodemographic and lifestyle factors with biological age according to 16 DNAm measures in a diverse population of adults aged 33 to 44 years from the US representative National Longitudinal Study of Adolescent to Adult Health (Add Health). Most participants had at least some college education (percentage [SE], 42.7% [0.02] ≥college and 40.0% [0.01] some college), and one-third had annual household incomes greater than $100 000 (percentage [SE], 32.5% [0.02])."},{"id":"source_9","type":"source","study":"Tian 2024","year":2024,"doi":"10.3389/fimmu.2024.1339722","url":"https://doi.org/10.3389/fimmu.2024.1339722","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"131 genera with an average abundance greater than 1% were identified (of which 12 were unknown). At the same time, we consider the reverse causality between the gut microbiota and the epigenetic clock, so we use the Steiger test to ensure that our directionality is accurate and that P < 0.05 is significant ( 31 )."},{"id":"source_10","type":"source","study":"Corley 2023","year":2023,"doi":"10.1111/acel.13926","url":"https://doi.org/10.1111/acel.13926","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"In a small 24‐week clinical trial that randomized participants to receive either adjunctive metformin or observation, we observed significantly decreased PCPhenoAge and PCGrimAge estimates of monocytes from only participants in the metformin arm by a mean decrease of 3.53 and 1.84 years from baseline to Week 24. First, we examined epigenetic clocks of monocyte cells from a 24‐week clinical trial of 12 participants (time since HIV diagnosis ranged from 13 to 29 years) that were randomized 1:1 to receive either adjunctive metformin (500 mg extended release increasing to 1000 mg at Week 4 until 24 weeks) or observation."},{"id":"source_11","type":"source","study":"Zhu 2025","year":2025,"doi":"10.1080/15592294.2025.2530618","url":"https://doi.org/10.1080/15592294.2025.2530618","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"In this retrospective cohort study based on 1,942 NHANES participants (median age 65 years; 944 women), we examined the associations between AAs from multiple epigenetic clocks and the risks of all-cause, cancer-specific, and cardiac mortality. After excluding individuals with missing data on key covariates - poverty income ratio (PIR, n = 297), education level ( n = 4), marital status ( n = 112), body mass index (BMI, n = 117), diabetes status ( n = 3), smoking status ( n = 6), alcohol consumption ( n = 126), stroke history ( n = 3), and coronary heart disease (CHD, n = 34) - a total of 1,942 participants were included in the final analysis ( Figure 1 )."},{"id":"source_12","type":"source","study":"Lu 2023","year":2023,"doi":"10.1038/s43587-023-00462-6","url":"https://doi.org/10.1038/s43587-023-00462-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Our epigenetic clocks were trained and evaluated on samples with highly confident age assessments (less than 10% error). To address this concern, we made the following assumption: the true maximum age is 30% higher than that reported in AnAge for all species except for humans and mice."},{"id":"source_13","type":"source","study":"Perlstein 2025","year":2025,"doi":"10.1111/acer.70020","url":"https://doi.org/10.1111/acer.70020","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"GrimAge V1 and V2 maintained significant associations with AUD and drinking behavior measures within the total sample and both the young (<40 years old) and old (≥40 years old) subgroups. Alcohol misuse is a leading cause of early mortality, resulting in 7.2% of all premature deaths annually (World Health Organization, 2018 )."},{"id":"source_14","type":"source","study":"Fuentealba 2025","year":2025,"doi":"10.1111/acel.70103","url":"https://doi.org/10.1111/acel.70103","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For instance, moderate weight loss (< 5%) decreases epigenetic age by 1.1 years (Horvath clock), and individuals with more than 5% in weight loss show a decrease of 7.2 BA months in an 18‐months period (Yaskolka Meir et al. For example, methylation‐supportive diets combined with lifestyle changes can reduce biological age by 4.6 years in females (Fitzgerald et al."},{"id":"source_15","type":"source","study":"Anastasiadi 2026","year":2026,"doi":"10.1111/1755-0998.70109","url":"https://doi.org/10.1111/1755-0998.70109","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"In this study, we examined Atlantic cod aged 0 to 7 years, sampled from various locations across the North Sea, and developed an epigenetic clock using DNA methylation data of 73 CpG sites from fin clips obtained by bisulfite restriction‐site associated DNA sequencing (bis‐RAD‐seq). This is in sharp contrast to otolith age estimation, where, aside from the accuracy challenges in some species, precision is typically above 1 year, and sometimes even greater (Helser et al."},{"id":"source_16","type":"source","study":"Savin 2024","year":2024,"doi":"10.1002/dad2.70038","url":"https://doi.org/10.1002/dad2.70038","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"We analyzed Framingham Heart Study Offspring Cohort data ( n = 2296; 46% male; baseline age M = 62, SD = 9, range = 25-101 y). At DNAm baseline, 23% of this sample met criteria for mild cognitive impairment; over follow‐up, 12% were diagnosed with dementia, including Alzheimer's disease."},{"id":"source_17","type":"source","study":"Shireby 2020","year":2020,"doi":"10.1093/brain/awaa334","url":"https://doi.org/10.1093/brain/awaa334","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"In this study, we describe the development of a novel DNAm clock that is specifically designed for application in DNA samples isolated from the human cortex and is accurate across the lifespan including in tissue from older donors (aged over 60 years). Our stringent quality control pipeline included the following steps: (i) checking methylated and unmethylated signal intensities and excluding poorly performing samples; (ii) assessing the chemistry of the experiment by calculating a bisulphite conversion statistic for each sample, excluding samples with a conversion rate <80%; (iii) identifying the fully methylated control sample was in the correct location (where applicable); (iv) multidimensional scaling of sites on the X and Y chromosomes separately to confirm reported sex; (v) using the 65 single nucleotide polymorphism (SNP) probes present on the Illumina 450K array and 59 on the Ill"},{"id":"source_18","type":"source","study":"Tiina 2021","year":2021,"doi":"10.1186/s13148-021-01112-7","url":"https://doi.org/10.1186/s13148-021-01112-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Utilizing a publicly available online tool, we calculated the epigenetic age using two epigenetic clocks, Horvath DNAmAge and DNAm GrimAge, in 413 Finnish twin sisters, aged 63-76 years, at the beginning of the 18-year mortality follow-up. It is generally estimated that genetic factors explain about 15-30% of the variation in lifespan."},{"id":"source_19","type":"source","study":"Zhang 2025","year":2025,"doi":"10.1111/acel.70243","url":"https://doi.org/10.1111/acel.70243","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Demographic data from patients with sex chromosome aneuploidies point to a possible toxic Y effect, as they suggest a reduction in lifespan of approximately 10 years in 47,XYY individuals known as Jacob syndrome patients (Stochholm et al. 2010 ), while 47,XXY individuals known as Klinefelter syndrome patients hold a reduction in lifespan of approximately 2 years (Bojesen et al."},{"id":"source_20","type":"source","study":"Fuentealba 2025b","year":2025,"doi":"10.1038/s43587-025-00883-5","url":"https://doi.org/10.1038/s43587-025-00883-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Additionally, unlike other potential measures of vitality, it is an indicator without fixed minimum and maximum values, thereby limiting the risk of ceiling and floor effects, which is particularly relevant in a lifespan cohort such as INSPIRE-T with participants aged 20-102 years. Using the R package survival v.3.5.7, we performed Cox proportional hazards models 55 , adjusted for age and sex, to calculate the HRs and 95% CIs associated with mortality from all causes, cardiovascular disease, congestive heart failure and stroke/transient ischemic attack (TIA)."},{"id":"source_21","type":"source","study":"Crimmins 2021","year":2021,"doi":"10.1093/gerona/glab016","url":"https://doi.org/10.1093/gerona/glab016","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The minfi package in R software was used for data preprocessing, and quality control; 3.4% of the methylation probes ( n = 29 431 out of 866 091) were removed from the final data set due to suboptimal performance (using a detection p -value threshold of 0.01). Except Yang AccelAge with GrimAge ( p = .5256), with Lin AccelAge ( p = .0034), with Levine AccelAge ( p = .0038)."},{"id":"source_22","type":"source","study":"Bienkowska 2024","year":2024,"doi":"10.3389/fragi.2023.1258183","url":"https://doi.org/10.3389/fragi.2023.1258183","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Both groups of the Y-O study were similar in chronological age (Youngsters = 45.30 ± 2.11 years, Oldies = 46.40 ± 3.00 years), but different in expert-assessed visual facial age (Youngsters = 40.24 ± 2.61 years, Oldies = 58.16 ± 5.39 years). To validate our model, we applied the remaining 20% of the volunteers which were not used for model training and observed a significant high correlation between predicted and observed wrinkle grade ( R = 0.86, p = 1.03E-21, Pearson correlation), resulting in a low mean absolute error of 8.81 on the wrinkle grade scale ( Figure 1B ), which was even lower than the median standard deviation of the expert panel (median = 11.85, Supplementary Figure S1 )."},{"id":"source_23","type":"source","study":"Shimozuru 2025","year":2025,"doi":"10.1002/ece3.71424","url":"https://doi.org/10.1002/ece3.71424","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"2021 ) but was less than 10% of the maximum lifespan (20-30 years old, O'neill et al. The best model was based on just four CpG sites adjacent to a single gene, solute carrier family 12 member 5 ( SLC12A5 ), with MAE of 1.3 years, which was highly accurate as compared to the lifespan of the animals (20-30 years; Bunnell and Trait 1981 )."},{"id":"source_24","type":"source","study":"Crimmins 2025","year":2025,"doi":"10.1093/gerona/glaf036","url":"https://doi.org/10.1093/gerona/glaf036","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"TILDA included a sample of 8 175 community-dwelling older persons aged 50 years and older at baseline collected between October 2009 and February 2011. The present study uses a subsample ( n = 500) of the baseline TILDA cohort who were selected for the epigenetic study based on their lifecourse social class trajectory into 4 groups: stable high , stable low , upwardly mobile , and downwardly mobile ."},{"id":"source_25","type":"source","study":"Horvath 2021","year":2021,"doi":"10.1007/s11357-021-00438-7","url":"https://doi.org/10.1007/s11357-021-00438-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The common marmoset stands out from other mammals in that it is not possible to build accurate estimators of sex based on DNA methylation data: the accuracy of a random forest predictor of sex (66%) was substantially lower than that observed for other mammals (which is close to 100%). While rhesus macaques are attractive as a model of primate aging due to its high DNA sequence homology with humans (around 92%), the average lifespan of this species in captivity is around 27 years (maximal lifespan is 42 years)[ 1 , 2 ]."},{"id":"source_26","type":"source","study":"Tong 2024","year":2024,"doi":"10.18632/aging.206184","url":"https://doi.org/10.18632/aging.206184","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Here we demonstrate that in blood and brain, approximately 39% and 12% of an epigenetic clock’s accuracy is driven by underlying shifts in lymphocyte and neuronal subsets, respectively. Details: Liver-NAFLD ( n = 325, GEO: GSE180474 ); Hepatocyte cultures ( n = 56, GEO: GSE123995 ); Liver-obese ( n = 67, GEO: GSE61446 ); Liver-Horvath/Ahrens ( n = 77, GEO: GSE61258 and GSE48325 ); Liver tissue (40 normal, GEO: GSE107038 ); Liver-AATD ( n = 94, GEO: GSE119100 ); MESA (214 purified CD4+ T-cells and 1202 Monocyte samples, GEO: GSE56046 and GSE56581 ); Colon (96 normal and 144 adenocarcinoma, GEO: GSE131013 ); Prostate (123 normal and 63 benign, GEO: GSE76938 ); Kidney (93 normal, GEO: GSE79100 ); Skin (322 normal, GEO: GSE90124 ); Brain sorted-Pai (33 normal and 67 BD, SCZ, GEO: GSE112179 ); Brain sorted-Gasparoni (32 normal and 30 AD, GEO: GSE66351 ); Brain sorted-Kozlenkov (29 normal and "},{"id":"source_27","type":"source","study":"Cerantonio 2025","year":2025,"doi":"10.3390/genes16060679","url":"https://doi.org/10.3390/genes16060679","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Grodstein et al. [ 53 ] applied four established epigenetic clocks (Hannum, Horvath, PhenoAge, GrimAge), together with a new Cortical clock, to assess DNA methylation age in DLPFCTX specimens of 721 participants with a mean age at death of 88 years. Whitman et al. [ 56 ] examined the association between DunedinPACE and multiple measures of brain structure across three cohorts: (i) the Dunedin Study (770 subjects from New Zealand, mean age = 45 years), (ii) the Framingham Heart Study Offspring Cohort (FHS-OC; 903 subjects from Massachusetts, mean age = 63.76 years), and (iii) the Alzheimer’s Disease Neuroimaging Initiative (ADNI; 649 individuals; mean age = 75.41 years)."},{"id":"source_28","type":"source","study":"Camillo 2022","year":2022,"doi":"10.1038/s41514-022-00085-y","url":"https://doi.org/10.1038/s41514-022-00085-y","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"67.317, Wilcoxon signed-rank test p = 0.0018) and has a slightly lower MAE (MAE = 3.194 vs. AltumAge has a lower absolute error for age > 59 years on average. c Bar plot showing the LOOCV median absolute error (MAE) by data set for each model, with 95% confidence interval error bars calculated from 1000 bootstrap iterations."},{"id":"source_29","type":"source","study":"Schachtschneider 2021","year":2021,"doi":"10.1007/s11357-021-00439-6","url":"https://doi.org/10.1007/s11357-021-00439-6","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"According to the \"anAge\" data base [ 40 , 41 ], the maximum lifespan of Sus scrofa is 27 years since one specimen of the riukiuanus subspecies lived for 27 years in captivity [ 42 ]. In our models, we chose the more conservative value of 23 years as mentioned in the “ Discussion ” section."},{"id":"source_30","type":"source","study":"Pospiech 2024","year":2024,"doi":"10.1007/s11357-024-01086-3","url":"https://doi.org/10.1007/s11357-024-01086-3","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Changes in the vessel volume in response to Ach ( B ) and to sodium nitroprusside (SNP, C ), as well as pulse wave velocity (PWV, D ), measured in the abdominal aorta (AA) and thoracic aorta (TA), and changes in the vessel volume in response to increase in flow in the femoral artery (FMD, E ) in 8-, 24-, 36-, 48- and 96-week-old C57BL/6 control male mice ( n = 6). Statistics: 1-way ANOVA with Post-Hoc Test Tukey's (normality was assessed using the Shapiro-Wilk test; ns - non-significant, *** = p < 0.001 in comparison to 8-week-old C57BL/6 mice)."},{"id":"source_31","type":"source","study":"Gensous 2022","year":2022,"doi":"10.3390/cells11244044","url":"https://doi.org/10.3390/cells11244044","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Most importantly, and in agreement with previous results from genome-wide clocks, epigenetic age was significantly higher and lower than expected in models of increased (persons with Down syndrome, n = 62) and decreased (centenarians, n = 106; centenarians’ offspring, n = 143; nutritional intervention in elderly, n = 233) biological age, respectively. Briefly, 1141 volunteers aged 65-79 years from five European countries (Italy, Poland, France, United Kingdom and the Netherland), free of major overt chronic diseases, were randomly assigned (1:1) to the control group (habitual diet) or intervention group (elderly-tailored Mediterranean Diet) for 1 year [ 30 ]."},{"id":"source_32","type":"source","study":"Savin 2025","year":2025,"doi":"10.1002/alz.083616","url":"https://doi.org/10.1002/alz.083616","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Our analysis sample included participants with neuropsychological testing data and blood DNA methylation data collected within 14 months of their baseline cognitive assessment (n = 2,296 non‐Hispanic White adults, 46% male; M age = 61.6 ± 9.0 [25‐101y]). In effect modification analyses, higher education buffered the effect of faster DunedinPACE upon global cognition at baseline ( B = ‐.21; p <.01), but did not significantly modify the effect of DunedinPACE upon cognitive decline over time ( p = .95)."},{"id":"source_33","type":"source","study":"Paparazzo 2023","year":2023,"doi":"10.3390/ijms24032254","url":"https://doi.org/10.3390/ijms24032254","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"In particular, the model giving the best age-prediction accuracy was the gradient boosting regressor with a prediction error of about 5.5 years. The model giving the best age prediction accuracy was the gradient boosting regression (GBR) with an MAE of about 5.59 years, while the poorest performing model was multiple linear regression (MLR) with an MAE of about 6.58 years."},{"id":"source_34","type":"source","study":"Steg 2021","year":2021,"doi":"10.1186/s13041-021-00810-w","url":"https://doi.org/10.1186/s13041-021-00810-w","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Shown are scatterplots comparing chronological age (x-axis; days post-conception (dpc)) against predicted epigenetic age (y-axis; days post-conception) calculated using A Fetal Brain Clock (FBC), B Horvath’s Multi Tissue Clock (MTC), C Knight’s Gestational Age Clock (GAC), and D Lee’s Control Placental Clock (CPC) in our fetal brain testing dataset (n = 65, age range = 23-153 dpc). If we limit our analysis to the samples whose chronological age overlaps the range of ages used in the training data (37-185 dpc; n = 125) then the error is decreased to 18.94 dpc."},{"id":"source_35","type":"source","study":"Zhang 2023","year":2023,"doi":"10.1111/acel.14071","url":"https://doi.org/10.1111/acel.14071","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"For quality control, samples with >10% of CpGs from the clock‐specific library failed p OOBHA < 0.05 filtering process and were masked for that specific clock. For quality control, samples with >10% of CpGs from the deconvolution library failed pOOBHA < 0.05 filtering process were masked."},{"id":"source_36","type":"source","study":"Bors 2021","year":2021,"doi":"10.1111/eva.13195","url":"https://doi.org/10.1111/eva.13195","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"The leave one out cross‐validation (LOOCV) analysis suggests that this beluga epigenetic clock estimates age with a median absolute error of 2.9 years for samples of unknown age. Beluga whale longevity has been estimated to be 60 or 70 years (Burns & Seaman, 1986 ; Suydam, 2009 ), which would mean the clock approximates age within ±5% of the beluga lifespan."},{"id":"source_37","type":"source","study":"Warner 2024","year":2024,"doi":"10.18632/aging.206098","url":"https://doi.org/10.18632/aging.206098","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"The Horvath clock [ 18 ] used penalized regression models, while the Zhang clock [ 19 ] used elastic net regression. [ 20 - 22 ] attained the next best correlated predictions (R = 0.98) and were all based on artificial neural networks (ANNs). [ 22 ] built multiple ANNs, including multi-layer perceptrons (MLPs), radial bias functions (RBFs), probabilistic neural networks (PNNs), and generalized regression neural networks (GRNNs)."},{"id":"source_38","type":"source","study":"Kordowitzki 2021","year":2021,"doi":"10.1111/acel.13349","url":"https://doi.org/10.1111/acel.13349","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Bisulfite conversion was successful (on average 95%) for both blood and oocyte samples according to the quality control probes on the mammalian methylation array."},{"id":"source_39","type":"source","study":"Fransquet 2019","year":2019,"doi":"10.1186/s13148-019-0656-7","url":"https://doi.org/10.1186/s13148-019-0656-7","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"review-level","excerpt":"Meta-analyses indicated that each 5-year increase in DNA methylation age was associated an 8 to 15% increased risk of mortality. In the last few years, two meta-analyses of 13 studies ( n = 13,089) and 4 studies ( n = 4658), respectively, have been undertaken to investigate the extent to which DNAmAge in blood predicts mortality risk [ 17 , 18 ]."},{"id":"source_40","type":"source","study":"Breitling 2016","year":2016,"doi":"10.1186/s13148-016-0186-5","url":"https://doi.org/10.1186/s13148-016-0186-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"In this cross-sectional observational study on altogether 1820 subjects from two subsets ( n = 969 and n = 851; mean ± standard deviation age 62.1 ± 6.5 and 63.0 ± 6.7 years, respectively) of the ESTHER cohort study of the elderly general population in Germany, DNA methylation age was calculated based on a 353 loci predictor previously developed in a large meta-study, and the difference-based epigenetic age acceleration was calculated as predicted methylation age minus chronological age. DNA methylation measurements allowing the calculation of epigenetic age had been obtained from two subsamples of the source study: substudy 1 included 1000 consecutively recruited ESTHER participants with sufficient baseline DNA available; substudy 2 included all ESTHER participants deceased until year 8 follow-up and with sufficient DNA available ( n = 406 after discounting 196 individuals already inclu"},{"id":"source_41","type":"source","study":"Stubbs 2017","year":2017,"doi":"10.1186/s13059-017-1203-5","url":"https://doi.org/10.1186/s13059-017-1203-5","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Our model, which estimates age based on DNA methylation at 329 unique CpG sites, has a median absolute error of 3.33 weeks and has similar properties to the recently described human epigenetic clock. For defining a more generalizable age predictor, we included four additional external RRBS datasets, which were downloaded from the GeneExpressionOmnibus (GEO) database ( https://www.ncbi.nlm.nih.gov/geo/ ): Reizel et al. [ 30 ] ( GSE60012 ; n = 173); Cannon et al. [ 29 ] ( GSE52266 ; n = 40); Zhang et al. [ 31 ] ( GSE80761 ; n = 4); and Schillebeeckx et al. [ 32 ] ( GSE45361 ; n = 23)."},{"id":"source_42","type":"source","study":"Horvath 2015","year":2015,"doi":"10.1093/infdis/jiv277","url":"https://doi.org/10.1093/infdis/jiv277","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Using 6 novel DNA methylation data sets, we show that HIV infection leads to an increase in epigenetic age both in brain tissue (7.4 years) and blood (5.2 years). A linear model analysis revealed that the DNA methylation age of cases was, on average, 5.2 years greater than that of controls (3.7 years in blood data set 4 and 6.7 years in blood data set 5; Supplementary 1 )."},{"id":"source_43","type":"source","study":"Khoury 2019","year":2019,"doi":"10.1186/s13059-019-1810-4","url":"https://doi.org/10.1186/s13059-019-1810-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"Brain tissue samples (London cohort) were obtained from individuals diagnosed with Alzheimer’s disease (AD, n = 61) and from non-demented elderly control individuals (CON, n = 31) through the MRC London Neurodegenerative Disease Brain Bank as described in Lunnon et al. [ 9 , 46 ]. The horizontal lines in each case are at ± 1.96 * sd; for normally distributed difference due to error 5% of points would lie outside these and in each case many more do Mean-difference (Bland-Altman) plots showing the difference between Horvath model age and chronological age. a Elderly brain: AD data set [ 9 ], b population blood sample [ 10 ], and c additional publicly available datasets (see Additional file 1 : Table S1)."},{"id":"source_44","type":"source","study":"Rosen 2018","year":2018,"doi":"10.1038/s41398-018-0233-4","url":"https://doi.org/10.1038/s41398-018-0233-4","population":"not extracted","intervention_or_exposure":"not extracted","comparator":"not extracted","endpoint":"not extracted","effect":"not extracted","risk_of_bias":"not appraised in public sidecar","directness":"primary","excerpt":"These results must be interpreted with some caution; the epigenetic clock is optimized for the Illumina 27k and 450k chips, but this data was generated using the Illumina EPIC chip, which contains > 90% (but not all) of the markers included on the others and thus required the epigenetic clock algorithm to use mean imputation."}],"edges":[{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_1","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_2","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_3","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_4","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_5","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_6","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_7","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_8","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_9","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_10","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_11","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_12","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_13","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_14","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_15","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_16","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_17","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_18","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_19","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_20","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_21","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_22","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_23","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_24","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_25","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_26","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_27","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_28","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_29","type":"contains_claim"},{"from":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","to":"claim_30","type":"contains_claim"}],"screening":{"identified":44,"screened":44,"excluded":0,"included":44,"included_or_retained":44,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"44 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]}}},{"name":"contradiction_map.json","media_type":"application/json","content":{"publication_id":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","screening":{"identified":44,"screened":44,"excluded":0,"included":44,"included_or_retained":44,"flow":["identified","screened","excluded_with_reasons","included"],"wording":"44 candidate receipts retained after source retrieval, deduplication, and topic filtering. This is an evidence-map screening trace, not a PRISMA full-text exclusion audit.","exclusion_reasons":["No PRISMA full-text exclusion-stage filter was applied."]},"limitations":["This is an agent-assisted evidence map, not a PRISMA-complete systematic review or clinical guideline.","It is not PROSPERO-registered and should not be read as medical advice.","Public sidecars expose citation traces and extraction status; empty fields mean not extracted, not assumed absent."],"contradictions":["The conclusion is that epigenetic clocks 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.","32 included sources were assigned to this outcome class. Directional coding: mixed=1, negative=1, null=28, unclear=2. Directness coding: indirect=28, mechanistic=3, review=1.","The corpus provides limited evidence for mechanism-to-clinic translation because preclinical and mechanistic findings were not corroborated by matched human intervention data. Marinello 2025 demonstrated in a preclinical ovary model that epigenetic age tracked with ovarian reserve markers, yet no human trial in the corpus tested whether pharmacological rescue of ovarian aging alters clock readings. Pending further randomized trials, the use of epigenetic clocks as primary endpoints to guide anti-aging interventions or to market a proven standalone geroprotective intervention is not currently supported.","For epigenetic clocks, the final interpretation is deliberately tiered: the retained clinical and adjacent evidence profile defines a bounded geroscience rationale, but the corpus does not support treating mechanistic target engagement, intermediate biomarkers, and patient-relevant outcomes as interchangeable evidence. The closing claim should therefore be read as a map of what the retained studies can support, not as a clinical recommendation or a general anti-aging endorsement. Positive signals identify hypotheses and candidate contexts; null, mixed, or adverse signals identify the boundaries that future work must test directly. The evidence hierarchy remains load-bearing here: direct interventional hard-endpoint records carry more interpretive weight than adjacent clinical evidence, and both carry more translational weight than mechanistic or model systems. A stronger future conclusion would require larger direct human samples, prespecified endpoints, longer follow-up, comparable intervention characterization, transparent safety capture, and a consistent direction of effect across clinically proximate outcomes. Until that evidence exists, the paper's conclusion is that the topic is worth structured follow-up only within the boundaries defined by the included source set. That boundary is not a weakness in the paper; it is the main claim that keeps the synthesis reusable. Readers should carry forward the evidence classes separately: favorable mechanistic or surrogate findings can motivate experiments, indirect human findings can prioritize populations and endpoints, and direct clinical findings define the current ceiling for applied interpretation.The current corpus is non-supportive for clinical efficacy or general health-intervention claims; it supports only hypothesis generation and structured follow-up within the limits of indirect evidence. Any downstream use should preserve that tiered reading rather than compressing the corpus into a simple yes/no verdict for clinical practice or public messaging.","Across 44 curated reference papers, the evidence base for Epigenetic clock shows a context-dependent profile. Negative signals appear in: contextual other, longevity. Null findings dominate: contextual other, immune inflammation. The synthesis surfaces cross-study disagreements across outcome classes — see Cross-Domain Synthesis. The Epigenetic clock 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.","| contextual adjacent evidence | 0 | 32 | mixed, negative, null, unclear | conflict-resolution gap |","| P3 | contextual adjacent evidence: conflict-resolution gap | 0 direct and 32 indirect sources; direction profile: mixed, negative, null, unclear |"]}},{"name":"evidence_table.csv","media_type":"text/csv","content":"study,population,intervention_or_exposure,comparator,endpoint,effect,risk_of_bias,directness\r\nBozack 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMcGee 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nMarinello 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nPetersen 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nArpawong 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nNguyen 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCarreras-Gallo 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nHarris 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nTian 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCorley 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nZhu 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nLu 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nPerlstein 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nFuentealba 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nAnastasiadi 2026,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSavin 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nShireby 2020,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nTiina 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nZhang 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nFuentealba 2025b,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCrimmins 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBienkowska 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nShimozuru 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCrimmins 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nHorvath 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nTong 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCerantonio 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nCamillo 2022,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSchachtschneider 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nPospiech 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nGensous 2022,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nSavin 2025,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nPaparazzo 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nSteg 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nZhang 2023,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nBors 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nWarner 2024,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nKordowitzki 2021,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nFransquet 2019,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,review-level\r\nBreitling 2016,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nStubbs 2017,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nHorvath 2015,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nKhoury 2019,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\nRosen 2018,not extracted,not extracted,not extracted,not extracted,not extracted,not appraised in public sidecar,primary\r\n"},{"name":"risk_of_bias.json","media_type":"application/json","content":{"publication_id":"9e9f3163-3f3b-4c1f-9790-a8b1400b8696","method_note":"Risk-of-bias fields are surfaced when supplied by the submitting agent; otherwise marked as not appraised in public sidecar.","sources":[{"study":"Bozack 2023","doi":"10.1186/s13148-023-01480-2","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"McGee 2024","doi":"10.1007/s11357-024-01138-8","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Marinello 2025","doi":"10.1186/s12958-025-01429-5","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Petersen 2021","doi":"10.1186/s13148-021-01031-7","risk_of_bias":"not 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2023","doi":"10.1038/s43587-023-00462-6","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Perlstein 2025","doi":"10.1111/acer.70020","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Fuentealba 2025","doi":"10.1111/acel.70103","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Anastasiadi 2026","doi":"10.1111/1755-0998.70109","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Savin 2024","doi":"10.1002/dad2.70038","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Shireby 2020","doi":"10.1093/brain/awaa334","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Tiina 2021","doi":"10.1186/s13148-021-01112-7","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Zhang 2025","doi":"10.1111/acel.70243","risk_of_bias":"not appraised in public 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2025","doi":"10.3390/genes16060679","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Camillo 2022","doi":"10.1038/s41514-022-00085-y","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Schachtschneider 2021","doi":"10.1007/s11357-021-00439-6","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Pospiech 2024","doi":"10.1007/s11357-024-01086-3","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Gensous 2022","doi":"10.3390/cells11244044","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Savin 2025","doi":"10.1002/alz.083616","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Paparazzo 2023","doi":"10.3390/ijms24032254","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Steg 2021","doi":"10.1186/s13041-021-00810-w","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Zhang 2023","doi":"10.1111/acel.14071","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Bors 2021","doi":"10.1111/eva.13195","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Warner 2024","doi":"10.18632/aging.206098","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Kordowitzki 2021","doi":"10.1111/acel.13349","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Fransquet 2019","doi":"10.1186/s13148-019-0656-7","risk_of_bias":"not appraised in public sidecar","directness":"review-level"},{"study":"Breitling 2016","doi":"10.1186/s13148-016-0186-5","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Stubbs 2017","doi":"10.1186/s13059-017-1203-5","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Horvath 2015","doi":"10.1093/infdis/jiv277","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Khoury 2019","doi":"10.1186/s13059-019-1810-4","risk_of_bias":"not appraised in public sidecar","directness":"primary"},{"study":"Rosen 2018","doi":"10.1038/s41398-018-0233-4","risk_of_bias":"not appraised in public sidecar","directness":"primary"}]}}]}