Research Synthesis: Epigenetic Clocks

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. The paper therefore interprets the corpus as a tiered evidence profile rather than as a single pooled effect.

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.

Results

Outcome-class note: Contextual Adjacent Evidence denotes background, boundary-condition, or adjacent-outcome sources. It is not pooled with direct outcome evidence; these sources bound scope, safety, methods, and translation rather than serving as equal-weight support for the main efficacy claim.

Outcome class	Corpus slice	Strongest signal	Directness	Main limitation
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
Longevity	n=5; claims=83	no extracted directional signal in 3/5 sources	5 indirect	limited corpus depth in this outcome class
Immune and Inflammation	n=3; claims=59	no extracted directional signal in 3/3 sources	3 indirect	limited corpus depth in this outcome class
Mortality and Survival	n=3; claims=39	unclear signal in 2/3 sources	1 indirect; 2 review	limited corpus depth in this outcome class
Frailty	n=1; claims=103	mixed signal in 1/1 sources	1 indirect	single-source slice; hypothesis-generating

This evidence brief reports outcome packets as a map of retained evidence rather than as a full journal Results narrative or pooled effect estimate.

Contextual Adjacent Evidence Outcomes

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.

Longevity Outcomes

5 included sources were assigned to this outcome class. Directional coding: negative=1, null=3, unclear=1. Directness coding: indirect=5.

Immune Inflammation Outcomes

3 included sources were assigned to this outcome class. Directional coding: null=3. Directness coding: indirect=3.

Mortality Survival Outcomes

3 included sources were assigned to this outcome class. Directional coding: null=1, unclear=2. Directness coding: indirect=1, review=2.

Frailty Outcomes

1 included source were assigned to this outcome class. Directional coding: mixed=1. Directness coding: indirect=1.

Limitations

Verification note: Reference-only or no-abstract records are treated as verification-limited context, not as equal-weight support for the main claim.

The 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.

Several 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.

Enrolled 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.

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.

Conclusion

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.

What This Synthesis Adds

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.

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.

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.

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.

Boundary-Condition Matrix

Outcome class	Direct sources	Indirect / mechanism sources	Direction profile	Interpretation boundary
longevity	0	5	negative, null, unclear	direct interventional hard-endpoint gap
frailty	0	1	mixed	direct interventional hard-endpoint gap
contextual adjacent evidence	0	32	mixed, negative, null, unclear	conflict-resolution gap
mortality and survival	0	3	null, unclear	direct interventional hard-endpoint gap
immune and inflammation	0	3	null	direct interventional hard-endpoint gap

Evidence-Gap Priority

Priority	Gap	Rationale
P1	longevity: direct interventional hard-endpoint gap	0 direct and 5 indirect sources; direction profile: negative, null, unclear
P2	frailty: direct interventional hard-endpoint gap	0 direct and 1 indirect source; direction profile: mixed
P3	contextual adjacent evidence: conflict-resolution gap	0 direct and 32 indirect sources; direction profile: mixed, negative, null, unclear
P4	mortality and survival: direct interventional hard-endpoint gap	0 direct and 3 indirect sources; direction profile: null, unclear
P5	immune and inflammation: direct interventional hard-endpoint gap	0 direct and 3 indirect sources; direction profile: null

Next-Study Design Recommendation

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.

Evidence Snapshot

The manuscript foregrounds the load-bearing evidence; the full evidence tables remain in the supplement.

Classification Criteria

• Outcome class is assigned from the source's bound endpoint, population, and claim text; adjacent/background sources are separated from clinical outcome slices.
• Directness is coded as direct only when a source tests the topic against a clinically proximate outcome in the relevant population; a qualifying direct source would be a human interventional or hard-endpoint study of the topic itself. Indirect human, review-level, and mechanistic sources are weighted separately.
• Directional signal is counted within the assigned outcome class only. A no extracted directional signal cell means the retained sources in that outcome slice did not yield a coded positive, negative, or mixed direction for that slice; it is not a claim that the source reports no associations anywhere else.
• Evidence tier follows the deterministic tier/directness taxonomy used in the source builder; the prose writer cannot move a source between classes after sources are frozen.

Source Classification Map

Each retained source is mapped to its public evidence role so the evidence landscape can be checked without opening the supplement.

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Sociodemographic and Lifestyle Factors and Epigenetic Aging in US Young Adults: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=50.
• 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.
• 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.
• GrimAge and GrimAge2 Age Acceleration effectively predict mortality risk: a retrospective cohort study: outcome=longevity; directness=indirect; tier=B2; direction=negative; claims=40.
• Universal DNA methylation age across mammalian tissues: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=unclear; claims=36.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Epigenetic Clock Analysis of Sex Chromosome Aneuploidies: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=17.
• 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.
• 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.
• 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.
• 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.
• 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.
• DNA methylation age analysis of rapamycin in common marmosets: outcome=longevity; directness=indirect; tier=B2; direction=null; claims=13.
• 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.
• A pan-tissue DNA-methylation epigenetic clock based on deep learning: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=10.
• 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.
• Epigenetic clock and DNA methylation analysis of porcine models of aging and obesity: outcome=longevity; directness=indirect; tier=B2; direction=null; claims=9.
• HIV-1 Infection Accelerates Age According to the Epigenetic Clock: outcome=immune inflammation; directness=indirect; tier=B2; direction=null; claims=8.
• A Targeted Epigenetic Clock for the Prediction of Biological Age: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=7.
• An ELOVL2-Based Epigenetic Clock for Forensic Age Prediction: A Systematic Review: outcome=contextual adjacent evidence; directness=review; tier=B2; direction=null; claims=6.
• 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.
• 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.
• 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.
• Systematic underestimation of the epigenetic clock and age acceleration in older subjects: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=4.
• An epigenetic clock to estimate the age of living beluga whales: outcome=longevity; directness=indirect; tier=B2; direction=null; claims=3.
• 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.
• DNA methylation age is accelerated in alcohol dependence: outcome=contextual adjacent evidence; directness=indirect; tier=B2; direction=null; claims=1.

Load-Bearing Included Studies

• Fransquet 2019; Review / meta-analysis; tier=B1; directness=review; N=—; population=—; endpoint=mortality survival; direction=unclear; representative statistic=P = 0.008.
• Bozack 2023; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.001.
• McGee 2024; Observational; tier=B2; directness=indirect; N=—; population=older adults; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.0058.
• Petersen 2021; Observational; tier=B2; directness=indirect; N=—; population=older adults; endpoint=frailty; direction=mixed; representative statistic=P < 0.01.
• Arpawong 2023; Observational; tier=B2; directness=indirect; N=—; population=older adults; endpoint=contextual adjacent evidence; direction=null; representative statistic=P < 0.0001.
• Nguyen 2026; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=negative; representative statistic=P = 0.01.
• Carreras-Gallo 2025; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=null; representative statistic=P = 0.0038.
• Harris 2024; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=null.
• Tian 2024; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=immune inflammation; direction=null; representative statistic=P = 0.0002.
• Corley 2023; Observational; tier=B2; directness=indirect; N=—; population=adults; endpoint=contextual adjacent evidence; direction=mixed; representative statistic=P = 0.01.

Load-Bearing Tensions

Additional corpus sources included animal/preclinical evidence; - Severity 4 disagreement: Bozack 2023 vs Corley 2023; Bozack 2023 (null) vs Corley 2023 (mixed) on contextual other

• Severity 4 disagreement: Arpawong 2023 vs Corley 2023; Arpawong 2023 (null) vs Corley 2023 (mixed) on contextual other
• Severity 4 disagreement: Lu 2023 vs Corley 2023; Lu 2023 (unclear) vs Corley 2023 (mixed) on contextual other
• Severity 4 disagreement: Corley 2023 vs Bienkowska 2024; Corley 2023 (mixed) vs Bienkowska 2024 (null) on contextual other
• Severity 4 disagreement: Corley 2023 vs Pospiech 2024; Corley 2023 (mixed) vs Pospiech 2024 (null) on contextual other
• Severity 4 disagreement: Corley 2023 vs Harris 2024; Corley 2023 (mixed) vs Harris 2024 (null) on contextual other
• Severity 4 disagreement: Corley 2023 vs McGee 2024; Corley 2023 (mixed) vs McGee 2024 (null) on contextual other
• Severity 4 disagreement: Corley 2023 vs Savin 2024; Corley 2023 (mixed) vs Savin 2024 (null) on contextual other

Methods

Review type and protocol

This 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.

Information sources

Sources were retrieved across PubMed, Europe PMC, OpenAlex, Semantic Scholar, Crossref, DOAJ, OpenAIRE, PMC OAI, bioRxiv, medRxiv, arXiv, and ClinicalTrials.gov. Retrieval window: 2026-06-03.

Search strategy

The following topic-anchored queries were executed against the information sources listed above:

Eligibility criteria

• Sources whose primary content addresses epigenetic clocks.
• Sources with extractable quantitative or qualitative findings.
• Peer-reviewed primary research, systematic reviews, or meta-analyses; preprints accepted only when source-traceable.
• Sources with verifiable bibliographic identifiers (DOI / PMID / canonical handle).

Selection of sources of evidence

The synthesis did not begin from an unfiltered database export. It began from a pre-curated receipt-candidate set generated by the retrieval and claim-binding pipeline. Of 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.

source admission funnel

Admission bucket	n
Receipt candidate union	188
Classified source candidates	68
No extractable claims	24
None-only claim binding	13
Mixed partial-or-none claim-binding candidates	59
Partial-only claim-binding candidates	18
Strict high-confidence sources	6
Admitted final sources	44

Exclusion reasons

• Non-traceable findings (claim could not be linked to source text): 0 records.
• Wrong population / off-topic sources excluded at screening.
• Duplicate records deduplicated by DOI / PMID before screening.

Data items

The following fields were extracted from each included source: study design, population / cohort, intervention or exposure, comparator, outcome class, effect direction, effect size, confidence interval or credible interval, p-value, sample size, follow-up duration, risk-of-bias rating. Under the calibration rule, source verification in the public bundle is limited to reference-level metadata; exact statistics and effect directions are drawn from these structured extraction artifacts (the synthesis manifest, risk-of-bias appraisal, and claim registry) rather than from re-parsed full text.

Risk-of-bias appraisal

Per-source risk-of-bias was rated using design-appropriate Cochrane RoB-2 (RCTs), ROBINS-I (non-randomised studies), and AMSTAR-2 (systematic reviews / meta-analyses). Ratings recorded in risk_of_bias.json.

Synthesis approach

Evidence-tension synthesis: claims grouped by outcome class (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.

AI-use disclosure

Source retrieval, claim extraction, evidence routing, and prose drafting were assisted by large language models under a deterministic audit-trail protocol. Every manuscript claim is traceable to a source record in the supplementary manifest.json. Final eligibility and interpretation decisions are author-verified.

Accountability

Accountability is established through reproducible artifacts: a deterministic protocol (methods_pack.json), a complete claim and citation registry, extracted numeric trace, deterministic gates (full_paper.journal_surface.json, pre_submit_gate.json, artifact_consistency.json), and a versioned correction path documented in the run's submission record. This run is certified under the researka_agent_certified accountability model — trust is machine-verifiable rather than dependent on author signoff.

Additional 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.

References

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Lu 2023. Universal DNA methylation age across mammalian tissues. Nature Aging, 2023. DOI: 10.1038/s43587-023-00462-6. PMID: 37563227.
• 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.
• 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.
• 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.
• 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.
• Shireby 2020. Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex. Brain, 2020. DOI: 10.1093/brain/awaa334. PMID: 33300551.
• 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.
• 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.
• 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.
• Zhang 2025. Epigenetic Clock Analysis of Sex Chromosome Aneuploidies. Aging Cell, 2025. DOI: 10.1111/acel.70243. PMID: 41025454.
• 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.
• 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.
• 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.
• 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.
• 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.
• Horvath 2021. DNA methylation age analysis of rapamycin in common marmosets. GeroScience, 2021. DOI: 10.1007/s11357-021-00438-7. PMID: 34482522.
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