Biological age measured by DNA methylation clocks and frailty: a systematic review and meta-analysis
Bibliographic record
Abstract
Background Frailty is an age-related condition characterised by multisystem physiological decline, which increases vulnerability to adverse outcomes. Biomarkers of ageing might identify individuals at risk and enable early interventions. This systematic review and meta-analysis aimed to examine cross-sectional and longitudinal associations between DNA methylation-based biological age metrics (eg, DNA methylation age, epigenetic-age acceleration [EAA], and age deviation) and frailty. Methods In a systematic search of six databases (Embase, Cochrane Central Register of Controlled Trials, PubMed, Ovid, Scopus, and Web of Science) from Jan 1, 2011, to June 6, 2025, we identified population-based cohort studies reporting associations between DNA methylation age, EAA, or age deviation and frailty from general or disease-specific populations with a control group. Risk of bias was assessed using an adapted Newcastle–Ottawa Scale. Random-effects meta-analyses with Hartung–Knapp adjustments were performed on standardised β coefficients and SEs. Publication bias, influence, and sensitivity analyses were conducted. Findings From 34 437 records screened, 24 studies met the inclusion criteria (17 cross-sectional studies, one longitudinal study, and six studies that were both cross-sectional and longitudinal), encompassing 28 325 participants (14 757 [52·1%] female; median of mean age 65·2 years [IQR 62·2–69·4]). DNA methylation age and age deviation showed no association with frailty. In cross-sectional meta-analyses, higher Hannum EAA (nine studies; n=11 162; standardised β coefficient 0·06 [95% CI 0·02–0·09], I 2 =71·4%), PhenoAge EAA (eight studies; n=10 371; 0·07 [0·03–0·11], I 2 =81·7%), GrimAge EAA (eight studies; n=10 371; 0·11 [0·06–0·15], I 2 =90·5%), and pace of ageing (five studies; n=7895; 0·10 [0·01–0·19], I 2 =91·0%) were significantly associated with higher frailty. In longitudinal meta-analyses, higher GrimAge EAA (five studies; n=6143; 0·02 [0·00–0·05], I 2 =46·0%, p=0·0481) was significantly associated with increases in frailty, whereas PhenoAge EAA and pace of ageing were not significantly associated with frailty. Interpretation Higher GrimAge EAA is consistently associated with higher frailty. Future research should focus on developing and validating DNA methylation clocks that integrate molecular surrogates of health risk and are specifically trained to predict frailty in large, harmonised, longitudinal cohorts, enabling their translation into clinical practice. Funding National University of Singapore.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.018 | 0.047 |
| Meta-epidemiology (narrow) | 0.003 | 0.002 |
| Meta-epidemiology (broad) | 0.018 | 0.035 |
| Bibliometrics | 0.008 | 0.008 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".