Epigenetic clocks have existed for long enough for numerous large study databases to include data on their use. Thus meta-analysis papers are emerging to assess this body of data as a whole. This is a necessary part of the process of gaining confidence in the ability of epigenetic clocks, and indeed aging clocks in general, to rapidly assess the potential of any novel form of intervention intended to slow or reverse aspects of aging. This is a much needed capability. In many ways, efforts to treat aging as a medical condition proceed blindly, given just how much time and funding is required in order to understand whether one approach is better or worse than another. If there was a way to quickly assess the quality of an anti-aging therapy immediately after its application, then the field could adjust quickly to pursue the best paths forward. The hope is that aging clocks can be that tool - but we are clearly not there yet.
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.
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 female; median of mean age 65.2 years). 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), PhenoAge EAA (eight studies; n=10,371; standardised β coefficient 0.07), GrimAge EAA (eight studies; n=10,371; standardised β coefficient 0.11), and pace of ageing (five studies; n=7,895; standardised β coefficient 0.10) were significantly associated with higher frailty. In longitudinal meta-analyses, higher GrimAge EAA (five studies; n=6,143; standardised β coefficient 0.02) was significantly associated with increases in frailty, whereas PhenoAge EAA and pace of ageing were not significantly associated with frailty.
In conclusion, 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.
Link: https://doi.org/10.1016/j.lanhl.2025.100773
View the full article at FightAging
