ABSTRACT Frailty emerges as the intermediate stage preceding disability, but there is a gap in molecular signatures for early detection of subclinical cellular changes, which could help predict frailty onset or the effectiveness of interventions. In this randomized, controlled study, we assessed phenotypical and functional changes in frail individuals before and after a 6‐month multidomain lifestyle intervention (nutritional supplement and supervised exercise) vs habitual care. We also analyzed whole‐blood methylome, including five epigenetic clocks, a DNA methylation‐based telomere length estimator, and the Rate of Epigenetic Aging (REA). Between October 2019 and July 2022, we recruited 47 frail, community‐dwelling individuals in Spain. Mean age was 80.2 years (SD 3.1) in the control group (CG; n = 19) and 80.5 years (4.3) in the intervention group (IG; n = 28). Compared with the CG, a significant reduction in frailty, assessed by the SHARE‐FI score, was observed in the IG ( p < 0.0001). The IG also showed improved grip strength ( p = 0.0053), gait speed ( p = 0.0125), the Tinetti score ( p = 0.0031), and Barthel Index ( p = 0.0484). The intervention was also associated with statistically significant improvements in nutritional blood markers, indicators of biological aging, including reduced DNAm PhenoAge ( p = 0.0253) and preserved telomere length ( p = 0.0246). REA using DNAm PhenoAge indicated an acceleration of epigenetic aging in the CG ( p = 0.0300). Other epigenetic clocks showed nonsignificant changes. Our findings suggest potential geroprotective effects of a multidomain intervention and indicate that DNAm PhenoAge and methylation‐based telomere length may serve as complementary markers for assessing health span‐related changes in frail older adults. Trial Registration: This trial was retrospectively registered: NCT06975540
Olaso‐Gonzalez et al. (Sun,) studied this question.