Lower Epigenetic Age Acceleration in Older Adults with Preserved Global Cognitive Performance

Epigenetic clocks estimate biological age, yet evidence linking decelerated epigenetic aging to healthy cognitive performance in community-dwelling older adults is limited. Cross-sectional study within the population-based ALEXANDROS cohort (Santiago, Chile). Healthy Cognitive Agers (HCA) were participants aged ≥80 years who consistently maintained a MMSE score =30 across all cohort assessments. Controls were cognitively normal peers from the same cohort (MMSE 28.5 ± 2.9). Epigenetic age was estimated using the Horvath, GrimAge, and PhenoAge clocks. Epigenetic age acceleration (EAA) was calculated as residuals from regressing control-calibrated epigenetic age on chronological age. DNA methylation-derived telomere length (DNAmTL, kb) was also assessed. Eighty community-dwelling older adults were included (40 HCA and 40 controls). HCA exhibited substantially lower control-calibrated EAA than controls across all clocks, including Horvath (-13.55 ± 5.28 vs 0.00 ± 4.34 years; p < 0.001; Cohen's d = -2.80), PhenoAge (-9.72 ± 8.37 vs 0.00 ± 4.56 years; p < 0.001; Cohen's d = -1.44), and GrimAge (-3.16 ± 3.08 vs 0.00 ± 4.14 years; p < 0.001; Cohen's d = -0.87). HCA also exhibited substantially longer DNAm-derived telomere length (6.39 ± 0.27 vs 5.39 ± 0.21 kb; p < 0.001; Cohen's d = 4.15). Preserved cognitive performance in late life, based primarily on persistent MMSE performance, is associated with a decelerated biological aging profile in community-dwelling older adults. Although longitudinal studies are required to clarify temporality, these findings are consistent with the hypothesis that DNA methylation-derived epigenetic markers may help characterize healthy cognitive aging trajectories.