Peripheral Epigenetic Aging Predicts Survival in Cognitively Healthy Centenarians Independent of Brain Aging-Related Biomarkers

Abstract Centenarians exhibit marked heterogeneity in biological aging despite their exceptional longevity. To identify biological factors linked to survival at extreme old age, we examined DNA methylation-based measures of aging in 247 cognitively healthy Dutch centenarians using PacBio long-read methylation sequencing. Age acceleration derived from the DNA methylation clock GrimAge emerged as a robust predictor of mortality (HR = 1.60, 95% CI: 1.28-2.00), independent of markers previously associated with mortality in centenarians, such as Mini-Mental State Examination (MMSE) scores (HR = 0.68, 95% CI: 0.56-0.84) and plasma neurofilament light chain (NfL) levels (HR = 1.29, 95% CI: 1.09-1.53). GrimAge acceleration showed limited association with phenotypes related to brain aging, including cognitive performance, neurodegeneration- and Alzheimer’s disease-related plasma biomarkers, and neuropathological measures. By contrast, it was associated with hematological markers consistent with age-related myeloid shift, although these did not fully account for its association with survival. Together, these findings suggest that GrimAge reflects a mortality-associated dimension of aging that is distinct from brain aging and remains informative even at extreme old age.