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

Zhang, Y., Hulsman, M., Tesi, N., Rohde, S., Luimes, M., Lorenz, L., van der Lee, S. J., Graat, M., van der Hoorn, M., Daatselaar, D., Teunissen, C., Vijverberg, E. G. B., Salazar, A., Holstege, H.

Amsterdam UMC · medrxiv

Paper

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.

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Research summary

GrimAge acceleration is a robust predictor of mortality in cognitively healthy centenarians, independent of brain aging-related biomarkers. The study addresses biological factors linked to survival at extreme old age, contributing to the understanding of aging mechanisms rather than merely treating age-related diseases.

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