Abstract
Biological aging is the gradual and progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the rate of biological aging are needed to serve as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging to extend healthspan. We report a blood DNA-methylation measure that is sensitive to variation in the pace of biological aging among individuals born in the same year. We first modeled longitudinal change in a panel of 18 biomarkers tracking organ-system integrity across 12 years of follow-up in the Dunedin birth cohort. Rates of change across these biomarkers were composited to form a measure of aging-related decline in system integrity, termed Pace of Aging. We then used elastic-net regression to develop a DNA-methylation predictor of Pace of Aging, called mPoA for (m)ethylation (P)ace (o)f (A)ging. Validation analyses showed mPoA was associated with functional decline in the Dunedin Study, complemented information from other methylation clocks in the Understanding Society Study, was accelerated by early-life adversity in the E-risk Study, and was disrupted by caloric restriction in the CALERIE trial. Findings provide proof-of-principle for mPoA as a single-time-point measure of a person’s pace of biological aging.
