Abstract
Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood-DNA-methylation measure that is sensitive to variation in pace of biological aging among individuals born the same year. We first modeled change-over-time in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in n = 954 members of the Dunedin Study born in 1972-1973. Rates of change in each biomarker over ages 26-38 years were composited to form a measure of aging-related decline, termed Pace-of-Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace-of-Aging, called DunedinPoAm for Dunedin(P)ace(o)f(A)ging(m)ethylation. Validation analysis in cohort studies and the CALERIE trial provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person's pace of biological aging.
Highlights
Aging of the global population is producing forecasts of rising burden of disease and disability (Harper, 2014)
Human trials of these treatments are challenging because humans live much longer than model animals, making it time-consuming and costly to follow up human trial participants to test treatment effects on healthy lifespan
The 46-CpG elastic-net-derived DunedinPoAm algorithm, applied in the age-38 Dunedin DNA methylation data, was associated with the longitudinal 26–38 Pace of Aging measure (Pearson r = 0.56, Figure 1—figure supplement 1). This is likely an overestimate of the true out-of-sample correlation because the analysis is based on the same data used to develop the DunedinPoAm algorithm; bootstrap-cross-validation analysis estimated the out-of-sample correlation to be r = 0.33 (Figure 1—figure supplement 2)
Summary
Aging of the global population is producing forecasts of rising burden of disease and disability (Harper, 2014). Human trials of these treatments are challenging because humans live much longer than model animals, making it time-consuming and costly to follow up human trial participants to test treatment effects on healthy lifespan This challenge will be exacerbated in trials that will give treatments to young or middle-aged adults, with the aim to prevent the decline in system integrity that antedates disease onset by years. Translation of geroprotector treatments to humans could be aided by measures that quantify the pace of deterioration in biological system integrity in human aging Such measures could be used as surrogate endpoints for healthy lifespan extension (Justice et al, 2016; Justice et al, 2018; Moskalev et al, 2016), even with young-to-midlife adult trial participants. A useful measure should be non-invasive, inexpensive, reliable, and highly sensitive to biological change
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