Validating a 3rd-generation methylation measure of accelerated aging: DunedinPoAm4x

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We propose to validate and export to the aging field a novel tool to measure a person’s pace of biological aging: DunedinPoAm4x. The measure will be useful for basic aging research and also for testing whether an intervention has slowed a person’s pace of aging. We began this work under NIA R01 AG032282 (Belsky et al PNAS 2015). Over two decades, we tracked a 19-biomarker panel of the physiological functions of 1,000 individuals born the same year (1972-73) in the population- representative Dunedin Study. Our goal has been to measure, in people the same chronological age, variation in biological aging defined per geroscience theory as: gradual, progressive decline simultaneously affecting multiple organ systems. We tracked declines in the cardiovascular, metabolic, pulmonary, renal, dental, hepatic, and immune functions of participants by repeating biomarkers at ages 26, 32, 38 and 45 years (94% retention). Growth-curve modelling of this one-of-a-kind dataset yielded a pace-of-aging metric that quantified how slowly or rapidly each participant in our cohort had been aging (Elliott et al Nature Aging, 2021). The next stage of the work applied machine-learning to participants’ age-45 whole-genome DNA methylation data, training an algorithm on the pace-of-aging metric to derive a score called DunedinPoAm4x (Pace of Aging methylation, 4 waves). This technical advance means that a person’s pace of aging can be estimated from just a single blood sample, and the metric can be exported to any research sample that has blood methylation data. Previously we had reported validation checks on a preliminary version of DunedinPoAm, up to age 38, showing that people who had faster methylation pace of aging scores subsequently experienced advanced facial age, declines in cognitive and physical functioning, chronic diseases, and early mortality (Belsky et al eLife 2020). Our Aims propose a systematic out-of-sample validation evaluation of DunedinPoAm4x in 19+ data sets, testing its applicability in older adults, young people, race/ethnic groups, and several countries. Each Aim will also test existing leading methylation clocks for comparison. Our overarching hypothesis is that DunedinPoAm4x will characterize biological aging with greater precision than the clocks, and in so doing will bring added information value over and above the clocks. In addition to aim- specific publications, we plan a final, synthesis publication. We will deliver, to basic scientists and intervention researchers, a reliable, valid, open-access measure of how rapidly a person has been aging.