Biological-Age Clocks

DunedinPACE (Pace of Aging Calculated from the Epigenome) is an epigenetic clock published in 2022 by Belsky and colleagues that estimates the rate of biological ageing rather than a static age. It was trained in the Dunedin 1972-1973 birth cohort on longitudinal change across 19 organ-system biomarkers and translated into a DNA-methylation score using 173 CpGs. The score is calibrated so that 1 represents the cohort-mean pace of one year of biological aging per chronological year; values above 1 indicate faster-than-average ageing. DunedinPACE shows good test-retest reliability and predicts morbidity and mortality.

Epigenetic age is a biological-age estimate derived from DNA-methylation patterns at selected CpG sites, computed by algorithms known as epigenetic clocks (e.g. Horvath, Hannum, PhenoAge, GrimAge, DunedinPACE). The difference between epigenetic and chronological age, called epigenetic age acceleration, is associated with mortality, cardiovascular disease and cancer in research cohorts. Validation depends on the specific clock; first-generation clocks track chronological age, while mortality-trained clocks better predict health outcomes. Commercial consumer tests vary in reliability.

GrimAge is a second-generation epigenetic clock introduced by Lu et al. (2019, with Steve Horvath as senior author). Instead of predicting chronological age, it is trained on time-to-death and combines DNA-methylation surrogates for seven plasma proteins (e.g. PAI-1, GDF-15) and DNAm-based smoking pack-years. In multiple cohorts GrimAge and the updated GrimAge2 (2022) outperform earlier clocks at predicting all-cause mortality, cardiovascular disease and cancer. It is widely used in research; clinical use as a diagnostic endpoint remains investigational.

The Horvath clock is a multi-tissue epigenetic age estimator published by Steve Horvath in 2013. It uses DNA methylation levels at 353 CpG sites to predict chronological age across more than 50 tissues and cell types with a median error of about 3.6 years. It is the most-cited epigenetic clock and well validated as a predictor of chronological age, but its association with mortality and disease is weaker than that of later, mortality-trained clocks such as GrimAge.

PhenoAge is a composite biological-age measure developed by Levine and colleagues in 2018. The original blood-based version combines nine clinical biomarkers including albumin, creatinine, glucose, C-reactive protein and white blood cell count with chronological age, calibrated against mortality. A DNA-methylation version, DNAm PhenoAge, transfers the score to epigenetic data. PhenoAge predicts all-cause mortality and multimorbidity better than chronological age and has been validated in several large cohorts, although clinical use is still emerging.