Association between pace of aging estimated from blood DNA methylation and all-cause mortality: the HUNT study

Epigenetic clocks, developed using blood DNA methylation data, can be used to estimate biological ages and pace of aging. We aimed to identify potential determinants of the pace of aging, estimated using blood DNA methylation, and to investigate the association between the pace of aging and all-cause mortality in a population-based Norwegian cohort with repeated DNA methylation measurements.

This study included 140 cancer-free controls from a lung cancer nested case-control study within the Trøndelag Health Study (HUNT). DNA methylation was measured in blood samples in both HUNT2 (1995-97) and HUNT3 (2006-08), 11 years apart. The pace of aging was estimated using two established measures of biological age, DNAmPhenoAge and DNAmGrimAge2, and two direct measures of pace of aging, DunedinPoAm and DunedinPACE, all derived from blood DNA methylation data. All-cause mortality was followed up until 2023.

There was a moderate to excellent reliability of the repeated measurements, with intraclass correlation coefficient (ICC) values ranged from 0.69-0.91. University education appeared to be associated with a slower pace of aging, while smoking and obesity were associated with a faster pace. A one-standard deviation increase in the pace of aging, as measured by DNAmGrimAge2, was associated with a hazard ratio (HR) of 2.42 (95% confidence interval (CI) 1.25 to 4.68) for all-cause mortality in HUNT2, and a HR of 2.30 (95% CI 1.22 to 4.33) in HUNT3 after adjustment for the established risk factors.

The pace of aging, as estimated using blood DNA methylation, appears to be an independent predictor of all-cause mortality. This measure may reflect the combined influence of genetic, lifestyle, and environmental factors on individual aging trajectories.