Extending the GrimAge Epigenetic Clock with Physical Fitness Measures
An aging clock can be built from near any collection of data that changes with age. The first epigenetic clocks used DNA methylation status for many different locations on the genome, but just about any biochemical or physiological measure can be incorporated into a clock algorithm. Since early epigenetic clocks were insensitive to physical fitness, it is interesting to see an attempt to extend a later epigenetic clock by adding assessments of physical fitness. Can there be a hypothetical best clock, one that accurately reflects the result of any intervention in aging, or will it always be the case that clocks will only approximate the complex reality, and there will always be issues in which a clock is too sensitive or not sensitive enough to one or more mechanisms of aging? That is the question.
Physical fitness is a well-known correlate of health and the aging process and DNA methylation (DNAm) data can capture aging via epigenetic clocks. However, current epigenetic clocks did not yet use measures of mobility, strength, lung, or endurance fitness in their construction. We develop blood-based DNAm biomarkers for fitness parameters gait speed (walking speed), maximum handgrip strength, forced expiratory volume in one second (FEV1), and maximal oxygen uptake (VO2max) which have modest correlation with fitness parameters in five large-scale validation datasets.
We then use these DNAm fitness parameter biomarkers with DNAmGrimAge, a DNAm mortality risk estimate, to construct DNAmFitAge, a new biological age indicator that incorporates physical fitness. DNAmFitAge is associated with low-intermediate physical activity levels across validation datasets, and younger/fitter DNAmFitAge corresponds to stronger DNAm fitness parameters in both males and females. DNAmFitAge is lower and DNAmVO2max is higher in male body builders compared to controls.
Physically fit people have a younger DNAmFitAge and experience better age-related outcomes: lower mortality risk, coronary heart disease risk, and increased disease-free status. These new DNAm biomarkers provide researchers a new method to incorporate physical fitness into epigenetic clocks.