Physical Fitness Correlates with Slower Epigenetic Aging in Newer DNA Methylation Clocks
Epigenetic clocks that measure chronological or biological age are at present largely based on patterns of DNA methylation that change in characteristic ways over a lifetime. There are other options, such as looking at histones, but they are not as well explored. DNA methylation is the process or adding and removing methyl groups from nuclear DNA, changing its structure in ways that expose or hide gene sequences from the machinery of gene expression. These epigenetic decorations this control the production of proteins, and are continually changing in response to environmental factors and cell processes.
Since epigenetic clocks were produced via machine learning, a process of identifying patterns from raw data, it remains largely unknown as to why specific DNA methylation sites on the genome tend to become methylated or unmethylated with age. Explaining these clocks is a work in its infancy, despite their increasing use in research. One of the quirks of the early epigenetic clocks is that they proved to be insensitive to exercise and physical fitness. For example, see the results from a study of sedentary versus physically fit twin pairs. In general, we might take this as a warning that a specific epigenetic clock may well have hidden biases that make it unsuitable to assess a specific intervention to slow or reverse aging. The only way to find out in certainty would be to test the clock and therapy in long, expensive studies.
When it comes to physical fitness, which we know has a measurable, beneficial effect on health and late life mortality, and which should be reflected in a good epigenetic clock, it is reassuring to see that later DNA methylation clocks do appear to react in the right way. Unfortunately, these results have no bearing on whether or not more recent clocks will correctly assess, say, the results of clearing senescent cells, or transplanting mitochondria, or any of the other avenues to eventual human rejuvenation. Finding out will likely require years and a great deal of funding.
DNA methylation-based age estimators (DNAm ageing clocks) are currently one of the most promising biomarkers for predicting biological age. However, the relationships between cardiorespiratory fitness (CRF), measured directly by expiratory gas analysis, and DNAm ageing clocks are largely unknown. We investigated the relationships between CRF and the age-adjusted value from the residuals of the regression of DNAm ageing clock to chronological age (DNAmAgeAcceleration: DNAmAgeAccel) and attempted to determine the relative contribution of CRF to DNAmAgeAccel in the presence of other lifestyle factors.
DNA samples from 144 Japanese men aged 65-72 years were used to appraise first-generation (i.e., DNAmHorvath and DNAmHannum) and second-generation (i.e., DNAmPhenoAge, DNAmGrimAge, and DNAmFitAge) DNAm ageing clocks. Various surveys and measurements were conducted, including physical fitness, body composition, blood biochemical parameters, nutrient intake, smoking, alcohol consumption, disease status, sleep status, and chronotype.
Both oxygen uptake at ventilatory threshold (VO2/kg at VT) and peak oxygen uptake (VO2/kg at Peak) showed a significant negative correlation with GrimAgeAccel, even after adjustments for chronological age and smoking and drinking status. Notably, VO2/kg at VT and VO2/kg at Peak above the reference value were also associated with delayed GrimAgeAccel. Multiple regression analysis showed that calf circumference, serum triglyceride, carbohydrate intake, and smoking status, rather than CRF, contributed more to GrimAgeAccel and FitAgeAccel. In conclusion, although the contribution of CRF to GrimAgeAccel and FitAgeAccel is relatively low compared to lifestyle-related factors such as smoking, the results suggest that the maintenance of CRF is associated with delayed biological ageing in older men.