Associations between cardiorespiratory fitness and lifestyle-related factors with DNA methylation-based aging clocks in older men: WASEDA’S Health Study

DNA methylation-based age estimators (DNAm aging clocks) are currently one of the most promising biomarkers for predicting biological age. However, the relationships between objectively measured physical fitness, including cardiorespiratory fitness, and DNAm aging clocks are largely unknown. We investigated the relationships between physical fitness and the age-adjusted value from the residuals of the regression of DNAm aging clock to chronological age (DNAmAgeAcceleration: DNAmAgeAccel) and attempted to determine the relative contribution of physical fitness variables to DNAmAgeAccel in the presence of other lifestyle factors. DNA samples from 144 Japanese men aged 65–72 years were used to calculate first- ( i.e. , DNAmHorvath and DNAmHannum) and second- ( i.e. , DNAmPhenoAge, DNAmGrimAge and DNAmFitAge) generation DNAm aging clocks. Various surveys and measurements were conducted, including physical fitness, body composition, blood biochemical parameters, nutrients intake, smoking, alcohol consumption, disease status, sleep status, and chronotype. The peak oxygen uptake (VO2peak) per kg body weight had a significant negative correlation with GrimAgeAccel ( r = -0.222, p = 0.008). A comparison of the tertile groups showed that the GrimAgeAccel of the highest VO2peak group was decelerated by 1.6 years compared to the lowest group ( p = 0.035). Multiple regression analysis suggested that rather than physical fitness, serum triglycerides, carbohydrate intake, and smoking status, were significantly associated with DNAmAgeAccel. In conclusion, the contribution of cardiorespiratory fitness to DNAmAgeAccel was relatively low compared to lifestyle factors such as smoking. However, this study reveals a negative relationship between cardiorespiratory fitness and DNAmAgeAccel in older men. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was supported by Grant-in-Aid for Early-Career Scientists (20K19520) from the Japan Society for Promotion of Science, and Grant for Special Research Projects from Waseda University (2020-410). This project is a collaborative research project with the Institute of Stress Science, Public Health Research Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Research Ethics Committee of Waseda University (approval numbers: 2014-G002 and 2018-G001) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The measurement data used to support the findings of this study is available from the corresponding author upon reasonable request.