A Novel Blood-Based Epigenetic Clock for Intrinsic Capacity Predicts Mortality and is Associated with Clinical, Immunological and Lifestyle Factors

Age-related decline in intrinsic capacity (IC), defined as the sum of an individuals physical and mental capacities, is a cornerstone for promoting healthy aging and longevity, as it emphasizes maximizing function throughout the aging process instead of merely treating diseases. However, accurate assessments of IC are resource-intensive, and the molecular and cellular basis of its decline are poorly understood. Herein, we used the INSPIRE-T cohort, consisting of 1,014 individuals aged 20 to 102, to construct the IC clock, a DNA methylation (DNAm)-based predictor of IC trained on the clinical evaluation of cognition, locomotion, psychological well-being, sensory abilities, and vitality. In the Framingham Heart Study, age-adjusted DNAm IC correlates with first- and second-generation epigenetic clocks, predicts all-cause mortality, and is strongly associated with changes in molecular and cellular immune and inflammatory biomarkers, functional and clinical endpoints, health risk factors, and diet.