Accelerated Epigenetic and Inflammatory Aging and Intrinsic Capacity.

Abstract

Extending the health span requires shifting from disease-centered to preventive, function-oriented medicine. To support healthy longevity, the World Health Organization (WHO) developed intrinsic capacity (IC), a composite of physical and mental capacities an individual can mobilize; however, molecular drivers of age-related IC decline remain poorly understood. To investigate cross-sectional and longitudinal associations of accelerated epigenetic and inflammatory aging with global IC and, secondarily, to examine domain-specific IC, sex differences, and interactions between epigenetic and inflammatory aging. This population-based cohort study included participants aged 20 years or older from the longitudinal INSPIRE Lifespan Translational Cohort. The 3-year prospective cohort study was initiated in October 2019. Data analysis was conducted from June to December 2025. At baseline, accelerated epigenetic aging was measured using Horvath Pan Tissue, Horvath Skin and Blood, Hannum, PhenoAge, and GrimAge clocks; accelerated inflammatory aging was measured with the iAge clock. Global IC was operationalized as a 5-domain construct: cognition (Mini-Mental State Examination), mobility (Short Physical Performance Battery), psychology (Patient Health Questionnaire for depression), vitality (grip strength), and sensory (WHO simple eye chart; whisper test) capacity and evaluated annually. Among 970 participants (median [IQR] chronological age, 64 [48-77] years; 602 [62.1%] female) with a median (IQR) follow-up time of 3.01 (2.97-3.04) years, accelerated epigenetic aging was associated with lower global IC, with a greater detrimental outcome associated with advancing chronological age (interaction with linear: β = -1.17; 95% CI. -2.02 to -0.33; false-discovery rate [FDR]-adjusted P = .04) and quadratic (β = -0.39; 95% CI, -0.71 to -0.08; FDR-adjusted P = .04) terms of chronological age. Accelerated inflammatory aging showed comparatively weaker associations with lower global IC across aging (eg, interaction with linear chronological age: β = -0.45; 95% CI, -0.77 to -0.12; FDR-adjusted P = .04). The co-occurrence of both biological aging processes resulted in greater functional impairment. The greater detrimental association of accelerated epigenetic aging with global IC was evident predominantly in male participants. In domain-specific IC analyses, mobility showed the greatest vulnerability. In this cohort study of participants spanning the adult lifespan, accelerated epigenetic aging was associated with lower global IC, with a greater detrimental outcome as chronological age advanced. Accelerated inflammatory aging showed weaker associations. These findings have meaningful implications for precision medicine, highlighting the potential of biomarkers derived from epigenetic and, to a lesser extent, inflammatory aging clocks to support early identification of high-risk individuals and guide targeted healthy longevity interventions.