Systemic Metabolic Bottlenecks as Constraints on Exercise Responsiveness and Functional Healthspan During Aging

Regular physical exercise is a cornerstone of healthy aging, yet its efficacy progressively diminishes with age, posing a central challenge to preventive medicine. This study leverages a data-driven conceptual integration of a whole-body metabolic atlas of aging to define the molecular constraints driving this decline. Our analysis reveals three core findings: (1) metabolic aging follows significant organ-specific trajectories with persistent sex dimorphism, most notably in cardiac redox metabolism, where females exhibit enhanced glutathione activity; (2) trans-4-hydroxyproline was identified as a pan-organ biomarker whose systemic decline indicates impaired collagen turnover and a systemic defect in extracellular matrix (ECM) remodeling; and (3) α-ketoglutarate (AKG) was independently identified as a core metabolic regulator linking cellular energy status to epigenetic maintenance. Our central hypothesis posits that the age-related attenuation of exercise benefits reflects the cumulative limitation of cellular adaptive capacity by these metabolic bottlenecks. Targeting these conserved molecular constraints represents a rational strategy to restore tissue responsiveness to exercise and promote a functional healthspan.