The Impact of Biological Mechanisms of Aging on Response Variability to Resistance Training in Older Adults (BRIO)

SUMMARY In most individuals, exercise counters the onset and progression of chronic diseases (e.g., type 2 diabetes, cardiovascular disease, cognitive decline, and cancers), geriatric syndromes (e.g., frailty), and disability, even when introduced in later-life. However, the physiological effects conveyed by exercise are highly variable across individuals. In line with RFA-AG-24-045, this application builds on a robust scientific foundation and will use innovative, multidisciplinary approaches to critically test the central hypothesis that biological mechanisms of aging are modulators of exercise response heterogeneity (ERH) in older adults. Our proposal centers on cellular senescence and epigenetics as causes of ERH in two distinct, clinically meaningful co-primary outcomes: physical function and insulin sensitivity. Senescence is a cell fate that contributes to age-related tissue pathology and impairs regeneration. Recently, we characterized hallmarks of cellular senescence in human skeletal muscle and observed negative associations with measures of physical function and insulin sensitivity. We have also demonstrated that circulating biomarkers of cellular senescence are associated with deficits in physical function and are responsive to exercise training. Epigenetic modifications effectively govern transcriptional programs that regulate cellular homeostasis and adaptations to stimuli. DNA methylation (DNAm) at CpG sites is a key epigenetic modification that changes radically with advancing age. In skeletal muscle, age-associated alterations in DNAm affect the expression of genes central to functional and metabolic adaptations to exercise. Based on these observations, we will conduct a randomized, two-site clinical trial of a 6-month structured progressive resistance training intervention (n = 200) and a health education intervention (HE) (n = 100) to define the ERH in physical function (Specific Aim 1) and insulin sensitivity (Specific Aim 2) in community dwelling older (³ 65 years) women and men with evidence of mobility limitations. We will use state-of-the-art molecular profiling to rigorously examine cellular senescence and DNAm in skeletal muscle in parallel with their blood-based biomarkers. Through predictive approaches to treatment effect heterogeneity, we will examine how these biological mechanisms, key clinical variables (sex, BMI, comorbid conditions, medications, depression, and fatigue), and behavioral factors (nutrition, habitual physical activity, sleep, fatigue, and depressive symptoms), and their interactions, mediate ERH.