Lower CD8+ T‐cell senescence partially mediates the neuroprotection of higher aerobic fitness

Abstract INTRODUCTION Immunosenescence – age‐related changes in immunity – may exacerbate the pathologic processes of Alzheimer's disease (AD), a condition that disproportionately affects African Americans. Fortunately, a higher level of aerobic fitness is linked to both reduced immunosenescence and lower AD risk. However, it remains unclear whether higher aerobic fitness and decreased AD is mediated by lower proportions of T‐cell senescence. In a cohort of older African Americans, we aimed to (1) examine the relationship between aerobic fitness and generalization (a cognitive indicator of AD risk) and (2) investigate whether T‐cell senescence mediated this relationship. METHODS A total of 231 older African American participants from the Aging M education = 14.02 years, SD = 2.25; M MoCA = 23.16, SD = 2.63) responded to demographic, health, and lifestyle questionnaires; completed a cognitive battery including a generalization task (stimulus differentiation and transfer task); underwent anthropometric and physical performance measures; and provided a blood sample for T‐cell senescence characterization. Peripheral blood mononuclear cells were isolated and analyzed for senescence‐associated beta‐galactosidase activity as a measure of proportions of cytotoxic CD8+ T‐cell senescence. Aerobic fitness (VO 2 peak) was estimated from the six‐minute walk test. Covariates included age, sex, education, and waist‐to‐hip ratio. RESULTS Higher aerobic fitness was significantly associated with fewer generalization errors. Furthermore, higher aerobic fitness was associated with lower CD8+ T‐cell senescence ( = −0.15, p = 0.02), which was associated with fewer generalization errors (= −0.17, p = 0.01). Overall, 15% of the effect of higher aerobic fitness on fewer generalization errors was mediated by lower CD8+ T‐cell senescence. DISCUSSION One pathway by which higher aerobic fitness is associated with lower AD risk in older African Americans is through lower proportions of CD8+ T‐cell senescence. These results highlight the immune and cognitive function benefits of a physically active lifestyle, particularly in a demographic that faces a higher risk for AD.