Mitochondrial blood-based biomarker is related to cardiorespiratory fitness and aging in a sex-dependent manner.

INTRODUCTION: A sedentary lifestyle increases the risk for Alzheimer's disease (AD), whereas exercise has been shown to benefit brain health. Physiological factors, such as female sex, are linked to lower cardiorespiratory fitness and can increase the risk of AD, which might impact exercise benefits to the brain. Exploring cellular mechanisms underlying fitness in older adults is essential to understanding exercise and AD risk and how sex might impact this interaction. METHODS: We collected blood from 34 cognitively healthy older adults (age 65+, 18 male, 16 female) enrolled in the COMbined Exercise Trial (COMET; NCT04848038). Subjects underwent a blood draw and clinical assessments for cardiorespiratory fitness and body composition. Blood was collected in ACD tubes, and lymphocytes were isolated. Fluorescent stains used were MitoTracker, Annexin V, MitoSOX, TMRE (tetramethylrhodamine ethyl ester), and Hoechst, analyzed by flow cytometry, and used to calculate a composite mitochondrial function index (MFI). RESULTS: As expected, males had higher lean mass and VO2peak than females (p = 0.01), but groups did not differ in body mass index (p = 0.51). Males had a higher MFI compared to females (p = 0.01). Within each sex, we observed unique metabolic relationships. In males, there was an age-associated decline in MFI (R 2 = 0.382, p = 0.01). In females, our systemic measure of mitochondrial superoxides had a negative relationship with lean mass (R 2 = 0.648, p < 0.01) and oxygen uptake efficiency slope (OUES) (R 2 = 0.271, p = 0.04). DISCUSSION: We combined an MFI with measures related to fitness in a cognitively healthy older adult population. We explored physiological factors that impact cardiorespiratory fitness, such as sex. We observed relationships between mitochondrial superoxides and OUES and lean mass in females, whereas males had higher MFI overall. Sex-dependent differences in mitochondrial function and superoxide might be an underlying factor of variable cardiorespiratory fitness between sexes and could help explain differences in AD risk. Highlights: Mitochondrial blood-biomarker shows sex-dependent relationships in aging.Mitochondrial function index is higher in older adult males.Mitochondrial function index declines with age in males.Mitochondrial reactive oxygen species (ROS) are negatively associated with fitness in females.Mitochondrial ROS are negatively associated with lean mass in females.