Sex-specific decline in prefrontal cortex mitochondrial bioenergetics in aging baboons correlates with walking speed

Mitochondria play a crucial role in brain homeostasis and changes in mitochondrial bioenergetics are linked to age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. We investigated changes in the activities of the electron transport chain (ETC) complexes in normally aging baboon brains and determined how these changes relate to donor sex, morning cortisol levels, and walking speed. We assessed mitochondrial bioenergetics from archived prefrontal cortex (PFC) tissues from a large cohort (60 individuals) of well-characterized aging baboons (6.6–22.8 years, approximately equivalent to 26.4–91.2 human years). Aging was associated with a decline in mitochondrial ETC complexes in the PFC, which was more pronounced when normalized for citrate synthase activity, suggesting that the decline is predominantly driven by changes in the specific activity of individual complexes rather than global changes in mitochondrial content. When donor sex was used as a covariate, we found that ETC activity was preserved with age in females and declined in males. Males had higher activities of each individual ETC complex and greater lactate dehydrogenase activity at a given age relative to females. Circulating cortisol negatively correlated with walking speed when male and female data were combined. We also observed a robust positive predictive relationship between walking speed and respiration linked to complexes I, III, and IV in males but not in females. This data reveals a link between frailty and PFC bioenergetic function and highlights a potential molecular mechanism for sexual dimorphism in brain resilience.