<p>Alterations in mitochondrial function and in reactive oxygen species generation have been associated with physiological aging. In this study, mice aged 3, 10, 20, and 24 months were utilized to investigate the changes in mitochondrial function and reactive oxygen species (ROS) at synapses. Mitochondrial membrane potential was 21% decreased in 20 months-old animals, while it increased (24%) at advanced age (24 months), compared with young mice. Coupling efficiency and ATP synthesis decreased in synaptosomes from 24-months old mice. Regarding mitochondrial respiratory complex activity, reductions in complex II-III and IV activity were observed (42% and 47%, respectively) at 10 months of age. A significant increase in complex I-III activity (48%) was found at 20 months, with no changes in complexes II-III or complex IV enzymatic activities. Likewise, complex II-III activity showed an increase (100%) at 24 months, while complex I-III significantly decreased (37%). An age-related increase in superoxide generation was observed, consistent with impaired respiratory chain function. Interestingly, H₂O₂ production rates were 43% decreased in 20-months old mice, compared to young animals. This study presents evidence that the aging process leads to changes in mitochondrial function in brain cortex synaptosomes, which become significantly impaired at the age of 20 months. Even though at more advanced ages, compensatory mechanisms might appear to counteract the impact of mitochondrial dysfunction and oxidative damage, mitochondrial bioenergetics seems to be severely compromised.</p>