Abstract

Aging is a progressive process characterized by cellular and molecular damage leading to mitochondrial dysfunction and cognitive decline. Mitochondrial dysfunction is a critical factor in memory impairment in aging and neurodegenerative diseases. While sex differences in aging have been observed across various species, the underlying cellular and molecular mechanisms remain poorly understood, mainly focused on mitochondrial proteostasis. This study examined hippocampal-dependent cognitive decline and mitochondrial dysfunction in aged male and female C57BL/6 J mice. Our results reveal sex-dependent differences in cognitive impairment, with aged males exhibiting more significant deficits in spatial and localization memory, while aged females show impairments in recognition memory. Additionally, aged males display increased oxidative stress and exacerbated mitochondrial superoxide production, leading to more severe bioenergetic deficiencies. Conversely, aged females exhibit heightened mitochondrial permeability transition pore (mPTP) activity, suggesting a distinct mechanism of mitochondrial dysfunction, which could explain, almost in part, the cognitive differences in aging. Investigating possible mechanisms responsible for this mitochondrial dysfunction, we found that mitochondrial proteostasis is more prone to failure in aged males, with a significant decrease in the protease activity of Lonp1, a key matrix mitochondrial protease degrading >50% of the mitochondrial proteome. To further reinforce these findings, we replicated key experiments in SAMP8 mice, a model of accelerated aging, obtaining consistent results that strengthen the robustness and generalization of our conclusions. These findings suggest that sex influences hippocampal aging at multiple levels, highlighting the need to consider sexual dimorphism in aging research. This study also emphasizes the critical role of mitochondrial proteostasis in maintaining mitochondrial function in aging in a sex-dependent manner. Understanding these differences could facilitate the development of sex-specific strategies to mitigate age-related cognitive decline and neurodegeneration.