Age-dependent effects of exercise on gut microbiota-mitochondria axis and cognitive function in aging mice

Aging is accompanied by progressive impairments in mitochondrial bioenergetics, apoptosis regulation, and gut microbiota homeostasis, all of which contribute to cognitive decline. In this study, we investigated whether the effects of treadmill exercise on the gut microbiota-mitochondrion-neuronal plasticity axis differed between young (15 months) and old (28 months) mice. Male C57BL/6 mice were randomly assigned to the following groups: early sedentary, early exercise, late sedentary, or late exercise groups and completed an 8-week treadmill training protocol. Cognitive function was assessed using the passive avoidance test and the Morris water maze test. Hippocampal mitochondrial respiration, Ca²⁺ retention capacity, and Bax/Bcl-2 expression were quantified, and the gut microbiota composition was analyzed using 16S ribosomal RNA sequencing. Mice that did not exercise in old age exhibited memory impairment, decreased mitochondrial oxidative respiration, reduced Ca²⁺ retention, increased Bax expression, decreased Bcl-2 levels, and decreased abundance of <i>Lactobacillus</i>, <i>Bifidobacterium</i>, and <i>Akkermansia</i>. Exercise significantly improved behavioral performance, mitochondrial function, and apoptosis balance, while also increasing beneficial gut microbiota. Notably, these effects were significantly greater in late-aged compared to early-aged mice. These results demonstrate that the efficacy of exercise in modulating the microbiota-mitochondrion-brain axis varies with age. Early-aged appears to represent a more responsive biological period during which exercise is more effective in improving mitochondrial integrity, microbiota composition, and cognitive resilience. These results suggest that initiating exercise early in the aging process may maximize neuroprotective effects and delay age-related functional decline.