Population aging is associated with progressive declines in physical and cognitive function driven by chronic low-grade inflammation and dysregulation of interconnected biological systems. Within the geroscience framework, we tested whether chronic swimming initiated in late midlife attenuates age-related deficits by modulating body composition, systemic and hippocampal inflammation, episodic-like memory and gut microbiota composition. Male C57BL/6 mice were trained for 8 weeks starting at 14 months; age-matched controls remained sedentary. Swimming reduced weight gain and epididymal fat mass and progressively improved muscle strength and endurance. Exercised mice showed enhanced short-term spatial discrimination and long-term associative recognition in object location and object-in-place tasks without changes in locomotion or anxiety-like behavior. These cognitive benefits coincided with reduced circulating pro-inflammatory cytokines and a hippocampal shift toward a neuroprotective profile, with down-regulation of inflammatory and glial activation markers and up-regulation of brain-derived neurotrophic factor (BDNF). Muscle performance correlated positively with hippocampus-dependent memory, linking physical resilience to cognitive outcomes. In parallel, 16S rRNA gene sequencing revealed an exercise-induced remodeling of the gut microbiota, characterized by significant changes in community structure and coordinated shifts in the relative abundance of shared taxa. Exercise enriched genera associated with metabolic homeostasis and anti-inflammatory functions, including Akkermansia, Odoribacter and Alistipes, while reducing taxa more prevalent in sedentary animals, such as Romboutsia. Collectively, these findings demonstrate that moderate-intensity swimming initiated during late middle age concurrently improves physical performance, cognitive resilience, inflammatory status and gut microbiota composition, supporting exercise as a multi-system intervention associated with coordinated adaptations across the muscle-gut-brain axis during aging.
