TSP50 in Neural Stem Cells Regulates Aging‐Related Cognitive Decline and Neuroinflammation by Altering the Gut Microbiota

Aging is a process of gradual decline in physical and cognitive function and is a major risk factor for mortality. Despite the increasing number of relevant studies, the mechanisms regulating the aging process have not been fully elucidated. Genetic factors have long been recognized as key factors in controlling the rate of aging. Testes-specific protease 50 (TSP50) has been shown to be involved in the regulation of embryonic development and intestinal homeostasis, but its role in the regulation of aging remains unclear. Here, we showed that TSP50 expression was reduced in the hippocampus of both aged humans and mice. TSP50 deficiency in neural stem cells (NSCs) drove accelerated aging in mice, characterized by exacerbated age-related cognitive impairments and significantly elevated neuroinflammation. Notably, aged mice with NSCs-specific knockout of TSP50 exhibited impaired intestinal mucosal barriers, dysbiosis of gut microbiota, and a marked reduction in the production of short-chain fatty acids (SCFAs). Restoring gut microbial ecology using fecal microbiota transplantation (FMT) and overexpressing TSP50 successfully alleviated aging-associated cognitive decline and neuroinflammation. Taken together, our study suggests that TSP50 plays a critical role in the aging process and identifies gut microbiota as a pivotal mediator of TSP50's influence on age-related cognitive decline and neuroinflammation. These findings highlight the potential therapeutic value of targeting TSP50 and gut microbiota for aging, offering insights into aging mechanisms and interventions for aging-related neurodegenerative diseases.