Butyrate is one of the better known metabolites generated by microbial populations within the gut microbiome, a product of the fermentation of dietary fiber. Butyrate has been shown to produce beneficial effects in a range of tissues, such as via increased BDNF signaling to improve brain and muscle health. Production of butyrate declines with age, a consequence of harmful shifts in the composition of the gut microbiome that take place with age. Here, researchers show that butyrate is senomorphic, in that is reduces the number of cells entering a senescent state. This sort of effect is thought to be beneficial over time, as it allows the normal mechanisms of senescent cell clearance, impaired with age but still operating, to catch up and reduce the age-related burden of senescence.
Advancing age is accompanied by an accumulation of senescent T cells that secrete pro-inflammatory senescence-associated secretory phenotype (SASP) molecules. Gut-microbiota-derived signals are increasingly recognised as immunomodulators. In the current study, we demonstrated that ageing and the accumulation of senescent T cells are accompanied by a reduction in microbial-derived short-chain fatty acids (SCFAs).
Culturing aged T cells in the presence of butyrate suppresses the induction of a senescence phenotype and inhibits the secretion of pro-inflammatory SASP factors, such as IL6 and IL8. Administration of faecal supernatants from young mice rich in butyrate prevented in vivo accumulation of senescent spleen cells in aged mice. The molecular pathways governing butyrate's senomorphic potential include a reduced expression of DNA damage markers, lower mitochondrial reactive oxygen species (ROS) accumulation, and downregulation of mTOR activation, which negatively regulates the transcription factor NFκB.
Our findings establish butyrate as a potent senomorphic agent and provide the evidence base for future microbiome restitution intervention trials using butyrate supplements for combating T cell senescence, ultimately reducing inflammation and combating age-related pathologies to extend lifelong health.
Link: https://doi.org/10.1111/acel.70257
View the full article at FightAging
