Defining microbiota-derived metabolite butyrate as a senomorphic: therapeutic potential in the age-related T cell 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 is accompanied by a reduction in microbial-derived short-chain fatty acids (SCFAs). Culturing aged T cells in the presence of butyrate supresses 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 ROS accumulation and downregulation of mTOR activation, which negatively regulates the transcription factor NFκB. Our findings establish butyrate as a potent senomorphic agent and provides the evidence base for future microbiome restitution intervention trials using butyrate supplements for combatting T cell senescence ultimately reducing inflammation and combatting age-related pathologies to extend lifelong health.