BioProject

Inhibition of the nutrient-responsive mTOR (mammalian target of rapamycin) signalling pathway including the key downstream S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice. More...

Inhibition of the nutrient-responsive mTOR (mammalian target of rapamycin) signalling pathway including the key downstream S6 kinase 1 (S6K1) extends lifespan and improves healthspan in mice. However, the underlying mechanisms contributing to the profound age-related benefits observed with loss of S6K1 signalling are unclear. Cellular senescence is a stable growth arrest accompanied by an inflammatory phenotype (termed the senescence-associated secretory phenotype, or SASP). Whileboth cellular senescence and SASP-mediated chronic inflammation contribute to age-related pathology the specific role of S6K1 signalling in these process have not been determined . Here, focussing on mouse liver a key target tissue for the beneficial health effects of loss of S6K1 signalling, we show that S6K1 deletion does not reduce senescence but ameliorates inflammation and immune cell infiltration in aged livers. Using human and mouse models of senescence, we demonstrated that reduced inflammation is a liver intrinsic effect associated with S6K deletion. Furthermore, gene expression analysis suggested that downregulated cGAS/STING and IRF3 activation might mediate the impaired SASP observed upon S6K deletion. Using a hepatic oncogene induced senescence model, we showed in vivo that S6K1 deletion results in reduced IRF3 activation, impaired production of cytokines such as IL1 and reduced immune infiltration. Overall, deletion of S6K reduces inflammation in the liver suggesting that suppression of the inflammatory SASP by S6K could contribute to explain the beneficial effects of inhibiting these pathways on healthspan and lifespan. Overall design: Transcriptomics data from whole liver homogenates from S6K1 WT and KO mice derived from young (90 days) and old (600 days) mice. Transcriptomics data from mouse embryonic fibroblasts undergoing replicative senescence or RAS-induced senescence derived from S6K1 WT/KO mice or S6K1/S6K2 WT/DKO mice. Less...