Inhibition of S6K lowers age-related inflammation and immunosenescence and increases lifespan through the endolysosomal system

The nutrient-sensing Target of Rapamycin complex 1 (TORC1) is an evolutionarily conserved regulator of longevity and healthspan. S6 kinase (S6K) is an essential downstream mediator for the effect of TORC1 on longevity. However, mechanistic insights on how TORC1-S6K signalling promotes lifespan and healthspan are still limited. Here we show that activity of S6K in the Drosophila fat body is essential for rapamycin-mediated longevity. Fat-body-specific activation of S6K blocked lifespan extension upon rapamycin feeding and induced accumulation of multilamellar lysosomal enlargements. By proteomics analysis we identified Syntaxin 13 (Syx13) as an important downstream mediator of TORC1-S6K signalling involved in regulating lysosomal morphology. Inhibition of TORC1-S6K signalling decreased age-associated hyperactivation of the NF-κB-like IMD pathway in the fat body and promoted bacterial clearance, mediated by Syx13, suggesting that lysosomal and immune function are connected during ageing. Middle-age-onset repression of IMD pathway in the fat body by Relish RNAi promoted bacteria clearance and extended fly lifespan. In mice, chronic rapamycin treatment elevated Syntaxin 12/13 (Stx12) level in liver. We identified alleviated immune processes in the aged liver as a common signature of S6K1-deficient and rapamycin-treated mice. Thus, our results indicate that suppression of the TORC1-S6K-Syx13 axis ameliorates both inflammageing and immunosenescence in hepatic tissues via the endolysosomal system and thereby extends longevity, providing a mechanistic explanation for the effects of rapamycin and suppression of S6K on immune function and lifespan in model organisms and, potentially, humans.