Decreased S6K expression is one of the downstream consequences of treatment with the mTOR inhibitor rapamycin, and is essential for mTOR inhibition to extend life in mice and other laboratory species. It is thought that the slowing of aging resulting from mTOR inhibition largely works via improved operation of the complex cell maintenance processes of autophagy, wherein damaged proteins are flagged, wrapped in membranes, and conveyed to a lysosome for recycling. Researchers here investigate the role of S6K, and note that it appears to reduce the excessive inflammatory signaling characteristic of old age in addition to improving lysosomal function, and thus autophagy.
Although S6K is a key downstream effector of mTOR signaling and has been implicated in determination of lifespan in invertebrates and mammals, the molecular and cellular mechanisms are still elusive. Here we show that, in Drosophila, lowered activity of S6K in the fat body is essential for mTOR-dependent longevity, and that it regulates endolysosomal morphology, inflammaging, and immunosenescence in the aging fat body.
Modifying endosome formation, but not autophagy, affected inflammaging by degrading rPGRP-LC, suggesting a causal link between endolysosome and inflammaging. We identified Syx13 as a molecular link that regulates endosome formation, inflammaging, and lifespan downstream of TORC1-S6K signaling. We uncovered a considerable sexual dimorphism in fat body inflammaging, potentially explaining the different lifespan impacts of S6K observed in males and females. Furthermore, repression of the NF-κB-like IMD pathway in the fly fat body enhanced clearance of bacteria and extended lifespan.
Importantly, long-term treatment with rapamycin increased Stx12 levels in mouse liver, and alleviation of immune processes was a common denominator of TORC1-S6K inhibition in RNA and proteomics profiles from the liver of old rapamycin-treated and S6K1 knockout mice. Furthermore, Rapa lowered age-associated activation of noncanonical NF-κB pathway in mouse liver, indicating that the effects of TORC1-S6K-Stx12 on immunoaging may be evolutionarily conserved from flies to mice. In summary, our findings highlight an important role for the TORC1-S6K-Syx13 signaling axis in inflammaging, immunosenescence and longevity.
Link: https://doi.org/10.1...587-024-00578-3
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