Decreased expression of S6K is a key outcome of rapamycin treatment, crucial for extending life through mTOR inhibition in mice and other lab species. This effect is believed to enhance aging slowdown by optimizing autophagy, a process where damaged proteins are identified, enclosed in membranes, and sent for recycling in lysosomes. Researchers explore S6K’s role, noting its potential in reducing age-related inflammation and boosting lysosomal function and autophagy efficiency.
Although S6K is a vital downstream effector of mTOR signaling impacting lifespan in various species, its exact cellular mechanisms remain a mystery. In Drosophila, reduced S6K activity in the fat body proves crucial for mTOR-driven longevity, regulating endolysosomal morphology, inflammaging, and immunosenescence during aging. Altering endosome formation affects inflammaging by degrading rPGRP-LC, pointing to a direct link between endolysosomes and inflammaging. Syx13 emerges as a molecular bridge connecting endosome formation, inflammaging, and lifespan under TORC1-S6K signaling. Notably, gender-specific differences in fat body inflammaging potentially explain the contrasting effects of S6K on male and female lifespans.
Long-term rapamycin treatment elevates Stx12 levels in mouse liver, showing a reduction in immune responses in old mice, along with S6K1 knockout mice, as seen in RNA and proteomics data. Rapamycin also diminishes age-associated noncanonical NF-κB pathway activation in mouse liver, suggesting an evolutionarily conserved TORC1-S6K-Stx12 pathway influencing immunoaging from flies to mice. These findings underline the significance of TORC1-S6K-Syx13 signaling in inflammaging, immunosenescence, and longevity.
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