Max Planck Institute for Biology of Ageing, Cologne, Germany.
Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.
Nat Aging. 2024 Apr;4(4):491-509. doi: 10.1038/s43587-024-00578-3. Epub 2024 Feb 27.
Suppression of target of rapamycin complex 1 (TORC1) by rapamycin ameliorates aging in diverse species. S6 kinase (S6K) is an essential mediator, but the mechanisms involved are unclear. Here we show that activation of S6K specifically in Drosophila fat-body blocked extension of lifespan by rapamycin, induced accumulation of multilamellar lysosomes and blocked age-associated hyperactivation of the NF-κB-like immune deficiency (IMD) pathway, indicative of reduced inflammaging. Syntaxin 13 mediated the effects of TORC1-S6K signaling on lysosome morphology and inflammaging, suggesting they may be linked. Inflammaging depended on the IMD receptor regulatory isoform PGRP-LC, and repression of the IMD pathway from midlife extended lifespan. Age-related inflammaging was higher in females than in males and was not lowered in males by rapamycin treatment or lowered S6K. Rapamycin treatment also elevated Syntaxin 12/13 levels in mouse liver and prevented age-related increase in noncanonical NF-κB signaling, suggesting that the effect of TORC1 on inflammaging is conserved from flies to mammals.
雷帕霉素抑制雷帕霉素靶蛋白复合物 1（TORC1）可改善多种物种的衰老。S6 激酶（S6K）是一种必需的介质，但涉及的机制尚不清楚。在这里，我们表明，雷帕霉素在果蝇脂肪体中特异性激活 S6K 会阻止寿命的延长，诱导多膜溶酶体的积累，并阻止与年龄相关的 NF-κB 样免疫缺陷（IMD）途径的过度激活，表明炎症老化减少。突触素 13介导了 TORC1-S6K 信号对溶酶体形态和炎症老化的影响，表明它们可能相关。炎症老化依赖于 IMD 受体调节同工型 PGRP-LC，从中年开始抑制 IMD 途径可延长寿命。与男性相比，女性的年龄相关性炎症老化更高，雷帕霉素治疗或降低 S6K 并不能降低男性的炎症老化。雷帕霉素处理还会提高小鼠肝脏中的突触素 12/13 水平，并防止与年龄相关的非典型 NF-κB 信号的增加，这表明 TORC1 对炎症老化的影响从苍蝇到哺乳动物都是保守的。
