Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
University of Michigan Geriatrics Center, Ann Arbor, MI 48109, USA.
Aging (Albany NY). 2022 Mar 19;14(6):2442-2461. doi: 10.18632/aging.203959.
Downregulation of mTOR (mechanistic target of rapamycin) can extend lifespan in multiple species, including mice. Growth hormone receptor knockout mice (GHRKO) and Snell dwarf mice have 40% or greater lifespan increase, and have lower mTORC1 function, which might reflect alteration in mTORC1 components or alteration of upstream proteins that modulate mTOR activity. Here we report reduction of mTORC components DEPTOR and PRAS40 in liver of these long-lived mice; these changes are opposite in direction to those that would be expected to lead to lower mTORC1 function. In contrast, levels of the upstream regulators TSC1 and TSC2 are elevated in GHRKO and Snell liver, kidney and skeletal muscle, and the ratio of phosphorylated TSC2 to total TSC2 is lower in the tissues of the long-lived mutant mice. In addition, knocking down TSC2 in GHRKO fibroblasts reversed the effects of the GHRKO mutation on mTORC1 function. Thus increased amounts of unphosphorylated, active, inhibitory TSC may contribute to lower mTORC1 function in these mice.
mTOR（雷帕霉素靶蛋白）的下调可以延长多种物种的寿命，包括老鼠。生长激素受体敲除小鼠（GHRKO）和斯奈尔矮小鼠的寿命增加了 40%或更多，并且 mTORC1 功能较低，这可能反映了 mTORC1 成分的改变或调节 mTOR 活性的上游蛋白的改变。在这里，我们报告了这些长寿小鼠肝脏中 mTORC 成分 DEPTOR 和 PRAS40 的减少；这些变化与预期导致 mTORC1 功能降低的变化方向相反。相比之下，GHRKO 和斯奈尔肝脏、肾脏和骨骼肌中的上游调节剂 TSC1 和 TSC2 的水平升高，长寿突变小鼠组织中磷酸化 TSC2 与总 TSC2 的比值降低。此外，在 GHRKO 成纤维细胞中敲低 TSC2 逆转了 GHRKO 突变对 mTORC1 功能的影响。因此，未磷酸化、活性、抑制性 TSC 的增加可能有助于这些小鼠中 mTORC1 功能降低。
