Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Genomics Novartis Foundation, San Diego, California.
J Gerontol A Biol Sci Med Sci. 2018 Jun 14;73(7):845-852. doi: 10.1093/gerona/glx249.
Rapalogs, inhibitors of mTORC1 (mammalian target of rapamycin complex 1), increase life span and delay age-related phenotypes in many species. However, the molecular mechanisms have not been fully elucidated. We determined gene expression changes comparing 6- and 24-month-old rats in the kidney, liver, and skeletal muscle, and asked which of these changes were counter-regulated by a clinically-translatable (short-term and low-concentration) treatment, with a rapalog (RAD001). Surprisingly, RAD001 had a more pronounced effect on the kidney under this regimen in comparison to the liver or skeletal muscle. Histologic evaluation of kidneys revealed that the severity of chronic progressive nephropathy lesions was lower in kidneys from 24-month-old rats treated with RAD001 compared with vehicle. In addition to other gene expression changes, c-Myc, which has been shown to regulate aging, was induced by aging in the kidney and counter-regulated by RAD001. RAD001 caused a decrease in c-Myc protein, which could be rescued by a proteasome inhibitor. These findings point to settings for use of mTORC1 inhibitors to treat age-related disorders, and highlight c-Myc regulation as one of the potential mechanisms by which mTORC1 inhibition is perturbing age-related phenotypes.
雷帕霉素靶蛋白（mTORC1）抑制剂能够延长多种物种的寿命并延缓与年龄相关的表型，但具体的分子机制尚未完全阐明。我们通过比较 6 个月和 24 个月大的大鼠的肾脏、肝脏和骨骼肌中的基因表达变化，来确定哪些变化可以被一种具有临床转化价值的（短期、低浓度）雷帕霉素类似物（RAD001）所逆转。令人惊讶的是，与肝脏或骨骼肌相比，RAD001 在该方案下对肾脏的影响更为显著。肾脏的组织学评估显示，与对照组相比，接受 RAD001 治疗的 24 个月大大鼠的慢性进行性肾病病变的严重程度更低。除了其他基因表达变化外，c-Myc 已被证明可以调节衰老，其在肾脏中的表达随衰老而增加，并可被 RAD001 逆转。RAD001 导致 c-Myc 蛋白减少，而蛋白酶体抑制剂可以挽救这种减少。这些发现为使用 mTORC1 抑制剂治疗与年龄相关的疾病提供了依据，并强调了 c-Myc 调控是 mTORC1 抑制干扰与年龄相关的表型的潜在机制之一。
