Pharmacological inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway with rapamycin can extend lifespan in several organisms. Although this includes the nematode Caenorhabditis elegans, effects in this species are relatively weak and sometimes difficult to reproduce. Here we test effects of drug dosage and timing of delivery to establish the upper limits of its capacity to extend life, and investigate drug effects on age-related pathology and causes of mortality. Liposome-mediated rapamycin treatment throughout adulthood showed a dose-dependent effect, causing a maximal 21.9% increase in mean lifespan, but shortening of lifespan at the highest dose, suggesting drug toxicity. Rapamycin treatment of larvae delayed development, weakly reduced fertility and modestly extended lifespan. By contrast, treatment initiated later in life robustly increased lifespan, even from Day 16 (or ~70 years in human terms). The rapalog temsirolimus extended lifespan similarly to rapamycin, but effects of everolimus were weaker. As in mouse, rapamycin had mixed effects on age-related pathologies, inhibiting one (uterine tumor growth) but not several others, suggesting a segmental antigeroid effect. These findings should usefully inform future experimental studies with rapamycin and rapalogs in C. elegans.

中文翻译：

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mTOR 抑制剂对秀丽隐杆线虫衰老影响的表征


雷帕霉素对雷帕霉素的机制靶标 （mTOR） 信号通路的药理抑制可以延长多种生物体的寿命。虽然这包括线虫秀丽隐杆线虫，但对该物种的影响相对较弱，有时难以复制。在这里，我们测试药物剂量和给药时间的影响，以确定其延长寿命的能力上限，并研究药物对年龄相关病理和死亡原因的影响。脂质体介导的雷帕霉素治疗在整个成年期显示出剂量依赖性效应，导致平均寿命最多增加 21.9%，但在最高剂量下寿命缩短，表明药物毒性。雷帕霉素治疗幼虫延缓了发育，生育能力较弱，适度延长了寿命。相比之下，在晚年开始的治疗大大延长了寿命，甚至从第 16 天（或人类的 ~70 岁）开始。雷帕洛酯替西罗莫司与雷帕霉素类似地延长了寿命，但依维莫司的作用较弱。与小鼠一样，雷帕霉素对与年龄相关的病理反应混合，抑制一种（子宫肿瘤生长）但不抑制其他几种，表明节段性抗老细胞作用。这些发现应该为未来在秀丽隐杆线虫中使用雷帕霉素和雷帕洛格的实验研究提供有用的信息。