Princess Máxima Center for Pediatric Oncology, Genome Instability and Nutrition, ONCODE Institute, Utrecht, The Netherlands.
Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands.
Aging Cell. 2021 Feb;20(2):e13302. doi: 10.1111/acel.13302. Epub 2021 Jan 23.
Dietary restriction (DR) and rapamycin extend healthspan and life span across multiple species. We have recently shown that DR in progeroid DNA repair-deficient mice dramatically extended healthspan and trippled life span. Here, we show that rapamycin, while significantly lowering mTOR signaling, failed to improve life span nor healthspan of DNA repair-deficient Ercc1 mice, contrary to DR tested in parallel. Rapamycin interventions focusing on dosage, gender, and timing all were unable to alter life span. Even genetically modifying mTOR signaling failed to increase life span of DNA repair-deficient mice. The absence of effects by rapamycin on P53 in brain and transcription stress in liver is in sharp contrast with results obtained by DR, and appoints reducing DNA damage and transcription stress as an important mode of action of DR, lacking by rapamycin. Together, this indicates that mTOR inhibition does not mediate the beneficial effects of DR in progeroid mice, revealing that DR and rapamycin strongly differ in their modes of action.
饮食限制（DR）和雷帕霉素可延长多种物种的健康寿命和寿命。我们最近表明，在早衰型 DNA 修复缺陷小鼠中进行 DR 可显著延长健康寿命并将寿命延长三倍。在这里，我们表明，雷帕霉素虽然显著降低了 mTOR 信号，但未能改善 DNA 修复缺陷的 Ercc1 小鼠的寿命或健康寿命，这与平行测试的 DR 相反。针对剂量、性别和时间的雷帕霉素干预均无法改变寿命。即使对 mTOR 信号进行基因改造也未能增加 DNA 修复缺陷小鼠的寿命。雷帕霉素对大脑中 P53 和肝脏转录应激的影响缺失与 DR 获得的结果形成鲜明对比，并指出降低 DNA 损伤和转录应激是 DR 的一种重要作用模式，而雷帕霉素则缺乏这种作用模式。综上所述，这表明 mTOR 抑制不会介导 DR 在早衰型小鼠中的有益作用，揭示了 DR 和雷帕霉素在作用模式上存在强烈差异。
