Max-Planck Institute for Biology of Ageing, Cologne, Germany; Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.
Max-Planck Institute for Biology of Ageing, Cologne, Germany.
Mol Metab. 2024 Mar;81:101902. doi: 10.1016/j.molmet.2024.101902. Epub 2024 Feb 13.
Rapamycin, a powerful geroprotective drug, can have detrimental effects when administered chronically. We determined whether intermittent treatment of mice can reduce negative effects while maintaining benefits of chronic treatment.
From 6 months of age, male and female C3B6F1 hybrid mice were either continuously fed with 42 mg/kg rapamycin, or intermittently fed by alternating weekly feeding of 42 mg/kg rapamycin food with weekly control feeding. Survival of these mice compared to control animals was measured. Furthermore, longitudinal phenotyping including metabolic (body composition, GTT, ITT, indirect calorimetry) and fitness phenotypes (treadmil, rotarod, electrocardiography and open field) was performed. Organ specific pathology was assessed at 24 months of age.
Chronic rapamycin treatment induced glucose intolerance, which was partially ameliorated by intermittent treatment. Chronic and intermittent rapamycin treatments increased lifespan equally in males, while in females chronic treatment resulted in slightly higher survival. The two treatments had equivalent effects on testicular degeneration, heart fibrosis and liver lipidosis. In males, the two treatment regimes led to a similar increase in motor coordination, heart rate and Q-T interval, and reduction in spleen weight, while in females, they equally reduced BAT inflammation and spleen weight and maintained heart rate and Q-T interval. However, other health parameters, including age related pathologies, were better prevented by continuous treatment.
Intermittent rapamycin treatment is effective in prolonging lifespan and reduces some side-effects of chronic treatment, but chronic treatment is more beneficial to healthspan.
雷帕霉素是一种强大的抗衰老药物，但长期使用会产生有害影响。我们旨在确定间歇性治疗能否在维持慢性治疗益处的同时降低负面作用。
从 6 月龄开始，雄性和雌性 C3B6F1 杂交小鼠连续喂食 42mg/kg 雷帕霉素，或通过每周交替喂食 42mg/kg 雷帕霉素食物和对照食物进行间歇性治疗。与对照动物相比，我们测量了这些小鼠的存活率。此外，我们还进行了纵向表型分析，包括代谢（身体成分、GTT、ITT、间接测热法）和健康相关的表型（跑步机、转棒、心电图和旷场）。在 24 月龄时评估了器官特异性病理学。
慢性雷帕霉素治疗会导致葡萄糖不耐受，间歇性治疗部分改善了这种情况。慢性和间歇性雷帕霉素治疗在雄性中同等地延长了寿命，而在雌性中慢性治疗导致了略高的存活率。两种治疗方法对睾丸退化、心脏纤维化和肝脏脂肪变性都有同等的影响。在雄性中，两种治疗方案都导致了运动协调、心率和 Q-T 间隔的相似增加，脾脏重量的减少，而在雌性中，它们同样减少了 BAT 炎症和脾脏重量，维持了心率和 Q-T 间隔。然而，其他健康参数，包括与年龄相关的病理学，更能通过连续治疗得到预防。
间歇性雷帕霉素治疗在延长寿命和减少慢性治疗的一些副作用方面是有效的，但慢性治疗对健康寿命更有益。
