Late-life rapamycin treatment reverses age-related heart dysfunction.
Late-life rapamycin treatment reverses age-related heart dysfunction.
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DOI：
10.1111/acel.12109
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发表时间：
2013-10
期刊：
影响因子：
7.8
通讯作者：
Melov S
中科院分区：
文献类型：
--
作者：
Flynn JM;O'Leary MN;Zambataro CA;Academia EC;Presley MP;Garrett BJ;Zykovich A;Mooney SD;Strong R;Rosen CJ;Kapahi P;Nelson MD;Kennedy BK;Melov S
雷帕霉素已被证明可以在包括小鼠在内的许多模型生物中延长寿命，其中最显著的长寿作用是在雌性动物身上。然而，人们对这种延长寿命的范例在哺乳动物组织中的功能分支知之甚少。我们用雷帕霉素对24个月大的雌性C57BL/6J小鼠进行了为期3个月的治疗，并通过对单个小鼠心血管、骨骼和代谢健康的各种非侵入性测量来确定健康结果。我们确定，虽然雷帕霉素有轻微的暂时性代谢影响，但逆转或减弱心脏中与年龄相关的变化对晚年心血管功能有显著好处。治疗后心脏组织的RNA-SEQ分析表明，心脏组织的炎症、代谢和抗肥大表达的变化是介导功能改善的潜在机制。与喂食对照饮食的小鼠相比，雷帕霉素治疗还导致了这些小鼠有益的行为、骨骼和运动变化。根据这些发现，我们认为，晚年雷帕霉素治疗不仅延长了哺乳动物的寿命，还赋予了许多组织功能上的好处，并从机制上暗示改善了老年心脏的收缩功能和抗肥大信号，减少了与年龄相关的炎症。
Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity-enhancing paradigm in mammalian tissues. We treated 24-month-old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. We determined that while rapamycin has mild transient metabolic effects, there are significant benefits to late-life cardiovascular function with a reversal or attenuation of age-related changes in the heart. RNA-seq analysis of cardiac tissue after treatment indicated inflammatory, metabolic, and antihypertrophic expression changes in cardiac tissue as potential mechanisms mediating the functional improvement. Rapamycin treatment also resulted in beneficial behavioral, skeletal, and motor changes in these mice compared with those fed a control diet. From these findings, we propose that late-life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age-related inflammation.
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影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
影响因子：
4.9
作者：
Gao, Xiao-Ming;Wong, Geoffrey;Du, Xiao-Jun
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Du, Xiao-Jun
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9.2
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Benzer, S
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Astrinidis, Aristotelis;Kim, Jiyoon;Azizkhan-Clifford, Jane
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Azizkhan-Clifford, Jane
影响因子：
39.3
作者：
Buyse, Gunnar M.;Van der Mieren, Gerry;Meier, Thomas
通讯作者：
Meier, Thomas