Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment.,Aging Cell

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Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment.
Aging Cell ( IF 8.0 ) Pub Date : 2019-12-10 , DOI: 10.1111/acel.13086
Ellen Quarles ₁ , Nathan Basisty ₁ , Ying Ann Chiao ₁ , Gennifer Merrihew ₂ , Haiwei Gu ₃ , Mariya T Sweetwyne ₁ , Jeanne Fredrickson ₁ , Ngoc-Han Nguyen ₁ , Maria Razumova ₄ , Kristina Kooiker ₅ , Farid Moussavi-Harami ₅ , Michael Regnier ₄ , Christopher Quarles ₆ , Michael MacCoss ₂ , Peter S Rabinovitch ₁

Affiliation

Even in healthy aging, cardiac morbidity and mortality increase with age in both mice and humans. These effects include a decline in diastolic function, left ventricular hypertrophy, metabolic substrate shifts, and alterations in the cardiac proteome. Previous work from our laboratory indicated that short‐term (10‐week) treatment with rapamycin, an mTORC1 inhibitor, improved measures of these age‐related changes. In this report, we demonstrate that the rapamycin‐dependent improvement of diastolic function is highly persistent, while decreases in both cardiac hypertrophy and passive stiffness are substantially persistent 8 weeks after cessation of an 8‐week treatment of rapamycin in both male and female 22‐ to 24‐month‐old C57BL/6NIA mice. The proteomic and metabolomic abundance changes that occur after 8 weeks of rapamycin treatment have varying persistence after 8 further weeks without the drug. However, rapamycin did lead to a persistent increase in abundance of electron transport chain (ETC) complex components, most of which belonged to Complex I. Although ETC protein abundance and Complex I activity were each differentially affected in males and females, the ratio of Complex I activity to Complex I protein abundance was equally and persistently reduced after rapamycin treatment in both sexes. Thus, rapamycin treatment in the aged mice persistently improved diastolic function and myocardial stiffness, persistently altered the cardiac proteome in the absence of persistent metabolic changes, and led to persistent alterations in mitochondrial respiratory chain activity. These observations suggest that an optimal translational regimen for rapamycin therapy that promotes enhancement of healthspan may involve intermittent short‐term treatments.

中文翻译：

即使在停止治疗后，雷帕霉素仍能持续改善老年雄性和雌性小鼠的心脏功能。

即使在健康老龄化的情况下，小鼠和人类的心脏病发病率和死亡率也会随着年龄的增长而增加。这些影响包括舒张功能下降、左心室肥大、代谢底物变化和心脏蛋白质组的改变。我们实验室之前的工作表明，使用雷帕霉素（一种 mTORC1 抑制剂）进行短期（10 周）治疗可以改善这些与年龄相关的变化的测量。在本报告中，我们证明，雷帕霉素依赖性的舒张功能改善是高度持久的，而在男性和女性中，在停止 8 周的雷帕霉素治疗后 8 周，心脏肥大和被动僵硬度的减少基本上持续存在 22‐ 24 个月大的 C57BL/6NIA 小鼠。雷帕霉素治疗 8 周后发生的蛋白质组和代谢组丰度变化在不用药 8 周后具有不同的持续性。然而，雷帕霉素确实导致电子传递链（ETC）复合物成分的丰度持续增加，其中大部分属于复合物 I。尽管 ETC 蛋白丰度和复合物 I 活性在男性和女性中各自受到不同的影响，但复合物的比例雷帕霉素治疗后，男女复合体 I 蛋白丰度的 I 活性均等且持续降低。因此，雷帕霉素治疗老年小鼠持续改善舒张功能和心肌僵硬度，在没有持续代谢变化的情况下持续改变心脏蛋白质组，并导致线粒体呼吸链活性持续改变。这些观察结果表明，促进延长健康寿命的雷帕霉素治疗的最佳转化方案可能涉及间歇性短期治疗。

更新日期：2019-12-10

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