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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\u2010term (10\u2010week) treatment with rapamycin, an mTORC1 inhibitor, improved measures of these age\u2010related changes. In this report, we demonstrate that the rapamycin\u2010dependent improvement of diastolic function is highly persistent, while decreases in both cardiac hypertrophy and passive stiffness are substantially persistent 8\u00a0weeks after cessation of an 8\u2010week treatment of rapamycin in both male and female 22\u2010 to 24\u2010month\u2010old C57BL\/6NIA mice. The proteomic and metabolomic abundance changes that occur after 8\u00a0weeks 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\u2010term treatments.<\/jats:p>","DOI":"10.1111\/acel.13086","type":"journal-article","created":{"date-parts":[[2019,12,11]],"date-time":"2019-12-11T04:49:43Z","timestamp":1576039783000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7160-3939","authenticated-orcid":false,"given":"Ellen","family":"Quarles","sequence":"first","affiliation":[{"name":"Department of Pathology University of Washington Seattle WA 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