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Synthetic agonists of growth hormone\u2010releasing hormone (GHRH) exhibit several favorable effects on heart function and remodeling. Here we assessed whether GHRH agonist MR409 can modulate heart function and systemic parameters in old mice. Starting at the age of 15 months, mice were injected subcutaneously with MR409 (10\u2009\u00b5g\/day, <jats:italic>n\u2009<\/jats:italic>=\u20098) or vehicle (<jats:italic>n\u2009<\/jats:italic>=\u20097) daily for 6 months. Mice treated with MR409 showed improvements in exercise activity, cardiac function, survival rate, immune function, and hair growth in comparison with the controls. More stem cell colonies were grown out of the bone marrow recovered from the MR409\u2010treated mice. Mitochondrial functions of cardiomyocytes (CMs) from the MR409\u2010treated mice were also significantly improved with more mitochondrial fusion. Fewer \u03b2\u2010gal positive cells were observed in endothelial cells after 10 passages with MR409. In Doxorubicin\u2010treated H9C2 cardiomyocytes, cell senescence marker p21 and reactive oxygen species were significantly reduced after cultured with MR409. MR409 also improved cellular ATP production and oxygen consumption rate in Doxorubicin\u2010treated H9C2 cells. Mitochondrial protein OPA1 long isoform was significantly increased after treatment with MR409. The effects of MR409 were mediated by GHRH receptor and protein kinase A (PKA). In short, GHRH agonist MR409 reversed the aging\u2010associated changes with respect of heart function, mobility, hair growth, cellular energy production, and senescence biomarkers. The improvement of heart function may be related to a better mitochondrial functions through GHRH receptor\/cAMP\/PKA\/OPA1 signaling pathway and relieved cardiac inflammation.<\/jats:p>","DOI":"10.1002\/jcp.30490","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T16:20:47Z","timestamp":1625502047000},"page":"8197-8207","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Improvement of cardiac and systemic function in old mice by agonist of growth hormone\u2010releasing hormone"],"prefix":"10.1002","volume":"236","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8685-9673","authenticated-orcid":false,"given":"Pingping","family":"Xiang","sequence":"first","affiliation":[{"name":"Cardiovascular Key Laboratory of Zhejiang Province, Department of Cardiology, The Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 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