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However, the maladaptive responses in the heart that arise from prolonged obesity and the specific influence of biological age remain somewhat elusive. This study investigated the effects of diet-induced obesity (DIO) and aging on physical performance and cardiovascular function in mice. 22- and 76-week-old male C57BL\/6J mice were randomized to 8 weeks of chow or high-fat diet. Body weight was assessed weekly. Body composition was measured at the beginning and the end of the diet treatment. Muscular and cardiac function were evaluated at the end intervention. Aged mice with DIO exhibited faster and greater body weight gain and fat mass accumulation, reduced running distance, and lower aerobic capacity. Aged HFD mice also exhibited increased cardiac lipid accumulation and cardiomyocyte hypertrophy, with no major morphological changes observed in skeletal muscle. Proteomic analysis revealed differential expression of heart proteins associated with metabolic function in young mice, which was not observed in aged mice with DIO. Subsequently, aged mice with DIO developed overt heart failure with reduced ejection fraction, while cardiac function was unaffected by DIO in young mice. In conclusion, young mice with DIO were protected against diet-induced cardiac dysfunction, whereas DIO in aged mice led to heart failure and impaired physical performance. The protective effects observed in younger mice appear to be explained by proteomic-level remodeling of the heart oriented to sustain cardiac function.<\/jats:p>","DOI":"10.1007\/s11357-025-01775-7","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T09:52:08Z","timestamp":1752141128000},"page":"2295-2309","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Age-dependent impairment of cardiac function and physical performance in male mice with diet-induced obesity"],"prefix":"10.1007","volume":"48","author":[{"given":"Patricia","family":"Baumgarten","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justus","family":"Kamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Hegemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Deubel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"Berndt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Grune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang M.","family":"Kuebler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"Axelrod","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Kirwan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"H\u00f6hn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Heider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Ott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4775-9973","authenticated-orcid":false,"given":"Tilman","family":"Grune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,10]]},"reference":[{"key":"1775_CR1","doi-asserted-by":"publisher","unstructured":"Ren J, Dong F, Cai G-J, Zhao P, Nunn JM, Wold LE, Pei J. 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