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Therefore, compounds that enhance mitochondrial uncoupling are potentially attractive anti\u2010aging therapies; however, chronic ingestion is associated with a number of unwanted side effects. We have previously developed a controlled\u2010release mitochondrial protonophore (CRMP) that is functionally liver\u2010directed and promotes oxidation of hepatic triglycerides by causing a subtle sustained increase in hepatic mitochondrial inefficiency. Here, we sought to leverage the higher therapeutic index of CRMP to test whether mild mitochondrial uncoupling in a liver\u2010directed fashion could reduce oxidative damage and improve age\u2010related metabolic disease and lifespan in diet\u2010induced obese mice. Oral administration of CRMP (20\u00a0mg\/[kg\u2010day]\u00a0\u00d7\u00a04\u00a0weeks) reduced hepatic lipid content, protein kinase C epsilon activation, and hepatic insulin resistance in aged (74\u2010week\u2010old) high\u2010fat diet (HFD)\u2010fed C57BL\/6J male mice, independently of changes in body weight, whole\u2010body energy expenditure, food intake, or markers of hepatic mitochondrial biogenesis. CRMP treatment was also associated with a significant reduction in hepatic lipid peroxidation, protein carbonylation, and inflammation. Importantly, long\u2010term (49\u00a0weeks) hepatic mitochondrial uncoupling initiated late in life (94\u2013104\u00a0weeks), in conjugation with HFD feeding, protected mice against neoplastic disorders, including hepatocellular carcinoma (HCC), in a strain and sex\u2010specific manner. Taken together, these studies illustrate the complex variation of aging and provide important proof\u2010of\u2010concept data to support further studies investigating the use of liver\u2010directed mitochondrial uncouplers to promote healthy aging in humans.<\/jats:p>","DOI":"10.1111\/acel.13539","type":"journal-article","created":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T04:51:32Z","timestamp":1643345492000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Sex\u2010 and strain\u2010specific effects of mitochondrial uncoupling on age\u2010related metabolic diseases in high\u2010fat diet\u2010fed mice"],"prefix":"10.1111","volume":"21","author":[{"given":"Leigh","family":"Goedeke","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Yale School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey 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