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AMPK has emerged as a pertinent stress\u2010activated kinase that has been shown to have cardioprotective capabilities against myocardial ischemic injury. We identified the interaction between Sesn2 and AMPK in the ischemic heart. To determine whether ischemic AMPK activation\u2014modulated by the Sesn2\u2010AMPK complex in the heart\u2014is impaired in aging that sensitizes the heart to ischemic insults, young C57BL\/6 mice (age 3\u20134 mo), middle\u2010aged mice (age 10\u201312 mo), and aged mice (age 24\u201326 mo) were subjected to left anterior descending coronary artery occlusion for\n                    <jats:italic>in vivo<\/jats:italic>\n                    regional ischemia. The\n                    <jats:italic>ex vivo<\/jats:italic>\n                    working heart system was used for measuring substrate metabolism. The protein level of Sesn2 in hearts was gradually decreased with aging. Of interest, ischemic AMPK activation was blunted in aged hearts compared with young hearts (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05); the AMPK downstream glucose uptake and the rate of glucose oxidation were significantly impaired in aged hearts during ischemia and reperfusion (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05\n                    <jats:italic>vs.<\/jats:italic>\n                    young hearts). Myocardial infarction size was larger in aged hearts (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05\n                    <jats:italic>vs.<\/jats:italic>\n                    young hearts). Immunoprecipitation with Sesn2 Ab revealed that cardiac Sesn2 forms a complex with AMPK and upstream liver kinase B1 (LKB1) during ischemia. Of interest, the binding affinity between Sesn2 and AMPK upstream LKB1 is impaired in aged hearts during ischemia (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.05\n                    <jats:italic>vs.<\/jats:italic>\n                    young hearts). Furthermore, Sesn2\u2010knockout hearts demonstrate a cardiac phenotype and response to ischemic stress that is similar to wild\u2010type aged hearts (\n                    <jats:italic>i.e.<\/jats:italic>\n                    , impaired ischemic AMPK activation and higher sensitivity to ischemia\u2010 and reperfusion\u2010 induced injury). Adeno\u2010associated virus\u2013Sesn2 was delivered to aged hearts\n                    <jats:italic>via<\/jats:italic>\n                    a coronary delivery approach and significantly rescued the protein level of Sesn2 and the ischemic tolerance of aged hearts; therefore, Sesn2 is a scaffold protein that mediates AMPK activation in the ischemic myocardium\n                    <jats:italic>via<\/jats:italic>\n                    an interaction with AMPK upstream LKB1. Decreased Sesn2 levels in aging lead to a blunted ischemic AMPK activation, alterations in substrate metabolism, and an increased sensitivity to ischemic insults\u2014Quan, N., Sun, W., Wang, L., Chen, X., Bogan, J. S., Zhou, X., Cates, C., Liu, Q., Zheng, Y., Li J. Sestrin2 prevents age\u2010related intolerance to ischemia and reperfusion injury by modulating substrate metabolism. FASEB J. 31, 4153\u20134167 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                    \u2014Quan, Nanhu, Sun, Wanqing, Wang, Lin, Chen, Xu, Bogan, Jonathan S., Zhou, Xinchun, Cates, Courtney, Liu, Quan, Zheng, Yang, Li, Ji Sestrin2 prevents age\u2010related intolerance to ischemia and reperfusion injury by modulating substrate metabolism. FASEB J. 31, 4153\u20134167 (2017)\n                  <\/jats:p>","DOI":"10.1096\/fj.201700063r","type":"journal-article","created":{"date-parts":[[2017,6,7]],"date-time":"2017-06-07T21:00:37Z","timestamp":1496869237000},"page":"4153-4167","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["Sestrin2 prevents age\u2010related intolerance to ischemia and reperfusion injury by modulating substrate metabolism"],"prefix":"10.1096","volume":"31","author":[{"given":"Nanhu","family":"Quan","sequence":"first","affiliation":[{"name":"Cardiovascular Center First Hospital of Jilin University  Changchun China"},{"name":"Department of Physiology and Biophysics Mississippi Center for Heart Research University of Mississippi Medical Center  Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqing","family":"Sun","sequence":"additional","affiliation":[{"name":"Cardiovascular Center First Hospital of Jilin University  Changchun China"},{"name":"Department of Physiology and Biophysics Mississippi Center for Heart Research University of Mississippi Medical Center  Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"Cardiovascular Center First Hospital of Jilin University  Changchun China"},{"name":"Department of Physiology and Biophysics Mississippi Center for Heart Research University of Mississippi Medical Center  Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Mississippi Center for Heart Research University of Mississippi Medical Center  Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan S.","family":"Bogan","sequence":"additional","affiliation":[{"name":"Section of Endocrinology Department of Internal Medicine Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Department of Cell Biology Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinchun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pathology Cancer Institute University of Mississippi Medical Center  Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney","family":"Cates","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Mississippi Center for Heart Research University of Mississippi Medical Center  Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Liu","sequence":"additional","affiliation":[{"name":"Cardiovascular Center First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Cardiovascular Center First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics Mississippi Center for Heart Research University of Mississippi Medical Center  Jackson Mississippi USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,9,19]]},"reference":[{"key":"e_1_2_8_2_1","first-page":"268","article-title":"Myocardial injury after hypoxia in immature, adult and aged rats","volume":"9","author":"Starnes J. 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