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There is no therapy to prevent heart dysfunction in aging and diabetic individuals. In previous studies, a single administration of the longevity-associated variant (LAV) of the human\n                      <jats:italic>BPIFB4<\/jats:italic>\n                      gene halted heart decline in older and type 2 diabetic mice. Here, we asked whether orally administered LAV-BPIFB4 protein replicates these benefits.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>In two controlled, randomized studies, 18-month-old male C57BL\/6\u00a0J mice and 9-week-old C57BLKS\/J-Leprdb\/Leprdb\/Dock7\u2009+\u2009[db\/db] mice of both sexes underwent baseline echocardiography. They then received a recombinant purified LAV-BPIFB4 protein (3\u00a0\u00b5g\/animal, every three days) or vehicle by gavage. After 30\u00a0days, the animals underwent echocardiography, and the hearts were collected post-termination for histology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All the animals completed the study except one female diabetic mouse, which was culled prematurely because tooth malocclusion caused eating problems. There was no effect of the LAV-BPIFB4 protein on body weight in the two studies or glycosuria in the diabetic study. In aging mice, LAV-BPIFB4 increased myocardial Bpifb4 expression, improving heart contractility and capillarity while reducing perivascular fibrosis and senesce. In male diabetic mice, LAV-BPIFB4 therapy improved systolic function, microvascular density, and senescence, whereas the benefit was limited to systolic function in females.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study shows the feasibility and efficacy of a variant protein associated with human longevity in contrasting pivotal risk factors for heart failure in animal models. The diabetic study revealed that sex influences the treatment efficacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12933-024-02487-6","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T06:04:34Z","timestamp":1730786674000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Healthy longevity-associated protein improves cardiac function in murine models of cardiomyopathy with preserved ejection fraction"],"prefix":"10.1186","volume":"23","author":[{"given":"Valeria Vincenza","family":"Alvino","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sadie","family":"Slater","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Cattaneo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khaled Abdelsattar Kassem","family":"Mohammed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seamus","family":"Gate","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vealmurugan","family":"Sekar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annibale Alessandro","family":"Puca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Madeddu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,11,5]]},"reference":[{"key":"2487_CR1","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1161\/CIRCRESAHA.121.318172","volume":"128","author":"VL Roger","year":"2021","unstructured":"Roger VL. 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