Grant: Project Grant

Postmenopausal syndrome caused by estrogen deprivation can manifest itself as symptoms that decrease women's quality of life but also lead to serious health complications such as osteoporosis, metabolic syndrome and cardiovascular diseases. Estrogen replacement therapy is used to treat menopause associated disorders, but it is limited by significant side effects. In this application, we propose a new mechanism by which estrogen deprivation predispose postmenopausal women to serious health problems. Our preliminary data show that ovariectomy induces accumulation of senescent cells in several organs. These senescent cells can impair normal tissue regeneration and continuously secrete pro-inflammatory mediators, that induce tissue damage. We thus anticipate that elimination of senescent cells will provide a novel strategy to prevent and treat postmenopausal syndrome. To accomplish this goal, we will use mice engineered in a way that it will be possible to eliminate senescent cells. We will show that ovariectomy leads to accumulation of senescent cells and that elimination of senescent cells in these mice will prevent the pathologies associated with estrogen deprivation. In addition, we will test whether drugs that eliminate senescent cells called senolytics can also prevent these pathologies. We will try a novel formulation for administration of senolytic drugs as well as a new senolytic cocktail discovered in our laboratory Finally, we will test the hypothesis that macrophages are one of the major cell types undergoing senescence under estrogen deprivation and we will develop a cell culture model of macrophage senescence that will permit to discover new biomarkers of senescence that can be used in clinical trials to estimate the senescent cell burden.