GLUCAge

Aging is a progressive physiological decline that predisposes individuals to age-related pathologies such as cardiometabolic diseases, leading causes of death in Europe. Loss of adaptation to various stresses, including metabolic stresses, emerged as both a hallmark and a driver of the aging process. However, the implication of glucocorticoids (GCs)—central players in the response to metabolic stresses—in organismal aging has never been studied, and yet would be critical. Indeed, prolonged exposure to GCs induce age-related cardiometabolic disorders suggesting that GCs contribute to premature aging. GLUCAge aims at characterizing the impact of GCs and the glucocorticoid receptor (GR) on the aging process and healthspan. Especially, GLUCAge will (1) characterize the impact of supraphysiologic GC treatment on the premature aging in Human and on the dysfunction of insulin-sensitive tissues such as the adipose tissue (AT); (2) dissect the pro-senescent signals induced by GC/GR in primary adipose stem cells and fibroblasts deleted or not for the GR and induced to cellular senescence; (3) address how disrupting GR signaling within AT can extend the healthspan and lifespan, paving the way for tailored tissue-specific medicine to improve healthspan. In parallel, the impact of age itself on the resistance to GCs will be studied. To this end, (4) we will establish a mathematical model describing the age-dependent loss in the adaptive response to GCs in order to describe dynamics of activation of GR-downstream targets during cellular senescence in old and young mice. In fine, GLUCAge will help understand not only how GC signaling is affected during the aging process, but also how modulating GC signaling itself may lead to novel therapeutic strategies to delay cardiometabolic disorders and extend healthspan.