Aging exponentially increases the risk of cardiovascular disease and impairs baseline cardiac function, especially diastolic function. Diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF) are both increasing in prevalence in the aged population, contribute to exercise intolerance in the elderly, and are presently without effective treatment. While phenotypes of cardiac aging are well-characterized, the molecular mechanisms of cardiac aging have not been well-established.
My research program focuses on dissecting the molecular mechanisms of cardiac aging and age-related diastolic dysfunction, and developing potential interventions to treat cardiac aging and HFpEF. We use in vivo and in vitro approaches to study the physiological, biochemical and proteomic changes of cardiac aging in mouse models.
We and other have demonstrated that late-life inhibition of mTOR signaling, by caloric restriction (CR) or rapamycin, can reverse cardiac aging phenotypes in mice. Rapamycin treatment inhibits mTOR signaling and induces proteomic and metabolic remodeling in aged hearts. However, how these proteomic and metabolic changes mediate improved diastolic function remain to be established. The research in my laboratory aims to determine the molecular mechanisms of rapamycin-induced reversal of diastolic dysfunction in aged hearts. Specifically, our studies focus on 1) how rapamycin regulates cardiomyocyte relaxation properties in the aging hearts and 2) how rapamycin remodels cardiac extracellular matrix to modify passive myocardial stiffness. In addition, we hope to define the signaling pathways by which rapamycin mediates changes in these key determinants of diastolic function.
The overall goals of the laboratory are to identify novel regulators of cardiac aging and diastolic dysfunction, and to apply this knowledge to the development of therapeutics for cardiac aging and HFpEF.