Rejuvenation of the Aging Heart: Molecular Determinants and Applications

In Canada and worldwide, the elderly population (i.e., individuals >65 years of age) is increasing disproportionately relative to the total population. This is expected to have a substantial impact on the healthcare system, as increased aged is associated with a greater incidence of chronic non-communicable diseases. Within the elderly population cardiovascular disease is a leading cause of death, therefore developing therapies which can prevent or slow disease progression in this demography is highly desirable. Historically aging research has focused on the development of anti-aging therapies which are implemented early in life and slow the age-dependent decline in cell and organ function. However, accumulating evidence supports that late-in-life therapies can also benefit the aged cardiovascular system by limiting the age-dependent functional decline. Moreover, recent studies have also demonstrated that rejuvenation (i.e. reverting cellular function to that of a younger phenotype) of the already aged cardiovascular system is possible, opening new avenues to develop therapies for older individuals. In this review, we first provide an overview of the functional changes that occur in the cardiomyocyte with aging and how this contributes to the age-dependent decline in heart function. We then discuss the various anti-aging/rejuvenation strategies that have been pursued to improve the function of the aged cardiomyocyte, with a focus on therapies implemented late in life. These strategies include 1) established systemic approaches (caloric restriction, exercise), 2) pharmacological approaches (mTOR, AMPK, SIRT1, and autophagy targeting molecules), and 3) emerging rejuvenation approaches (partial reprogramming, parabiosis/modulation of circulating factors, targeting endogenous stem cell populations, and senotherapeutics). Collectively, these studies demonstrate the exciting potential and limitations of current rejuvenation strategies and highlight future areas of investigation which will contribute to the development of rejuvenation therapies for the aged heart.