In the United Sates, heart disease is the leading cause of death for men and women, killing about 610,000 people each year. The incidence of heart failure approximately doubles through each decade of life. Consequently, due to ongoing aging of human populations across the globe, heart disease and associated morbidity and mortality is expected to become an even greater social and economic burden. This trend will be exacerbated by the increasing incidence of obesity. The aging heart shows many and diverse changes with age, typically detrimental. These include structural changes, functional changes, impaired repair and increased cardiovascular disease. Evidence already indicates that age-associated changes to the epigenome and transcriptome contribute to pathologies of the aging heart. Importantly, the epigenome is maintained in a state of dynamic equilibrium and is prone to ?drift? over the lifespan. Accordingly, we hypothesize that homeostasis of the dynamic chromatin steady state (a process we have termed ?chromostasis?) of heart cardiomyocytes is critical for maintenance of an appropriate gene expression program and phenotype, and function at the cellular and tissue levels, over the life span. However, eventually, age-associated drift of the epigenome is likely to promote age-associated changes to the transcriptome and cell phenotype and so increased heterogeneity within aged tissues. We anticipate that this heterogeneity in old hearts is manifest at several levels: between cardiomyocytes isolated from normal and poor functioning whole aged hearts (in a population of aged flies, there is fly-to-fly variation in heart function); and between sub-regions of normal and impaired function within a single aged heart (in a single heart, there are regions of normal and impaired function). We hypothesize that age-associated epigenetic and transcriptomic alteration and tissue heterogeneity contribute to dysfunction of the aged heart. We further hypothesize that specific epigenetic regulators are required for homeostasis of the heart epigenome and transcriptome, and thereby promote healthy aging and longevity.
Specific Aim 1. Investigate age-associated transcriptomic alteration and heart heterogeneity and correlate with heart dysfunction.
Specific Aim 2. Identify additional epigenetic regulators that influence healthy aging of the heart.
In the United Sates, heart disease is the leading cause of death for men and women, and its incidence is projected to increase in line with two major risk factors, age and obesity. The effects of age and obesity are likely due in part to epigenetic dysregulation. Hence, this application seeks to identify key epigenetic regulators of heart aging, candidate targets for future therapeutic intervention.
