Cellular & Molecular Mechanisms of Cardiac Aging

Aging is a process whereby progressive decline of tissue homeostasis reduces system function and elevates risk of death. Age itself is a major risk factor for a range of human diseases, such as cancer, diabetes, neurodegeneration and heart disease. Specifically, aging is associated with an 8-fold increase of the incidence of sudden cardiac death (SCD), the leading cause of death in western countries. Resolving the contributing mechanisms of heart disease in any of its forms is a pressing goal of basic and translational aging research.

Organ Communication via Systemic Signals

The tissue-specific roles of known longevity pathways in the regulation of lifespan have been reported from several studies. However, it is unclear how genetic manipulation of these pathways within certain tissue can result in a systemic effect on organism’s fitness and survival. Besides cell-autonomous mechanisms (e.g., autophagy), it has become much appreciated that inter-tissue communication is also attributed to age-dependent decline of cardiac function. However, such non-autonomous regulation of cardiac aging has not yet been identified. The liver (oenocytes in flies) is a major endocrine organ, and aging significantly alters liver morphology and function. Patients with liver dysfunction, such as cirrhosis, often show increased cardiac arrhythmias. Thus, there is a clear connection between liver and heart.

Peroxisome and Inter-Organelle Communication

Peroxisomal import function is often compromised under stress and aging, as demonstrated in recent studies from our group and others. Although it has become more and more appreciated that defective peroxisomal import contributes significantly to the loss of cellular homeostasis and aging, little is known about how cells mount defense mechanisms to maintain cellular and metabolic function during peroxisomal import stress. Recently, we have applied genomic (RNA-Seq) and genetic approaches (CRISPR screening) to comprehensively characterize and uncover cellular stress responses to defective peroxisomal protein import. In addition, we have begun to explore the role of peroxisome-mitochondrion communication in tissue aging, given that inter-organelle communication plays an essential role in maintaining cellular homeostasis.