GENETIC ANALYSIS OF CARDIAC SENESCENCE

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

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Abstract

PROJECT SUMMARY (See instructions): The genetic control of aging is an intriguing and pervasive problem, but has been difficult to tackle. By studying genetically tractable model systems it has become clear in recent years that aging is indeed regulated/modulated by specific genes, such as insulin and its downstream effectors. How the aging process is orchestrated within an organism and how the functional and morphological decline of organ systems is initiated, coordinated and executed is still far from being understood. Since cardiac dysfunction is the most common cause of death in the elderly, it is of crucial importance to understand the progression and control of age-related changes in heart function. To date very little is known about the genetic mechanisms that control cardiac aging. We have recently implemented assays to study the genetic basis of cardiac aging in the simple Drosophila system, the only invertebrate genetic model system with a heart. Given the high degree of parallel genetic functions between flies and vertebrates in cardiogenesis, and given the strikingly common mechanisms that determine lifespan and rate of overall aging, it is likely that fundamental aspects of age-related changes of cardiac function and performance in flies are also conserved. Recent evidence indeed suggests that the fly's heart function is controlled by conserved aging genes and in ways that may turn out to be remarkably similar to vertebrates. The proposed studies are expected to provide a basic genetic understanding of age-dependent decline mechanisms in heart function that may serve as a prototype to guide similar studies in human cardiac aging and of age-related cardiac diseases. We propose to use the Drosophila model and its advanced molecular-genetic tools to study the control mechanisms by which the aging process of an individual organ, the heart, is regulated. For this purpose, we will first delineate the changes in cardiac function and fine-structure that occur with age (Aim la) and whether an age-dependent modulation of heart function (eg. by altered ion channel functions) also changes other aspects of cardiac aging. Then, we will study the genetic control of cardiac aging by insulin/TOR/JNK signaling (Aim 2a), including autonomous versus non-autonomous mechanisms (Aim 2b). It will be of particular interest to see whether manipulations that alter other aspects of functional aging (ie. immunity, gut, sleep) also influence cardiac aging. In order to discover new genes that are involved in cardiac aging, we will conduct a screen for modulators of the age-dependent changes in heart function (Aim 3).