Understanding the Causes of Aging

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DESCRIPTION (provided by applicant): Advanced age brings with it many diseases. Delaying the aging process has the potential to preclude the development of these diseases. It is thought that aging results from accumulation of senescence factors, including damaged forms of various cellular components and by-products of cellular metabolism. While severe damage is selected against during evolution because it limits fitness and reproduction, milder forms of damage, which slowly accumulate and limit postreproductive lifespan, are not. There may be many molecular causes of aging. Moreover, some senescence factors in one organism may not contribute to the same extent in the other, either because the damage may be more severe, which necessitates the development of natural protection systems, or because it is more mild and does not limit lifespan. However, since cells have a finite number of components with only some contributing to generating senescence factors, there must be a limited, even if large, number of damaged forms. Much of the current research on aging focuses on identifying pathways whose modulation influences lifespan. While these studies have the potential to extend lifespan by modulating the abundance of senescence factors, they provide little information on what causes aging nor do they identify senescence factors. We propose to characterize the nature of senescence factors using novel molecular tools and technologies. Specifically, we will (i) determine how aging is modulated when energy in the form of ATP is provided directly to cells, reducing the need for central catabolic processes; and (ii) characterize the nature of damaged forms by exchanging cellular components between young and old cells and diluting senescence factors in old cells. This research will use a simple model organism of aging, Saccharomyces cerevisiae, and a combination of molecular and bioengineering approaches, to understand the basic mechanisms of aging, which can then be applied to influence the aging process in men. PUBLIC HEALTH RELEVANCE: Understanding the basic mechanisms of aging could lead to strategies to slow down the aging process and delay the development of diseases associated with aging, such as cancer, neurodegenerative and heart diseases, and diabetes. It could afford the human population the opportunity to live a healthy, active, high-quality lifestyle at an advanced age. We propose to identify the nature of senescence factors in budding yeast, which is the simplest model organism to study aging.