Understanding the Causes of Aging

描述（申请人提供）：老年带来许多疾病。延缓衰老过程有可能阻止这些疾病的发展。人们认为衰老是衰老因素积累的结果，包括各种细胞成分的损伤形式和细胞代谢的副产物。在进化过程中，严重的伤害会限制适应性和繁殖，而较轻微的伤害会慢慢累积并限制繁殖后的寿命，但却不会。衰老可能有许多分子原因。此外，一种生物体中的某些衰老因素在另一种生物体中可能不会起到相同程度的作用，要么是因为损害可能更严重，这就需要开发自然保护系统，要么是因为它更温和，不会限制寿命。然而，由于细胞有有限数量的成分，只有一些有助于产生衰老因子，因此必须有有限的，即使是大量的损坏形式。目前许多关于衰老的研究都集中在确定影响寿命的调节途径上。虽然这些研究有可能通过调节衰老因素的丰度来延长寿命，但它们几乎没有提供导致衰老的原因的信息，也没有确定衰老因素。我们建议使用新的分子工具和技术来表征衰老因素的性质。具体来说，我们将(i)确定当能量以ATP的形式直接提供给细胞，减少对中枢分解代谢过程的需求时，衰老是如何被调节的；（ii）通过在年轻细胞和年老细胞之间交换细胞成分和稀释年老细胞中的衰老因子来表征受损形式的性质。这项研究将使用一种简单的衰老模式生物——酿酒酵母菌，并结合分子和生物工程方法，了解衰老的基本机制，然后应用于影响男性的衰老过程。

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.