Understanding the Causes of Aging

描述（由申请人提供）：高龄带来了许多疾病。延缓衰老过程有可能阻止这些疾病的发展。据认为，衰老是由衰老因子的积累引起的，包括各种细胞成分的受损形式和细胞代谢的副产物。虽然在进化过程中，严重的损害是被选择反对的，因为它限制了健康和繁殖，但温和形式的损害，慢慢积累并限制了繁殖后的寿命，不是。衰老的分子原因可能有很多。此外，一种生物体中的一些衰老因素可能不会对另一种生物体产生相同程度的影响，要么是因为损伤可能更严重，这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，由于细胞具有有限数量的组分，其中只有一些有助于产生衰老因子，因此必须有有限的，即使是大量的受损形式。目前关于衰老的大部分研究都集中在确定其调节影响寿命的途径上。虽然这些研究有可能通过调节衰老因子的丰度来延长寿命，但它们提供的关于衰老原因的信息很少，也没有确定衰老因子。我们建议使用新的分子工具和技术来表征衰老因子的性质。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时，衰老是如何调节的，减少了对中央分解代谢过程的需求;（ii）通过在年轻和年老细胞之间交换细胞成分并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，以及分子和生物工程方法的结合，来了解衰老的基本机制，然后可以应用于影响男性的衰老过程。 公共卫生相关性：了解衰老的基本机制可能会导致减缓衰老过程和延迟与衰老相关的疾病（如癌症，神经退行性疾病和心脏病以及糖尿病）发展的策略。它可以使人类有机会在老年时过上健康、积极、高质量的生活方式。我们建议确定芽殖酵母中衰老因子的性质，芽殖酵母是研究衰老的最简单的模式生物。

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.