Starvation Mediated Longevity in C. elegans Adults

描述(申请人提供)：饮食限制可以减缓生殖发育，延长寿命，并改善代谢和神经疾病的结局。在严格的饮食限制下，包括哺乳动物在内的许多生物会启动发育或生殖停滞或滞育的计划。在这些受阻的状态下，动物经受住了长期的饥饿，并在不显著损害繁殖产量或成年寿命的情况下恢复。在初步研究中，我们发现线虫HNF41同源基因NHR-49对于成年生殖滞育的长寿和生殖保护是必不可少的，这是一种有趣的生理状态，尚未在线虫中描述。与这种成虫滞育相关的许多特征使它引起了广泛的关注，最显著的是，它对生殖活动、胚胎发育、干细胞维持和能量代谢的影响。因此，对线虫NHR-49的研究为确定核受体在营养滞育中的作用提供了一个独特的机会。具体地说，我们将解决这次NHR-49依赖成年人被捕的三个方面。在目标1中，我们将进行实验，以了解生殖系干细胞在长期饥饿期间如何受到保护，区分生殖细胞静止和自我更新的模式，并评估干细胞生态位的作用。在目标2中，我们将测试我们的假设，即NHR-49依赖的脂肪支出刺激对于饥饿依赖的延长寿命和生殖寿命是必不可少的。此外，我们还将测试一个耐人寻味的假设，即即使在没有饮食限制或饥饿的情况下，结构性的脂肪消耗也可能足以延长寿命。公共卫生相关性：卡路里限制和间歇性禁食可以延长寿命，改善新陈代谢和神经系统疾病的结局。我们已经发现了一种基因，它对在饮食限制期间保持细胞功能和年轻很重要。我们认为，阐明该基因的功能可能会使药物治疗或饮食干预的发展能够模仿饮食限制的积极影响。

DESCRIPTION (provided by applicant): Dietary restriction can slow reproductive development, extend longevity, and improve the outcome of metabolic and neurological disease. Upon severe dietary restriction, many organisms, including mammals, initiate programs of developmental or reproductive quiescence, or diapause. In these arrested states, animals withstand prolonged starvation, and recover without significant detriment to reproductive output or adult longevity. In preliminary studies, we have found that the C. elegans HNF41 ortholog, NHR-49, is essential for longevity and reproductive protection in the adult reproductive diapause, an intriguing physiological state that has yet to be described in C. elegans. There are a number of features associated with this adult diapause that make it of broad interest, most notably, its impact on reproductive activity, embryonic development, stem cell maintenance, and energy metabolism. Thus, investigation of NHR-49 in C. elegans provides a unique opportunity to define the involvement of nuclear receptors in nutritional diapause. Specifically we will address three aspects of this NHR-49 dependent adult arrest. In Aim 1, we will conduct experiments to understand how germline stem cells are protected during extended periods of starvation, distinguishing between models of germ cell quiescence and self-renewal, and assessing the role of the stem cell niche. In Aim 2, we will test our hypothesis that an NHR-49 dependent stimulation of fat expenditure is essential for starvation dependent extension of lifespan and reproductive longevity. Additionally, we will test the intriguing hypothesis that constitutive induction of fat expenditure may be sufficient to increase longevity, even in the absence of dietary restriction or starvation. PUBLIC HEALTH RELEVANCE: Caloric restriction and intermittent fasting can extend longevity and improve the outcome of metabolic and neurological disease. We have discovered a gene that is important for preserving cellular function and youth during periods of dietary restriction. We propose that elucidating the function of this gene may enable the development of pharmacological treatments or dietary interventions that can mimic the positive effects of dietary restriction.