Starvation Mediated Longevity in C. elegans Adults

描述（由申请人提供）：饮食限制可以减缓生殖发育，延长寿命，并改善代谢和神经系统疾病的结局。在严重的饮食限制下，许多生物体，包括哺乳动物，开始发育或生殖静止或滞育的程序。在这些停滞状态下，动物可以承受长时间的饥饿，并在不显著损害生殖输出或成年寿命的情况下恢复。初步研究发现，C.线虫HNF-41的直系同源物NHR-49是成虫生殖滞育中长寿和生殖保护所必需的，这是一种有趣的生理状态，尚未在C.优雅有许多与这种成虫滞育相关的特征，使其引起广泛的兴趣，最值得注意的是，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，NHR-49在C.线虫提供了一个独特的机会，以确定参与营养滞育的核受体。具体来说，我们将解决这个NHR-49依赖成人逮捕的三个方面。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型，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依赖性刺激脂肪消耗对于饥饿依赖性寿命延长和生殖寿命是必不可少的。此外，我们将测试一个有趣的假设，即脂肪消耗的组成性诱导可能足以增加寿命，即使在没有饮食限制或饥饿的情况下。公共卫生相关性：热量限制和间歇性禁食可以延长寿命，改善代谢和神经系统疾病的结果。我们发现了一种基因，它对于在饮食限制期间保持细胞功能和青春非常重要。我们建议，阐明该基因的功能可能使药物治疗或饮食干预，可以模仿饮食限制的积极影响的发展。

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.