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.
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.
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