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 HNF4? 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079273-04
Application #
8288890
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Margolis, Ronald N
Project Start
2009-07-15
Project End
2012-10-31
Budget Start
2012-05-01
Budget End
2012-10-31
Support Year
4
Fiscal Year
2012
Total Cost
$109,755
Indirect Cost
$47,394
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Pathare, Pranali P; Lin, Alex; Bornfeldt, Karin E et al. (2012) Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships. PLoS Genet 8:e1002645
Angelo, Giana; Van Gilst, Marc R (2009) Starvation protects germline stem cells and extends reproductive longevity in C. elegans. Science 326:954-8