Research Project
10490498
Female reproductive aging is characterized by progressive, degenerative changes that result in birth defects and infertility. No drugs that delay age-related degeneration of reproduction are available, and it is a high priority to develop new therapeutic approaches. The long-term objective of this proposal is to characterize endogenous pathways that influence reproductive aging and identify drugs that delay age-related degeneration. To characterize reproductive aging, we performed detailed analyses of age-related changes in the C. elegans gonad, and we screened FDA-approved compounds and mutant strains for the ability to delay reproductive aging. Based on our results, we propose two innovative hypotheses. (1) Rapid, population-wide declines of germline stem cell number and slowing of the cell cycle contribute to reproductive aging. (2) An age-related decline in the GLP-1/Notch signaling pathway contributes to the decline in stem cell number and contributes to reproductive aging. To test these hypotheses, we propose three specific aims. Aim 1: Determine the role of the GLP-1/Notch signaling pathway during reproductive aging. The GLP-1/Notch pathway effectors SYGL-1 and LST-1 display age-related decreases in their expression domains, and overexpression of SYGL-1 was sufficient to delay reproductive aging. To determine if age-related changes in this pathway are regulated at the level of the ligand expression, we will characterize the expression and function of the LAG-2 ligand. To analyze the receptor and response pathway, we will characterize the function of GLP-1, SYGL-1, and LST-1 in the control of reproductive aging. These results will test the hypothesis that age-related withdrawal of GLP-1/Notch signaling is a key control point for reproductive aging. Aim 2: Elucidate the mechanism of delayed reproductive aging caused by mutations of daf-2, eat-2, phm-2, and sma-2. These mutations reduce early progeny production and increase late progeny production. To characterize the mechanism, we will use state-of-the-art assays to evaluate age-related changes in the morphology and function of the distal germline. The results will elucidate the mechanism of action of these genes and the functional significance of age-related changes in the germline. Aim 3: Characterize the role of sensory perception in reproductive aging by analyzing ethosuximide and che-3. Ethosuximide treatment and a che-3 mutation influence sensory perception, and they increase mid-life progeny production without decreasing early progeny production. To characterize the mechanism of action, we will evaluate age-related changes in the morphology and function of the distal germ line and the GLP-1/Notch signaling pathway. The results will establish the connection between neuronal activity and reproductive aging. By combining molecular and genetic approaches, these studies will elucidate the role of adult stem cells during aging and address important gaps in the current understanding of reproductive aging. Significantly, these studies will establish new therapeutic strategies for addressing age-related infertility in humans.
