Collaborative Research: Hyaluronan, NRF2 and Protracted Female Fertility in Long-lived Naked Mole-Rats

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Naked mole-rats are the longest-living rodents, with a maximum lifespan of 35 years, and females of this species show no decline in fertility as they age. Some degree of reproductive aging is typical of other mammals, with the naked mole-rat being a notable exception to this rule. The principal objective of this project is to determine if the molecule that is thought to provide naked mole-rats with nearly complete resistance to cancer also contributes to the long reproductive lifespan of females. The molecule is known as very high molecular weight hyaluronan, and the naked mole-rat form can be produced by transgenic mice. Mice that express the gene responsible for the synthesis of very high molecular weight hyaluronan have been shown to live a longer and healthier life than mice lacking this naked mole-rat gene, and the hypothesis to be tested is that female reproductive aging will be reduced in these specialized mice. If the naked mole-rat form of hyaluronan maintains female fertility in mice, then these results could be applicable to species that are of conservational and agricultural importance, as well as preserving fertility in women as they age. This project will provide hands-on research opportunities to trainees ranging in experience from high school students to postdoctoral associates. It will also provide zoos and animal parks that maintain naked mole-rat colonies with educational materials to add to their informational displays about the remarkable reproductive biology of this species.The main focus of this proposal is to discover the physiological mechanisms that underlie the remarkably long reproductive lifespan of female naked mole-rats, which show no aging-associated declines in fertility or fecundity into their third decade of life. Two of the physiological mechanisms that contribute to the naked mole-rat’s remarkable longevity and healthspan will be investigated for their impacts on ovarian structure, function and fertility as females age. These include the very high molecular weight form of hyaluronan and enhanced cytoprotective signaling by nuclear regulatory factor erythroid 2 (NRF2). Through interrogations of ovaries from naked mole-rats themselves, and from transgenic mice that express naked mole-rat hyaluronan synthase 2, this project will determine whether female reproductive aging is attenuated by very high molecular weight hyaluronan and/or enhanced NRF2 signaling. This would manifest as reduced ovarian inflammation, fibrosis and stiffness, more ovarian follicle numbers with better quality oocytes, and improved fertility in older females. The project will advance scientific knowledge about the roles that inflammation and fibrosis play in the process of ovarian aging and elucidate how long-lived mammals can maintain the size and quality of their ovarian reserves to support protracted fertility. The broader impacts include providing hands-on research experiences for trainees, including high school students enrolled in the Ithaca Youth Bureau’s College Discovery Program, establishing a Naked Mole-Rat Investigator Network (listserv), and helping North American zoos to expand their educational repertoires to include exciting information about naked mole-rat reproductive biology in order to increase public scientific literacy about these amazing animals.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.