Activation of SirT1 and NAMPT preserves late‐in‐life fertility of female Nothobranchius guentheri.

Abstract

The decline of female reproductive function is an early phenotype of aging, occurring only midway through the lifespan. Yet, women's ability to delay pregnancy and preserve fertility is an important reproductive freedom. The number of women delaying pregnancy continues to rise in industrialized societies due to personal or socioeconomic circumstances, often resulting in subfertility or difficulty conceiving. There are few defined mechanisms associated with this etiology, and equally few effective therapies. To combat this problem, we used a novel emerging model, Nothobranchius guentheri, with a lifespan of only 9–12 months, that recapitulates the age‐associated spectrum of changes that adversely affect human fertility. We hypothesized that activating SirT1 would maintain female fecundity into late life. SirT1 is an NAD+ dependent histone deacetylase, whose activity is regulated by the nicotinamide to NAD+ salvage pathway, especially the rate‐limiting enzyme NAMPT. In order to increase SirT1 activation via NAMPT, we fed N. guentheri a diet containing the polyphenol resveratrol (RSV) at 300 μg RSV/g food, beginning at sexual maturity. Our previous work showed that RSV‐fed fish at 5 months of age had significantly increased ovarian NAMPT protein levels, and our current data confirms that this result continues into late life (9+ months of age). Furthermore, we found an age‐related decline in NAMPT protein that was overcome by RSV supplementation. For the first time, we show that SirT1 activity, which declines with age, is preserved in the ovaries of our RSV‐fed model. Female N. guentheri fed RSV into late life also showed increased embryo production compared to those on Control diet without RSV. These results suggest that activating SirT1 via increasing NAD+ may have a positive effect on female fertility, and that dietary interventions may become an effective therapy to combat reproductive senescence.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.