CD38 in Ovarian Aging
The ovaries, like the thymus, are interesting for their comparatively early exhibition of age-related degeneration. Is there anything useful that can be learned about aging more generally by looking at the portions of the body that experience aging more rapidly? That remains to be seen. Here, researchers investigate NAD+ metabolism in the ovaries versus other tissues, noting that CD38, an enzyme that removes NAD+, is more active earlier in life. Approaches to maintain NAD+ levels slow ovarian aging, including knocking out CD38.
Delayed childbearing is prevalent worldwide, and ovarian senescence occurs earlier than most of the other organs in females. Ovarian function decreased dramatically in middle age, as shown by a decrease in oocyte quality and ovarian reserve. We hypothesized that middle-aged mice may be useful for investigating the molecular mechanisms underlying ovarian senescence. Our study showed the transcriptome changes that occur in the ovaries of middle-aged mice when many other organs showed no aging-related gene changes. In particular, gene transcripts in aging-related pathways, including the senescence-associated secretory phenotype (SASP), cell cycle, inflammation, and DNA repair, were misregulated in the ovary but not in multiple other organs when comparing middle-aged with young mice. Indeed, increased expression of aging markers, namely, p16 and p21, and inflammation-related factors was observed in the ovary but not in other organs from middle-aged mice. Our findings are consistent with a report classifying the aging-associated alterations in gene expression patterns of different tissues into four stages with ovarian aging occurring in 6-month-old to 12-month-old mice, which is earlier than for most of the other organs.
Importantly, the current study showed that the expression of inflammation-related genes rapidly increased in the middle-aged ovary, accompanied by activation of the NAD+ metabolizing enzyme CD38, whereas other key enzymes for NAD+ generation and metabolism were not changed in the ovaries from middle-aged mice. The activation of CD38 and inflammation-related transcripts was not observed in other organs. A previous study showed that CD38 levels increased in the liver, adipose tissue, spleen, and skeletal muscle in aged (approximately 18-month-old) mice, indicating that the increases in CD38 expression during middle age are likely a key event during ovarian senescence. We and several groups have reported that ovarian NAD+ levels decline during aging, whereas boosting NAD+ by supplementation with NAD+ precursors, such as nicotinamide riboside or nicotinamide mononucleotide, increased ovarian NAD+ levels and delayed ovarian aging by improving mitochondrial function. The present work found that deletion of CD38 prevented ovarian NAD+ decline, extended ovarian lifespan and resulted in increased litter sizes in aged mice. Importantly, increased ovarian follicle reserve was found in aged Cd38-/- mice compared with wild-type mice. Consistent with these findings, higher levels of serum anti-Mullerian hormone and decreased cell DNA damage and apoptosis were observed in the ovarian follicles of Cd38-/- mice than in those of age-matched wild-type mice.