Female fertility decline starts around 32 years of age, ending with exhaustion of ovarian follicles around 51 years of age and total loss of fecundity. Although assisted reproductive technology has allowed many subfertile patients to have babies, patients of advanced age suffer from the retrieval of fewer oocytes of lower quality after controlled ovarian hyperstimulation. Therefore, age-associated decline in oocyte quantity and quality represents a major hurdle for female infertility treatment in middle-aged women.
In patients, reduction of oocytes competent for fertilization and further development is due to increases in meiotic nondisjunction in aging oocytes. Likewise, rodent studies demonstrated that aging mice showed lower responses to superovulation induction and increased aneuploidy rates in oocytes. In addition, oocytes from aging mice have higher levels of DNA damage and decreased fertilization rates together with lower embryonic developmental potential. Although detailed molecular mechanisms underlying increased loss of germ cells in aging ovaries and decreased oocyte quality are poorly understood, it has been proposed that ovarian aging is a result of gradual accumulation of tissue damage by reactive oxygen species (ROS). ROS could damage mitochondria DNA (mtDNA) and contribute to mtDNA mutations; impaired mitochondria function could, in turn, promote production of ROS.
Mitochondria are ubiquitously present in the cytoplasm of all eukaryotic cells and generate most of the cellular energy in the form of adenosine triphosphate (ATP), thus playing a key role in cell aging and death. Several studies demonstrated that mitochondrial dysfunctions were closely related to ovarian aging. Moreover, being the largest cell type in the body, mature metaphase II oocytes can contain 100,000 mitochondria and 50,000–1,500,000 copies of the mitochondrial genome. In contrast, the number of mitochondria in mammalian somatic cells ranges from a few hundred to thousands. Indeed, oocytes are highly dependent upon optimal mitochondrial functions for their growth and maturation. The mitochondrial dysfunction was observed in aged oocytes when compared to that of young mice, as demonstrated by the alteration of morphology, decrease of copy numbers, and reduction in metabolic activity, indicating that improvement of mitochondria function in aging oocytes could be a strategy to delay age-associated fertility decline.
NAD+ (nicotinamide adenine dinucleotide), a cofactor of key enzymes in glycolysis, oxidative phosphorylation (Oxphos), and the tricarboxylic acid (TCA) cycle, declines with age in diverse human organs, including liver, kidney, muscle and others. In contrast, NAD+ repletion using precursors such as nicotinamide riboside (NR), reversed NAD+ decline and improved mitochondria functions. However, little is known about aging-associated changes in NAD+ levels within the ovary. Here, we demonstrated age-associated decreases in ovarian NAD+ content and tested whether age-related mitochondria dysfunction and ovarian aging induced infertility could be attenuated by supplementation with NR in aging mice.
As female mammals age, their reproductive performances decline precipitously unlike their male counterparts. Mammalian ovaries have a fixed number of oocytes that gradually deplete during the reproductive lifespan, leading to a progressive reduction in ovarian follicle reserve accompanied by decreased oocyte quality. However, safe and effective strategies are still lacking for reversing age-related ovarian infertility. Here, we found age-dependent decreases in ovarian NAD+ levels.
