Is NAD+ a key factor in ovarian aging and dysfunction? Insights and uncertainties from current research†

Recent findings highlight NAD+ as a central regulator of various cellular processes, including energy metabolism, stress response, and aging. Growing evidence of the benefits associated with dietary NAD+ precursors has elevated NAD+ to a promising therapeutic target for addressing female infertility. This review aims to evaluate existing literature on the mechanisms governing the availability and utilization of NAD+ in the ovaries and its alterations in female reproductive disorders, with a particular focus on ovarian aging and dysfunction including polycystic ovary syndrome and premature ovarian insufficiency. Alongside data from in vivo and in vitro studies on various NAD+ boosters, this review incorporates findings from research on genetic mutations, polymorphisms in human and animal populations, and insights from transgenic animal models. The present work emphasizes that NAD+ deficiency is largely driven by a combination of factors, including heightened consumption, impaired utilization efficiency, and diminished biosynthesis or transport. Based on this analysis, we suggest that the ovary possesses its own unique NAD+ metabolism, but our understanding of its regulatory mechanisms is still in its infancy. Key questions remain unanswered, such as how NAD+ and its precursors are transported into oocytes and ovarian cells, their specific preferences for different NAD+ precursors, as well as the specific changes associated with different ovarian dysfunctions. Finally, we reviewed methods for studying NAD+ metabolism as essential tools for investigating the potential of NAD+ boosting therapies to counteract ovarian aging and dysfunction.