Raising NAD+ Levels May Support Mitochondrial Health and Fertility in Aging
Increasing cellular nicotinamide adenine dinucleotide (NAD+) levels have been shown to restore metrics of fertility, such as oocyte (immature egg) count and health, among aging mice.
The Cycle of Life: Fertility and Aging
Aging is widely associated with declines in various biological systems, with one of the earliest being the female reproductive system [1]. With maternal age, both the quantity and quality of oocytes decrease, leading to increased risk for infertility or genetic diseases in newborns [2].
One potential culprit at the root of this decline is the mitochondria, known as “the powerhouse of the cell” because it provides the energy needed to support the growth and development of oocytes. Aging oocytes have significantly fewer mitochondria, and increasing their mitochondrial function has been suggested to mitigate age-related ovarian decline [3-5]. Aging is also associated with the loss of the cellular energy molecule NAD+, which has been hypothesized to be at the root of many age-related functional declines across various organ systems.
Of Mice and Mothers
Two studies in mice have now demonstrated that increasing levels of NAD+, and thereby promoting mitochondrial function, helped restore fertility in aging ovaries [6, 7].
In one study published in Cell, the NAD+ precursor nicotinamide mononucleotide (NMN) rejuvenated the quality of the mouse oocytes. NMN was also shown to reverse the adverse effects of maternal aging [6].
In humans, advanced maternal age is known to increase the risk of nondisjunction disorders like Down Syndrome, likely due to misalignment of chromosomes in aged eggs (female eggs are all formed during fetal life and remain dormant until ovulation) [7]. However, in the study, raising NAD+ levels was shown to normalize chromosomal alignment, leading to fewer errors. This, in turn, improved the egg count of the aged mice, as well as their fertility [6].
In another recent study, published in Free Radical Biology and Medicine, oral supplementation with the NAD+ booster nicotinamide riboside (NR) increased ovarian NAD+ levels and delayed age-related ovarian aging and infertility, as well as mitochondrial dysfunction in mice. NR supplementation also led to a 2-fold increase in ATP levels demonstrating an increase in ovarian energy production and a nearly 4-fold increase in ovarian follicles. Furthermore, NR supplementation increased live birth rate among aged mothers. This was likely due to the demonstrated improvement in mitochondrial function that came as a result of replenishing cellular NAD+ levels. These oocytes also had less metabolic damage and fewer chromosomal abnormalities due to improved mitochondrial function [8].
While both NMN and NR were shown to raise NAD+ levels and improve fertility in preclinical models, unlike NR, NMN has yet to demonstrate increases in NAD+ levels in humans when supplemented orally. Additionally, NMN is a New Dietary Ingredient (NDI) that has not been properly notified to the US FDA (a step required for new ingredients used in supplements after October, 1994).
Further testing is required to investigate whether the fertility-promoting effects of NAD+ can be replicated in humans. Nevertheless, with this most recent study confirming an age-related decline in ovarian NAD+ levels, further investigation of NAD+ supplementation in support of fertility is both an attractive and exciting opportunity.