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Shelly Albaum

Editor, Science of NAD

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  • Shelly Albaum

Studies show that NAD can help with fertility and egg quality

Updated: May 9


Woman looking through microscope


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Declining egg quality as women age is an important cause of infertility. Numerous mouse studies show that NAD replenishment can protect oocytes and improve egg quality by supporting mitochondrial function and limiting oxidative damage.

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Oocyte Quality


One of the most important issues in fertility is egg quality. "Oocytes" are immature egg cells held in "follicles," which are fluid-filled containers. Eventually an oocyte will break free from its follicle, travel down a fallopian tube, and potentially get fertilized and develop into an embryo.


But everything depends on the quality of the oocyte. If the oocyte is not properly formed, it will not properly develop into an embryo.


The quality of the oocyte determines the embryonic development potential.

-- Biomedicines, September 4, 2022


Oocyte quality is one of the most important factors in female reproduction.

-- Annals of Translational Medicine, December 2019


And oocyte quality degrades dramatically with age.


The human female reproductive system has a faster rate in aging than any other system of the body....The fact that the increase in maternal age is directly related to chromosomal abnormalities in the fetus confirms that primary oocytes are susceptible to damage as they age...

-- JBRA Assisted Reproduction, January 2022


The number of compromised oocytes will increase with maternal age, while mitochondrial dysfunction has been implicated in age-related poor oocyte.

-- Annals of Translational Medicine, December 2019


At age 30, most of the oocytes will probably be good. At age 40, most of them will probably not be. And once an oocyte's quality has degraded enough, its quality might not be recoverable. So maintaining egg quality is essential for sustaining fertility.


Oxidizing agents have been linked to oocyte damage, so you will find many sources that recommend antioxidants like coenzyme-Q (C0Q) to protect oocytes.


Oxidative stress caused by the accumulation of ROS in cells is among the principal factors that affect oocyte quality, leading to oocyte aging and a decline in fertility

-- Reproductive Biology and Endocrinology, April 21, 2022


But what is it that is getting damaged by the oxidizing agents? Mitochondria in the oocyte. It appears that mitochondrial damage and the failure of DNA repair mechanisms are at the root of the problem of aging oocytes.


Loss of active DNA repair apparatus, bioenergetics status and mitochondrial damage of the oocytes are possibilities for follicle/oocyte aging phenomenon. Other feasible mechanisms...are poorly defined

-- JBRA Assisted Reproduction, January 2022


Several hypotheses implicate that mitochondria are one of the critical indicators in oocyte quality

-- Annals of Translational Medicine, December 2019


...We discuss the underlying mechanisms of age-related decline in oocyte quality, focusing on oxidative stress (OS) in oocytes. The primary cause is the accumulation of spontaneous damage to the mitochondria arising from increased reactive oxygen species (ROS) in oocytes

-- Frontiers in Endocrinology, November 22, 2019


The reduction of mitochondrial activity produced by suboptimal CoQ10 availability plays a key role in age-related oocytes, and its lack causes infertility. Different studies on animal models have shown that injection of mitochondria or cytoplasm from young donor oocytes into an aged oocyte enhances oocyte competence, embryo quality, decreased fragmentation, and finally enabling successful implantation

-- JBRA Assisted Reproduction, January 2022


The adverse effect of aging upon the mitochondria within the oocyte has been widely reported: mitochondrial swelling, vacuolization, and cristae alteration have been described as common structural features of oocytes from advanced material age patients

-- Frontiers in Endocrinology, June 29, 2018


The exact relationship between reactive oxygen species, mitochondrial dysfunction, and degraded oocyte quality is not completely understood, but probably oxidative stress causes mitochondrial dysfunction, or vice versa, and the end result is inadequate cellular energy, which results in poor oocyte quality.


Mitochondrial dysfunction, which is caused by or causes oxidative stress, induces chromosomal non-disjunction, fertilization failure, and decrease in embryo competence. Since a large amount of ATP [cellular energy] is consumed in the process of meiosis completion, fertilization, and embryonic development, it is possible that the decrease in ATP production due to deterioration of mitochondrial function results in a decrease in oocyte quality.

-- Frontiers in Endocrinology, June 29, 2018


The mitochondria play an important role in oocyte maturation because this maturation needs an important level of ATP. Thus, a decrease in ATP and mitochondrial function leads to abnormalities of meiosis

-- Biomedicines, September 4, 2022


Oocytes are actually capable of repairing DNA damage.


...Oocytes are highly capable of functionally efficient DNA repair. These data implicate DNA repair as a key quality control mechanism in the female germ line and a critical determinant of fertility and genetic integrity.

-- Proceedings of the National Academy of Sciences USA, May 7, 2020


But that takes energy, too. So we will want to go beyond merely defending against reactive oxygen species and get to the heart of the problem, which is protecting the mitochondria and providing adequate cellular energy. That's what NAD replenishment does.


So it is smart to hypothesize that supporting mitochondrial health and cellular energy with NAD supplements could simultaneously protect both mitochondrial function and oocyte quality.


The Scientific Evidence for NAD Replenishment and Fertility


But we do not have to hypothesize. Scientists have already tested whether NAD replenishment could protect oocyte quality, and the results are very promising.


A mouse study published in October, 2022, in Reproduction, titled, "Nicotinamide Riboside supplementation ameliorated postovulatory oocyte quality decline" concluded that NR supplementation increased oocyte quality and would potentially improve success rates of assisted reproductive technology.


We and other groups have found that nicotinamide adenine dinucleotide (NAD+), a prominent redox cofactor and enzyme substrate, decreases in both aging ovaries and oocytes. In this study, we found that the NAD+ levels decreased in the postovulatory mouse oocytes during in vitro culture and this decrease was partly prevented by nicotinamide riboside (NR) supplementation. NR treatment not only restored MII oocyte quality but also enhanced early embryonic development potential of postovulatory oocytes via alleviating mitochondrial dysfunction and maintaining normal spindle/chromosome structure. Also, treatment with NR decreased the ROS levels and reduced DNA damage and apoptosis in postovulatory oocytes. Taken together, our findings indicated that NR supplementation increases the oocyte quality and early embryonic development potential in post-ovulatory oocytes which could potentially increase the successful rate in ART.

-- Reproduction, October 1, 2022


That is a very strong finding, but it is not a unique one. Another mouse study also observed that NR protects against post-ovulatory aging by improving the quality of aging oocytes:


We analyzed the association of NR supplementation with the aging-related deterioration of oocyte quality, such as mitochondrial dysfunction...NR supplementation exerted protective effects on morphological defects of oocytes, and that these protective effects were concentration dependent. We detected a significant decline in NAD+ levels in aging oocytes, however, NAD+ accumulation was present in aging oocytes after 200μM NR treatment, indicating that NR administration might be a feasible strategy to enhance the quality of aging oocytes. Furthermore, NR indeed elevated the embryonic development potential of postovulatory aging oocytes after fertilization. Our findings revealed that NR administration effectively ameliorated ROS accumulation

-- Human Reproduction, August 6, 2021


Same with this mouse study: nicotinamide riboside reversed age-dependent decreases in ovarian NAD levels, which increased the number of follicles, reduced reactive oxygen species, decreased spindle anomalies in aging oocytes, and increased live birth rate.


Here, we showed age-dependent decreases in ovarian Nicotinamide Adenine Dinucleotide (NAD+) levels in mice whereas supplementing aging mice with nicotinamide riboside (NR), an NAD+ precursor, increased ovarian NAD+ content. We found that increases in ovarian NAD+ levels in aging mice led to increased number of ovarian follicles and ovulatory potential as well as increased live birth rate. NR supplementation also reduced levels of reactive oxygen species and decreased spindle anomalies in aging oocytes, together with increased mitochondrial membrane potential (ΔΨm) and decreased mitochondrial clustering. In addition, NR supplementation improved ovarian mitochondrial energy metabolism. Our data suggested that supplementation with NAD+ precursors in vivo and in vitro could be potential therapeutic approaches for treating age-related ovarian infertility.

-- Free Radical Biology and Medicine, August 20, 2020


Same again with a different NAD precursor, NMN: replenishing NAD rejuvenated oocyte quality in aged animals, leading to restoration of fertility.


Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility...Although this study used NMN as an NAD+ precursor, alternative precursors from other pathways also raise NAD+, most notably NR. We anticipate that this and similar compounds will also exhibit efficacy in oocyte quality and fertility, and it is unlikely that these effects are unique to NMN.

-- Cell Reports, February 22, 2020

Another mouse study using a different NAD precursor (NAM) showed similar results. Moderate NAM supplementation improved follicle development, reduced oxidative stress, and improved fertilization rate, apparently improving oocyte quality by reducing oxidative stress damage.


The level of NAM in large follicles was significantly higher than that in small follicles. In mature FF, the NAM concentration was positively correlated with the rates of oocyte maturation and fertilization. Five mM NAM treatment during IVM increased maturation rate and fertilization rate in the oxidative stress model, and significantly reduced the increase of ROS levels induced by H2O2 in mice oocytes. Higher levels of NAM in FF are associated with larger follicle development. The supplement of 5 mM NAM during IVM may improve mice oocyte quality, reducing damage caused by oxidative stress...However, we found that an excessive NAM concentration inhibited the maturation and fertilization of oocytes.

-- Reproductive Biology and Endocrinology, April 21, 2022


It is worth noting in this study that although a moderate dose of NAM was helpful, doubling the NAM to a high dose proved counterproductive. That is one of the differences between NAM and Nicotinamide Riboside. High doses of NAM have negative side effects not seen with NR (sometimes called a "biphasic" effect, and it is a reason to prefer NR over NAM).


One more: This mouse study also showed that raising NAD levels improved oocyte quality. The researchers increased NAD levels by intermittent fasting, not an NAD precursor supplement, but the study was clear that it was the increased NAD+ levels that made the difference.


Just one month of every-other-day fasting was sufficient to improve oocyte quality [in mice]...Positive impact of intermittent fasting on aged oocytes was mediated by restoration of the nicotinamide adenine dinucleotide (NAD+)/Sirt1-mediated antioxidant defense system, which eliminated excessive accumulated ROS to suppress DNA damage and apoptosis.

-- Free Radical Biology and Medicine, December 26, 2022


Conclusion


Declining egg quality as women age is an important cause of infertility. Numerous mouse studies show that NAD replenishment can protect oocytes and improve egg quality, probably by supporting mitochondrial function and limiting oxidative damage.


We may have to wait a while for confirming human clinical studies, due to the ethical issues involved with experimenting on human eggs and embryos. However, the rodent studies are both consistent and promising.


Read More: What Is NAD, and Why Does It Matter?

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