Increasing maternal age and subsequent infertility have rapidly become a significant challenge to family planning, as a result of the irreversible decline in female fertility in mammals. The rate-limiting factor for successful pregnancy is oocyte quality, which significantly declines from late in the third decade of life in humans.
Despite the enormous demand, there are no clinically viable strategies to either preserve or rejuvenate oocyte quality during aging, which is defined by the capacity of the oocyte to support meiotic maturation, fertilization, and subsequent embryonic development. A non-invasive, pharmacological treatment to maintain or restore oocyte quality during aging would alleviate a rate-limiting barrier to pregnancy with increasing age that has driven demand for assisted reproduction technologies (ARTs) such as in vitro fertilization (IVF).
Although somatic tissues undergo continual regeneration through turnover by a self-renewing population of resident precursor stem cells, oocytes in the ovary are laid down during in utero development in humans, where they form a finite pool that does not undergo self-renewal. Oocytes are therefore highly susceptible to age-related dysfunction.
The molecular basis for the decline in oocyte quality with advancing age implicates genome instability, reduced mitochondrial bioenergetics, increased reactive oxygen species (ROS), and disturbances during meiotic chromosome segregation due to compromised function of the spindle assembly checkpoint (SAC) surveillance system. The molecular cause of chromosome mis-segregation in oocytes with advancing age is still unknown, and as a result, there are no pharmacological strategies to correct this problem. Understanding the molecular or metabolic basis of this defect could lead to therapies that could maintain or even rescue female fertility with advancing age.
The metabolite nicotinamide adenine dinucleotide (NAD+/NADH) is a prominent redox cofactor and enzyme substrate that is essential to energy metabolism, DNA repair, and epigenetic homeostasis. Levels of this essential cofactor decline with age in somatic tissues, and reversing this decline through treatment with metabolic precursors for NAD+ has gained attention as a treatment for maintaining late-life health.
A team of scientists at the University of Queensland reports sought to determine whether NAD+ declined in oocytes with age, contributing to infertility and declining oocyte quality, and whether this could be reversed through treatment with the NAD+ precursor nicotinamide mononucleotide (NMN).
To address these questions, they used mice, whose fertility starts to decline around 8 months of age due to oocyte defects that are similar to those in humans. Twelve-month-old females were treated with NMN in drinking water (2 g/L) for 4 weeks, following which mature metaphase-II (MII) oocytes were recovered and subjected to multispectral microscopy imaging of autofluorescence to determine the relative abundances of native fluorophores. Consistent with their hypothesis, they found that NAD(P)H levels declined in oocytes from aged animals, compared with young (4- to 5-week-old) animals, and NMN treatment increased NAD(P)H levels in oocytes from aged animals, restores oocyte quality and enhances ovulation rate and fertility. Furthermore, supplementation of NMN in embryo culture media reversed the adverse effects of age on development.
The present study supports the premise that age-related reductions in NAD+ availability are a determinant of declining oocyte quality and female infertility and that pharmacological restoration of NAD+ opens a therapeutic window for the treatment of age-related infertility.
Several questions remain, including how NMN treatment would restore oocyte quality in aged animals. One well-known consequence of poor oocyte quality with advancing age is chromosome segregation defects, which overwhelmingly affect the first meiotic division (MI). Indeed, 80%–90% of age-related embryonic aneuploidy is the consequence of female MI errors. Out of caution, we suggest that these supplements should not be taken by women wishing to become pregnant until further studies have been completed.
Having demonstrated that in vivo NMN treatment in aged animals improved oocyte quality and increased ovulation rate and birth rates, they next showed that supplementing embryo culture media with NMN improved embryo development in embryos derived from oocytes from aged animals, but not young animals, supporting the idea that this intervention addresses an age-related deficit in oocyte NAD+ levels.
This finding is highly relevant to the clinical practice of IVF. In addition to age-related issues of decreased oocyte numbers and oocyte quality, mitotic aneuploidy and poor preimplantation embryo development limit the number of euploid blastocysts available for transfer with increasing maternal age. The increasing preference for blastocyst-stage transfers in clinical IVF underscores the importance of reaching more advanced developmental milestones and clinical demand for interventions that can improve embryo development.
This work represents a clinically tractable pharmacological intervention to non-invasively treat female infertility caused by a loss of oocyte viability in reproductively aged females, with important clinical implications. They envisage this work could lead to the development of orally delivered therapeutics that enhance oocyte quality for natural conception or IVF. Moreover, this work could enhance the success rates of existing IVF protocols by improving embryo culture conditions and developmental outcomes.
Any intervention that improves fertility would lead to cost savings and lower the emotional stress of failed IVF rounds or infertility that can lead to long term psychological and social issues, including depression and relationship breakdown.
This could represent an intervention that enables women with poor oocyte quality to have children with their own genetic makeup, because currently, these women have no alternative but to use donated oocytes. While promising, they caution against the use of NAD+-raising supplements until these clinical studies have been completed.
Do you think this new discovery could be a revolution for IVF industry and woman fertility?
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