Researchers have lifted fertility rates in older female mice with small doses of a metabolic compound that reverses the aging process in eggs, offering hope for some women struggling to conceive.
The University of Queensland study found a non-invasive treatment could maintain or restore the quality and number of eggs and alleviate the biggest barrier to pregnancy for older women.
A team led by UQ’s Professor Hayden Homer found the loss of egg quality through aging was due to lower levels of a particular molecule in cells critical for generating energy.
“Quality eggs are essential for pregnancy success because they provide virtually all the building blocks required by an embryo,” Professor Homer said.
“We investigated whether the reproductive aging process could be reversed by an oral dose of a ‘precursor’ compound – used by cells to create the molecule.”
The molecule in question is known as NAD (nicotinamide adenine dinucleotide) and the ‘precursor’ as NMN (nicotinamide mononucleotide).
Professor Homer said fertility in mice starts to decline from around one year of age due to defects in egg quality similar to changes observed in human eggs from older women.
“We treated the mice with low doses of NMN in their drinking water over four weeks, and we were able to dramatically restore egg quality and increase live births during a breeding trial,” Professor Homer said.
The molecule in question is known as NAD (nicotinamide adenine dinucleotide) and the ‘precursor’ as NMN (nicotinamide mononucleotide). Image is adapted from the University of Queensland news release.
Professor Homer said poor egg quality had become the single biggest challenge facing human fertility in developed countries.
“This is an increasing issue as more women are embarking on pregnancy later in life, and one in four Australian women who undergo IVF treatment are aged 40 or older,” he said.
“IVF cannot improve egg quality, so the only alternative for older women at present is to use eggs donated by younger women.
“Our findings suggest there is an opportunity to restore egg quality and in turn female reproductive function using oral administration of NAD-boosting agents – which would be far less invasive than IVF.
It is important to stress, however, that although promising, the potential benefits of these agents remains to be tested in clinical trials”.
Mammalian oocytes undergo a protracted and discontinuous developmental programme that begins during fetal life and is not completed until postnatal adulthood (Gosden & Lee, 2010).
The majority of this time is spent in a prophase I‐arrested state with an intact nucleus, termed the germinal vesicle (GV) in oocytes (Adhikari & Liu, 2014; Solc, Schultz, & Motlik, 2010). Following an extended growth phase, GV oocytes acquire the competence to resume meiosis I marked by GV breakdown (GVBD).
After chromosome separation, oocytes extrude first polar body (Pb1) and are arrested at metaphase II (MII) stage awaiting for fertilization (Moor, Dai, Lee, & Fulka, 1998). Oocyte maturation is affected by a vast number of intra‐ and extra‐ovarian factors. In most mammals, oocyte quality declines with increase in maternal age (Yamamoto et al., 2010).
Despite various molecules have been suggested to contribute to this process, the underlying mechanisms remain to be discovered.
Nicotinamide adenine dinucleotide (NAD+) is a cofactor of key enzymes in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation, participating in multiple redox reactions in cells (Camacho‐Pereira et al., 2016).
Recently, the importance of NAD+has expanded from a key element in intermediate metabolism to a critical regulator of multiple cell signaling pathways and now plays a major role in aging and age‐related diseases (Bonkowski & Sinclair, 2016). Sirtuins (SIRT1–7) are a family of NAD+‐dependent deacetylases with remarkable abilities to prevent diseases and even reverse aspects of aging (Bonkowski & Sinclair, 2016).
For example, Sirt1 deficient mice showed a reduced lifespan, small size, and an increased frequency of abnormal sperm (Coussens, Maresh, Yanagimachi, Maeda, & Allsopp, 2008).
In addition, sirtuins have been shown to be able to impact oocyte quality by regulating the redox state (Di Emidio et al., 2014; Kawamura et al., 2010; Liu et al., 2012; Ma, Zhang, Zhang, Han, & Rui, 2015).
Loss of NAD+ has direct and indirect consequences on multiple cellular endpoints. In particular, depletion of intracellular NAD+ alters the NAD+/SIRT1 axis and leads to defects in mitochondrial homeostasis, reactive oxygen species (ROS) production, DNA repair, as well as cell survival (Croteau, Fang, Nilsen, & Bohr, 2017).
However, to date, it remains to be determined whether NAD+ generation involves in oocyte aging process. In the present study, we discovered that NAD+insufficiency, due to the reduced NMNAT2 expression, induces the metabolic dysfunction and meiotic defects in aged mouse oocytes.
University of Queensland