Research reverses the reproductive clock

Summary: Small doses of a metabolic compound reverses the aging process and could help restore the number of eggs in females.

Source: University of Queensland

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.

This shows an egg
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”.

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Source:
University of Queensland
Media Contacts:
Hayden Homer – University of Queensland
Image Source:
The image is adapted from the University of Queensland news release.

Original Research: Open access
“NAD+ Repletion Rescues Female Fertility during Reproductive Aging”. Hayden Homer et al.
Cell Reports doi:10.1016/j.celrep.2020.01.058.

Abstract

NAD+ Repletion Rescues Female Fertility during Reproductive Aging

Highlights
• Declining NAD(P)H is associated with oocyte dysfunction during reproductive aging
• Oocyte quality and fertility can be restored by NMN treatment in aged mice
• Supplementation of embryo media with NMN improves developmental milestones
• SIRT2 overexpression mimics benefits of NMN but is unlikely to mediate its effects

Summary
Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD+). Treatment with the NAD+ metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD+-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD+ levels represents an opportunity to rescue female reproductive function in mammals.

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