Nicotinamide Mononucleotide Supplementation Restores Lost Fertility in Aged Female Mice

Studies of the various approaches to raising NAD+ levels in aged mitochondria are a good illustration of the importance of the loss of mitochondrial function in degenerative aging. Researchers have studied this effect in numerous tissues and organs, with most such work examining muscle or the brain, both energy-hungry tissues and thus more dependent on their mitochondria for normal function. Today's open access paper is a study of mitochondrial function in a tissue that is less well studied in this context. The authors reporting that supplementation with nicotinamide mononucleotide (NMN) can restore lost fertility in old mice by improving mitochondrial function in oocytes.

Mitochondria are the power plants of the cell, responsible for packaging the chemical energy store molecule ATP that is used to power cellular operations. For reasons that remain poorly understood, meaning that they are not well connected to the underlying molecular damage of aging, mitochondria become dysfunctional throughout the body with advancing age. Mitochondria are the descendants of ancient symbiotic bacteria, and they normally divide and fuse like bacteria, as well as passing component parts of their molecular machinery from one to another. In cells in old tissues, these dynamics change in ways that make mitochondria resistant to the quality control processes responsible for clearing out damaged structures in the cell. Cells become populated by problematic, poorly functioning mitochondria, and suffer accordingly.

A reduced amount of NAD+, a utility molecule important to a number of processes in mitochondria, is one proximate cause of these issues. The pace of synthesis and recycling of NAD+ falls off due to lowered levels of precursors and other necessary ingredients for the chemical reactions involved. This might be traced back to altered levels of gene expression due to epigenetic changes characteristic of aging, but this is still an exploration of proximate causes, and says little about what the underlying root causes might be in any detail.

To the extent that providing more NAD+ to cells restores mitochondrial function and thus cellular function to some degree, and this outcome is well demonstrated in mice, these benefits may be largely the result of enabling sufficient clearance of worn mitochondria to improve overall ATP production. This is better maintenance rather than better function per se; other lines of research also suggest that quality control is the critical item in mitochondrial function. When it comes to the means of raising NAD+ levels, delivery of NAD+ itself is not very efficient, and most current approaches are thus focused on delivering precursor molecules used in the synthesis or recycling of NAD+. Of these only nicotinamide riboside has even early clinical data to show some form of benefit in aged humans, but that will likely change over the next few years as more groups publish their work.

NAD+ Repletion Rescues Female Fertility during Reproductive Aging

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), which is invasive, carries health risks, is expensive, and has a limited success rate.

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. Here, we show that loss of oocyte quality with age accompanies declining levels of 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.