NAD⁺repletion rescues female fertility during reproductive ageing

Abstract

2Female infertility is a common and devastating condition with life-long health, emotional and 3 social consequences. There is currently no pharmacological therapy for preserving oocyte 4 quality during aging, which is the strongest risk factor for infertility. This leads to an age 5 dependent decline in natural conception and IVF success rates (1). Here, we show that this is 6 due in part to declining levels of the metabolic cofactor nicotinamide adenine dinucleotide 7 (NAD + ), and that restoring NAD + levels with its metabolic precursor nicotinamide 8 mononucleotide (NMN) rejuvenates oocyte quality and quantity in aged animals, leading to 9 improved fertility. These benefits extend to the developing embryo, where NMN 10 supplementation in embryo culture media following IVF enhances blastocyst formation in 11 older mice. The NAD + dependent deacylase SIRT2 is sufficient, but not essential, to 12 recapitulate the benefits of in vivo NMN treatment, and transgenic overexpression of SIRT2 13 maintains oocyte spindle assembly, accurate chromosome segregation, decreased oxidative 14 stress and overall fertility with ageing. Pharmacological elevation of NAD + may be an 15 effective, non-invasive strategy for restoring and maintaining female fertility during ageing, 16 and for improving the success of IVF.17 18 19 risks (4), is expensive and has a limited success rate. Repeated IVF failures are a substantial 1 source of emotional distress, and failure to conceive offspring is a substantial source of 2 relationship breakdown (5). 4The rate-limiting factors for successful pregnancies in IVF are oocyte quantity and quality, 5 both of which start to decline from the middle of the third decade of life in humans (1, 3). 6 Despite the enormous need, there are no clinically viable strategies to either preserve or 7 rejuvenate oocyte quantity or quality during ageing. There is a major need in reproductive 8 medicine for a non-invasive, pharmacological treatment to maintain or restore oocyte quantity 9 and/or quality during ageing. The effect of such a therapy would be to alleviate a rate-limiting 10 barrier to IVF success, or increase the chances of unaided conception, without having to resort 11 to IVF. 12 13The molecular basis for the decline in oocyte quality with advancing age is not clear but is 14 certainly multifactorial. The key factors thought to be involved include genome instability, 15 reduced mitochondrial bioenergetics, increased reactive oxygen species (ROS), and impaired 16 fidelity during meiotic chromosome segregation due to disrupted spindle assembly and 17 compromised function of the spindle assembly checkpoint (SAC) surveillance system (6). This 18 latter hypothesis is evidenced by an increased rate of aneuploidy in embryos with increased 19

Nicotinamide Mononucleotide Supplementation Reverses the Declining Quality of Maternally Aged Oocytes

“…Interestingly, a recent work reported a similar finding, showing that supplementation of NMN in drinking water for 4 weeks prominently rejuvenated oocyte quality and restored the fertility of aged mice (Bertoldo et al, 2020). They further indicated that Sirt2 overexpression recapitulated the benefits of NMN treatment (Bertoldo et al, 2020). Our data validated that Sirt1 was also implicated in the effects of NMN on aged oocytes.…”

“…In particular, NMN restores mitochondrial function of aged oocytes to suppress accumulation of ROS and DNA damage, reducing apoptosis. Interestingly, a recent work reported a similar finding, showing that supplementation of NMN in drinking water for 4 weeks prominently rejuvenated oocyte quality and restored the fertility of aged mice (Bertoldo et al, 2020). They further indicated that Sirt2 overexpression recapitulated the benefits of NMN treatment (Bertoldo et al, 2020).…”

Supplementing media with NAD⁺ precursors enhances the <i>in vitro</i> maturation of porcine oocytes

“…Oocyte quality and quantity is the rate limiting factor in the production of embryos in vitro [5]. Unlike most cells that undergo constant regeneration from precursor stem cells, the number of oocytes contained within the ovaries is finitely set during prenatal development [6,7] and determines the reproductive lifespan of the female.…”

“…In humans and mice, NAD + deficiency brought about by aberrant expression of de novo synthesis pathway enzymes leads to birth defects [16]. In addition, supplementation of NAD + precursors, including nicotinamide mononucleotide and nicotinic acid, both in vitro and in vivo improved mouse oocyte quality and embryo development [5,17,18]. Furthermore, Sirtuins (SIRTs) and poly-ADP-ribose polymerases (PARPs) consume NAD + , and are known to play essential roles during oocyte maturation [19,20].…”

Bridge Integrator 2, a New Specific Target for Improving Reproductive Life Span through RPS6 and NNT

“…BAT transplantation could also improve oocyte quality of aging mice (28). However, the upper and most of other anti-oxidants, and BAT transplantation could not increase PFR, and non-enzymatic anti-oxidants are less efficient than enzymatic ROS detoxifiers such as SOD (superoxide dismutase) and Gpx (glutathione peroxidase) (23,25,26). It has been reported that supplement of melatonin (29), quercetin (30), or resveratrol (31) could improve both PFR and oocyte quality by reducing ROS and apoptosis.…”