NAD⁺ and reproductive ageingthe coenzyme the ageing ovary runs low on

01What NAD⁺ is

Nicotinamide adenine dinucleotide is the cell's hydrogen carrier for its redox enzymes, and more recently a signalling molecule too: through the enzymes that sense it, NAD⁺ controls hundreds of processes from energy metabolism to cell survival, rising and falling with food intake, exercise and the time of day (Rajman et al., Cell Metab 2018, PMID 29514064). Beyond redox chemistry it is an essential cofactor for sirtuins, CD38 and the poly(ADP-ribose) polymerases, and through them it reaches metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune-cell function (Covarrubias et al. 2021, PMID 33353981).

02It falls with age

NAD⁺ levels decline during ageing, and changes in NAD⁺ handling appear in nearly every age-related disease (Katsyuba et al., Nat Metab 2020, PMID 32694684). The decline has been measured in tissues and cells of many model organisms, rodents and humans included (Covarrubias et al. 2021, PMID 33353981), and restoring NAD⁺ in old or diseased animals has promoted health and extended lifespan (Rajman et al. 2018, PMID 29514064).

03The ageing ovary

As female mammals age, egg quality is the factor that limits fertility. In 2020 Bertoldo and colleagues showed in mice that the loss of egg quality with age goes hand in hand with falling NAD⁺ — and that it can be turned back (Bertoldo et al., Cell Rep 2020, PMID 32049001):

1. The declineEgg quality fell with age, and NAD⁺ fell with it.
2. The repletionAged mice given the NAD⁺ precursor nicotinamide mononucleotide (NMN) recovered egg quality, and their fertility was restored.
3. The enzymeRaising SIRT2, an NAD⁺-dependent deacylase, reproduced the benefit; deleting SIRT2 did not impair egg quality.
4. The next generationThe benefit carried into the embryo: NMN reversed the effect of maternal age on its developmental milestones.

The authors' conclusion: restoring NAD⁺ late in life is an opportunity to rescue female reproductive function in mammals (PMID 32049001).

04Where NAD⁺ meets kisspeptin

The two halves of KissNAD+ share a meeting point in the hypothalamus. SIRT1 is a deacetylase that runs on NAD⁺ and works as a cellular energy sensor (Choi et al., Endocrinology 2019, PMID 31127273). In the arcuate nucleus, kisspeptin neurons drive the GnRH neurons and are wired into the circuits that govern feeding, and SIRT1 has been reviewed as a regulator of that arcuate control of puberty and metabolism (Aylwin and Lomniczi, Curr Opin Endocr Metab Res 2020, PMID 32905232).

In mice whose astrocytes expressed a deacetylase-deficient SIRT1, oestrous cycles were disturbed, LH surges fell, fewer corpora lutea formed and hypothalamic Kiss1 expression was reduced — while the GnRH neurons still answered kisspeptin itself (Choi et al. 2019, PMID 31127273). The kisspeptin-10 science →

05The open frontier

The ovary study was done in mice, with the precursor NMN, in females. Whether restoring NAD⁺ brings the same benefits to ageing humans is the question the field is now working on (Covarrubias et al. 2021, PMID 33353981), and the links between SIRT1 and the kisspeptin system come from rodents and a review of them. That is the frontier, and it is where the questions worth asking now sit.

06NAD⁺ in KissNAD+

KissNAD+ carries NAD⁺ 200 mg in each single-shot Lyoprester SS, beside kisspeptin-10 200 mcg, kept dry under vacuum and argon until the moment of use. The Lyoprester is the only dual-chamber cartridge that is autoreconstitution-enabled, vacuum-sealed and argon-filled, which makes KissNAD+ the best-protected way to hold NAD⁺ and kisspeptin-10 until the second they are used. For NAD⁺ on its own in the same cartridge, see PruNAD+, NAD⁺ 200 mg in the Lyoprester SS; for the chemistry of carrying a charged, labile coenzyme, see PolyGluNAD, the NAD⁺ delivery problem.

Trending in the field

References

1. Rajman L, Chwalek K, Sinclair DA. Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metab 2018;27(3):529-547. PMID 29514064
2. Katsyuba E, Romani M, Hofer D, Auwerx J. NAD+ homeostasis in health and disease. Nat Metab 2020;2(1):9-31. PMID 32694684
3. Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol 2021;22(2):119-141. PMID 33353981
4. Bertoldo MJ, et al. NAD+ Repletion Rescues Female Fertility during Reproductive Aging. Cell Rep 2020;30(6):1670-1681.e7. PMID 32049001
5. Choi I, Rickert E, Fernandez M, Webster NJG. SIRT1 in Astrocytes Regulates Glucose Metabolism and Reproductive Function. Endocrinology 2019;160(6):1547-1560. PMID 31127273
6. Aylwin CF, Lomniczi A. Sirtuin (SIRT)-1: At the crossroads of puberty and metabolism. Curr Opin Endocr Metab Res 2020;14:65-72. PMID 32905232
7. Nicotinamide adenine dinucleotide, PubChem CID 5892.