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Small Dose of NMN Restores Fertility in Old Mice, Large Dose Does Not – Implications for Dosage Suggestions

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Recently published research shows that a small dose of NMN in the drinking water was able to improve the quality of eggs in older mice and reverse infertility.

Researchers at the Universities of Queensland and New South Wales  led by Dr. Lindsay Wu found that as mice age, levels of nicotinamide adenine dinucleotide (NAD+) decline, which affects the quality of eggs, leading to fertility problems in older female mice.

The research team gave older mice oral doses of the NAD+ precursor compound called nicotinamide mononucleotide (NMN) to increase NAD+ levels.

“Quality eggs are essential for pregnancy success because they provide virtually all the building blocks required by an embryo,” says Professor Hayden Homer, lead researcher on the study. “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.”

“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.”

If the results translate to humans, it could open up a new option for couples looking to improve their chances of conception.

Surprisingly, a daily dose 400% higher had no significant effect on live births.

Important implications for dosage of NAD+ precursors

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Researchers tested two different dosages of NMN in the drinking water of the mice, using either  0.5g/L  or 2 g/L.  After scaling for the size and increased metabolic rate of mice, this equates to approximately 350 mg or 1,400 mg for a 50 kg human.

The mice were 14-16 months old, which is near the limit of fertility in the breed of mice used.

You can see from the charts above that the smaller dose had a dramatic effect on the live births, while the larger dose had no significant effect.

If these results also apply to humans, it would seem that a dose between 350 mg and 1,400 mg per day would be best for fertility in humans.

Why LESS NMN could be better in some casestoo much Nicotinamide?

Many studies implicate there is an upper limit, after which there is no clear benefit to further dose increases.

This particular study implies smaller doses of NMN may be more effective than larger doses.

This could be related to an upper limit to NMN tolerability or the increased formation of the NMN degradation product nicotinamide, which is a sirtuin inhibitor ()

The Rabinowitz research shows that oral delivery of NR and NMN is nearly entirely metabolized to nicotinamide (NAM) in the liver.

The Trammel/Brenner research on nicotinamide riboside (NR) and other studies have shown that taking 1,000 mg of NR in a single dose results in a huge increase of NAM, which the body quickly methylates to MeNAM and excretes from the body.

Why scientists believe excess NAM is harmful

Supplementation with NAM shows some positive benefits in mice and humans, however, there are two reasons scientists believe that
providing excess NAM can be counterproductive:

How to avoid excess NAM for best results

If excess NAM is the reason for the upper limit on effectiveness as suggested by the authors in this current study, it is apparent that supplementing NMN while avoiding overproduction of NAM is critical.

The Rabinowitz research shows that oral supplements of NR and NMN are almost completely metabolized to NAM in the liver.

Taking smaller quantities, or spreading it out among several smaller dosages may help, but better delivery methods are needed.

Sublingual and Lipsomal delivery can bypass the liver and avoid excess NAM

Sublingual
Systemic delivery through the sublingual route has emerged from the desire to provide immediate onset of a pharmacological effect. Sublingual administration means placement under the tongue for immediate uptake into the bloodstream through the ventral surface of the tongue and floor of the mouth. NMN or other actives are rapidly absorbed into the reticulated vein which lies underneath the oral mucosa and transported through the facial veins, internal jugular vein and braciocephalic vein and then drained in to systemic circulation.

The main mechanism for the absorption into oral mucosa is via passive diffusion into the lipoidal membrane. The absorption of NMN through the sublingual route is 3 to 10 times greater than the oral route and is only surpassed by hypodermic injection.

Liposomal
Liposomal delivery may further improve upon bioavailability, as liposomes enclose the active in a “cocoon” to protect it from the harsh environment of the stomach and deliver the payload intact to circulation, resulting in minimal loss. They can also be taken sublingually.

Conclusion

This study found NMN restored fertility in older mice, a promising result which has not been achieved with any drug or surgery.

They found this benefit at a relatively small dosage equivalent to 350 mg per day in a 50 kg human.

Much larger doses – equivalent to 1,400 mg per day – did not show the benefit, suggesting an optimal dose is between 350 mg and 1,500 mg per day for humans.

Supplementing with NAD+ precursors in capsules will result in a large increase in NAM.

Large doses may increase NAM enough to inhibit sirtuin function significantly and outweigh any benefit.

Bypassing the liver with sublingual delivery directly to the bloodstream will greatly minimize the NAM produced.