NMNSmall dose of NMN restores fertility in old mice, large dose does not – implications for dosage suggestions

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ALIVEBYNATURE
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Small dose of NMN restores fertility in old mice, large dose does not – implications for dosage suggestions

Post by ALIVEBYNATURE » Sat Feb 15, 2020 5:38 pm

I just posted an article on the website:

Small dose of NMN restores fertility in old mice, large dose does not – implications for dosage suggestions

They found that giving old mice a small dose of NMN in drinking water improved the quality of eggs and greatly improved fertility.

A 4x larger dose did not have a significant effect on live births.

The authors believe the reason a larger dose is less effective may be due to excess NAM, which inhibits sirtuins.

If true, that may explain why research with oral supplements never come close to showing the effectiveness of IV.

Dumping more and more NMN or NR into the liver may increase NMN/NR somewhat, but results in more and more NAM and sirtuin inhibition. So its not just diminishing returns, but worsening.

So sublingual delivery might not just be more cost effective, but provide results that are unachievable with capsules no matter how much you take.




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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 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

Researchers tested 2 different dosages of NMN in the drinking water of the mice, using either .5g/l or 2 g/l. After scaling for the size and increased metabolic rate of mice, this equates to approximately 500 mg or 2,000 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 500 Mg and 2,000 Mg a day would be best for fertility in humans.

WHY LESS NMM could be better in some cases - too 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.

The researchers suggest this could be related to the increased formation of the NMN degradation product Nicotinamide, which
is a sirtuin inhibitor.

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 (Bitterman et al., 2002)

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:

Depletes Methyl groups. Excess NAM is methylated to MeNAM for excretion in urine. This can deplete methyl groups which results in increased homocysteine in the bloodstream. Some research indicates that long term or high doses of NAM are detrimental, because they lead to reductions in available methyl groups.
Inhibits sirtuins. NAM has been shown in research to inhibit sirtuins. Increasing NAD+ levels activate sirtuins, which is thought to be the pathway that provides the positive benefits.
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 NR or 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 smalller 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 blood stream 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 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 500 Mg per day in a 50 kg human.

Much larger doses – equivalent to 2,000 mg per day – did not show the benefit, suggesting an optimal dose is between 500 mg and 2,000 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 derived.

Bypassing the liver with Sublingual delivery direct to the bloodstream will greatly minimize the NAM produced.


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jocko6889
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Re: Small dose of NMN restores fertility in old mice, large dose does not – implications for dosage suggestions

Post by jocko6889 » Sun Feb 16, 2020 1:46 am

First I've heard that excessive NMN can inhibit sirtuins through increased NAM. I wonder if the increased bioavailability of liposomal NMN would mean we should use smaller doses?
Fred
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Re: Small dose of NMN restores fertility in old mice, large dose does not – implications for dosage suggestions

Post by Fred » Sun Feb 16, 2020 2:30 am

jocko6889 wrote:
Sun Feb 16, 2020 1:46 am
First I've heard that excessive NMN can inhibit sirtuins through increased NAM. I wonder if the increased bioavailability of liposomal NMN would mean we should use smaller doses?
But we don't even know the bioavailability of regular NMN, right?

There are no human data published on pharmacokinetics or bioavailability as of this writing. The only human NMN study published failed to measure any NMN in the blood, some technical problems the authors speculate:

"The subjects orally received 100, 250, or 500 mg of NMN in capsules at 9 AM after an overnight fasting at each visit and followed for 5 h at rest with drinking only water freely."

"Unfortunately, we failed to detect NMN in plasma samples in this study, most likely because freezing plasma samples before extraction might have caused the degradation of NMN.

The procedure of blood sampling could have also contributed to the failure of the detection of NMN, because the recent reports showed that NMN was degraded very rapidly in blood that was handled above 80°C"

https://www.jstage.jst.go.jp/article/en ... f/-char/en

It seems prudent to wait for that data before recommending dosage. But I understand that a company needs to give dosage suggestions for their products of course.

The metabolic conversion of NMN to nicotinamide and nicotinamide back to NMN and to the metabolites 2Py and 4Py:


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Fred
Registered dietitian, Sweden.
rhett
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Re: Small dose of NMN restores fertility in old mice, large dose does not – implications for dosage suggestions

Post by rhett » Sun Feb 16, 2020 11:39 am

If you do an allometric conversion of the doses in the study. The dose that increased fertility would be around 350mg for a human. And the dose that seemed to be too high would be around 1800mg for a human.
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Re: Small dose of NMN restores fertility in old mice, large dose does not – implications for dosage suggestions

Post by Newage » Sun Feb 16, 2020 5:12 pm

rhett wrote:
Sun Feb 16, 2020 11:39 am
If you do an allometric conversion of the doses in the study. The dose that increased fertility would be around 350mg for a human. And the dose that seemed to be too high would be around 1800mg for a human.
Thanks for that rhett.
So 750mg to 1 gram seems to be in the effective medium range without going over the top..
rhett
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Re: Small dose of NMN restores fertility in old mice, large dose does not – implications for dosage suggestions

Post by rhett » Mon Feb 17, 2020 3:18 pm

Actually... I think I got that wrong with the 2g/L conversion. It should be closer to 1500mg.

So 350mg is the lower dose and 1500mg is the higher dose
islaymist
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Re: Small dose of NMN restores fertility in old mice, large dose does not – implications for dosage suggestions

Post by islaymist » Tue Feb 18, 2020 1:45 am

Do we know how much of a 125mg NMN sublingual table is actually absorbed when taken sublingually? Would 4-8 tablets/day be considered as a dose of 500-1000mg, or is it only a percentage of this that is actually absorbed?
drkris69
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Re: Small dose of NMN restores fertility in old mice, large dose does not – implications for dosage suggestions

Post by drkris69 » Tue Feb 18, 2020 6:19 am

Thank you for the post. 500 to 1g daily seems to be the sweet spot for me.
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Re: Small dose of NMN restores fertility in old mice, large dose does not – implications for dosage suggestions

Post by Drdavid » Tue Feb 18, 2020 7:06 am

Fred is correct. This may have worked in mice but that does not mean that it will translate to humans even with a dosing conversion. Applying animal studies to human models is a rather dangerous assumption. Micro dosing may eventually make sense when we can actually see human data but right now it is a guessing game. In the clinic we have seen that those that micro dose NMN see some positive effects but not the effects that a standard dose may provide.
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