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David Sinclair on new mice study: NMN supplementation may be detrimental to sperm quality.

nmn sperm quality

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#1 Fredrik

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Posted 23 July 2019 - 08:42 AM


In this experiment i.p. injected NMN (500 mg/kg) caused sperm oxidative stress in mice but not a lower oral dose (400 mg/kg).

 

"Here, we add to the knowledge on how maternal obesity affects sperm quality in mice, as well as provide the first information on how NMN supplementation affects sperm quality in the context of normal weight, as well as obesity associated with both post-weaning and maternal HFD consumption.

 

We hypothesised that similar to improvements in body-wide and liver metabolism, sperm quality would benefit from NMN supplementation in obese mice. However, our results suggest that in some circumstances NMN supplementation may actually be detrimental to sperm quality."

 

AND

 

"As expected (Uddin et al. 20162017), in this experiment, NMN administration to mice fed a HFD reduced body weight, especially in the heaviest mice. However, we also found that NMN reduced sperm count and vitality and increased 8-OHdG.

 

One explanation for the increased oxidative stress (as indicated by 8-OHdG) was that the NMN administration was increasing ROS. We considered two mechanisms through which NMN could increase sperm ROS. Firstly, we and others have shown that NMN administration increases mitochondrial biogenesis and function (Gomes et al. 2013Uddin et al. 20162017). The mitochondria convert NADH to NAD+ through a series of processes in energy metabolism and a by-product of this conversion is ROS, therefore, an increase in mitochondrial activity could increase ROS and oxidative stress.

 

The NADH-dependent oxidoreductase reaction in mitochondria is the main source of ROS in sperm so potentially perturbation of NADH levels by NMN administration could increase mitochondrial ROS output. In support of this possibility, measurement of sperm mtDNA copy number in the mice showed an interaction between maternal diet and NMN. MtDNA copy number was increased in offspring from a chow-fed mother, but decreased in offspring from a HFD-fed mother. However, it is unknown whether both of these effects could result in similar increases in 8-OHdG. Secondly, ROS production from sperm plasma membranes is caused by NADPH oxidase (Shukla et al. 2005). Through a short biochemical pathway NMN could increase superoxide that is NMN to NADH (by NMNAT2), to NADPH (by NADH kinase) to superoxide (by NADPH oxidase).

 

Another possible mechanism that could explain the negative effects of NMN administration is that it could increase nicotinamide (NAM) levels as has been seen in mice with supplementation of another NAD+-precursor, nicotinamide riboside (NR) (Frederick et al. 2016). NAM is known to inhibit sirtuins (Bitterman et al. 2002) which are required for normal spermatogenesis (Coussens et al.2008). However, this may contrast with a study that associated long-term supplementation with the sirtuin-activating drug resveratrol with increased mouse sperm DNA damage and 8-OHdG levels (Katen et al. 2016).

 

It will be interesting to determine if other NAD+ precursors such as nicotinic acid riboside (NAR), nicotinic acid mononucleotide (NaMN) and NR have negative effect on sperm quality at high levels."

 

"This oral administration cohort therefore suggests that chronic NMN administration can have beneficial effects on angiogenesis (Das et al. 2018) without impacting sperm quality. It may be that the effects of NMN on sperm quality, as assessed by 8-OHdG, seen in the maternal obesity cohort relate to the surge in NMN following acute injection versus gradual ingestion over the darkness phase (i.e. through the night), although further work would be required to test this. In particular, a future study investigating a group of mice receiving NMN through i.p. injection and another group receiving the same dose in drinking water would be enlightening.

 

Potential explanations for the differences in sperm states between the maternal obesity (i.p. injected NMN) cohort and the oral administration cohort may lie in the NAD+ and NADH levels observed in the testes of representatives of each cohort (Fig. 4).

 

These experiments showed large increases in NAD+ and potentially NADH in the testes of the mice that had high sperm ROS, as well as low sperm count and vitality.

 

These data support the possibility that increases in NAD+ and/or NADH could alter ROS production through one, or several, of the mechanisms mentioned above, NADH-dependent oxidoreductase reactions, NADPH oxidases and Sirtuin-mediated reactions.

 

These precise mechanistic explanations for how i.p. NMN administration could cause sperm oxidative stress could in future be investigated through mass-spectrometry of testes or sperm for metabolites such as NAM, NADPH and NADH."

 

https://www.ncbi.nlm...les/PMC6589912/


Edited by Fredrik, 23 July 2019 - 09:25 AM.

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#2 able

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Posted 23 July 2019 - 06:41 PM

So they found that overfed mice had lower lower sperm quality.

 

Giving those fat mice 500 mg/kg a day of NMN  by injection resulted in weight loss, but also lower sperm quality.

 

Normal weight mice that were given 400 mg/kg a day NMN in drinking water did not suffer lower sperm quality.

 

They don't know if it was the extra 100 mg/kg a day, or the increased bioavailability of injection vs drinking water.  

 

Also,  those given NMN in water were not overweight while those given by injection were overweight, which makes the comparison a bit muddy imo.

 

This chart below shows 500 mg/kg injected NMN nearly doubled NAD+ in testis  vs  no significant effect for 400 mg/kg NMN in water.

 

So it seems 500 mg/kg by IP increases NAD+ in tissues far more than 400 mg/kg in drinking water (no surprise) , and may be near the upper  for benefit before we start seeing negative effects. 

 

The title of this thread seems a bit unfair, as  the oral NMN supplements that  we are interested in show no negative impact on sperm.

 

 

REP-18-0574fig4.jpg

 


Edited by able, 23 July 2019 - 06:43 PM.

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#3 Fredrik

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Posted 23 July 2019 - 09:32 PM

The title of this thread seems a bit unfair, as the oral NMN supplements that we are interested in show no negative impact on sperm.

 

 

 

The title of the thread is a direct and fair quote from the researchers own conclusions. I only removed the word "actually". They don't care what we are supplementing. That may feel unfair to you.

"However, our results suggest that in some circumstances NMN supplementation may actually be detrimental to sperm quality."


Edited by Fredrik, 23 July 2019 - 09:44 PM.

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#4 able

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Posted 23 July 2019 - 09:49 PM

The title of the thread is a direct and fair quote from the researchers own conclusions. I only removed the word "actually". They don't care what we are supplementing. That may feel unfair to you.

"However, our results suggest that in some circumstances NMN supplementation may actually be detrimental to sperm quality."

 

"In some circumstances NMN supplementation may actually be detrimental to sperm quality."

 

This direct quote is a more accurate representation than the partial quote you chose to use.

 

Your title is a bit deceptive, as it implies that NMN under normal conditions may be bad for sperm quality, which is not what they found.


Edited by able, 23 July 2019 - 10:02 PM.

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#5 Fredrik

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Posted 23 July 2019 - 10:14 PM

The title clearly says it MAY be detrimental. Not that it always is. Taking high doses of NAD precursors can never be described as "normal conditions" however you twist it. I don't understand what you are complaining about.

Edited by Fredrik, 23 July 2019 - 10:16 PM.

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#6 able

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Posted 24 July 2019 - 02:19 AM

The title clearly says it MAY be detrimental. Not that it always is. Taking high doses of NAD precursors can never be described as "normal conditions" however you twist it. I don't understand what you are complaining about.

 

I'm not twisting anything.  Many people take high doses of NMN or NR.  That is "normal" for readers here.  This study found no risk from that.

 

The study found there might be a negative side effect to a human injecting  the equivalent of 2.5 grams a day.

 

I doubt anyone is injecting any NMN, and certainly not 2.5 grams a day.  It is not at all applicable to what anyone here does.

 

Yet someone reading only the title of this thread will think there is reason to believe the NMN capsules they take might be unsafe.


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#7 Fredrik

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Posted 24 July 2019 - 06:38 AM

I'm not twisting anything.  Many people take high doses of NMN or NR.  That is "normal" for readers here.  This study found no risk from that.

 

The study found there might be a negative side effect to a human injecting  the equivalent of 2.5 grams a day.

 

I doubt anyone is injecting any NMN, and certainly not 2.5 grams a day.  It is not at all applicable to what anyone here does.

 

Yet someone reading only the title of this thread will think there is reason to believe the NMN capsules they take might be unsafe.

 

The NMN wasn´t injected into the blood stream, it was injected in the body cavity (https://en.wikipedia...oneal_injection).

 

There´s been no safety or toxicology studies published with administration of NMN in humans. You can´t call it safe OR unsafe at this stage.

 

When the human safety studies are published we´ll know if NMN is safe for human consumption (beyond the anecdotes online).

 

I think NMN won´t be acutely toxic, but I don´t know anything about long-term safety...and neither does anyone here. The increase in reactive oxygen species may apply to other NAD-precursors also.

 

You are not meant to only read the title of anything and make assumptions from it.

 


Edited by Fredrik, 24 July 2019 - 07:01 AM.

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