LONGECITY

Exp Physiol. 2018 Jul 14. doi: 10.1113/EP086964. [Epub ahead of print]

Nicotinamide riboside supplementation dysregulates redox and energy metabolism in rats: Implications for exercise performance.

Kourtzidis IA1, Dolopikou CF1, Tsiftsis AN1,2, Margaritelis NV1,2, Theodorou AA3, Zervos IA4, Tsantarliotou MP4, Veskoukis AS1,5, Vrabas IS1, Paschalis V3,6, Kyparos A1, Nikolaidis MG1.

 

Nicotinamide riboside ... can increase NAD(P) levels. NAD(P) play key roles in energy metabolism and their main function is the transfer of electrons in various cellular reactions. Research in aged or diseased mice reported that nicotinamide riboside increases NAD(H) levels, reduces morbidity and improves health and muscle function.

We have recently shown that in healthy young rats, chronic administration of nicotinamide riboside decreased exercise performance by 35% (p = 0.071). [MR: we have discussed that earlier study (PMID: 27489522) before: see here, here, and later in that thread].

 

As a follow-up to this finding, we analyzed samples from these animals, trying to reveal the potential mechanisms driving this adverse effect, focusing on redox homeostasis and bioenergetics. ... Nicotinamide riboside supplementation increased the levels of NADPH in liver (P = .050), increased the levels of F₂ -isoprostanes [a marker of lipid peroxidation] in plasma (P = .047), decreased the activity of glutathione peroxidase (P = .017), glutathione reductase (P < .001) and catalase (P = .024) [antioxidant enzymes] in erythrocytes, increased the levels of glycogen in liver (P < .001) and decreased the levels of glucose (P = .016) and maximal lactate accumulation in plasma (P = .084). [MR: These last three might be taken to be good things in a person while inactive, but in the context of exercise to exhaustion could indicate a failure to release needed fuel from the glycogen stores].

 

These findings support the prevailing idea that exogenously administered redox agents in heathy populations may lead to adverse and not necessarily to beneficial or neutral effects.

 

PMID: 30007015

DOI: 10.1113/EP086964

 

As we've discussed before, it certainly seems plausible that these effects might be seen in very young animals (including human animals) while still being benficial "in aged or diseased" mice and people. Such beneficial effects have not been exactly shining through in human trials, however.

300mg per KG. That’s a lot of NR, human equivalent of? 20,000mg?
Wouldn’t one expect some glutathione depletion? Even though well tolerated, human trial doses have only been in the 250-2000 mg range if I remember correctly.
Edited by Kevnzworld, 17 July 2018 - 12:54 AM.

300mg per KG. That’s a lot of NR, human equivalent of? 20,000mg?
Wouldn’t one expect some glutathione depletion? Even though well tolerated, human trial doses have only been in the 250-2000 mg range if I remember correctly.

 

300mg/kg in rats is equivalent to 48mg/kg in human which means 3400mg. 

https://www.fda.gov/...s/ucm078932.pdf

 

Yes it is a large dose although I'm sure some people on this forum are close to this value on daily supplementation.

What about daily supplementation of 500mg (250 morning and night), for someone who exercises four times a week? 

 

From what I understand the study shows that it inhibits the body's natural response to exercise stress which is what provides the net benefit of exercise? Am I interpreting that correctly? That's not good.

What you guys are missing here is that the dose used in this study is on the low end of what's been used in most of the animal studies, which is usually 400-500 mg/kg. One can't both be impressed by favorable results obtained at 400-500 mg/kg and dismissive of ill effects observed at 300 mg/kg.

A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects
https://academic.oup.../nqy132/5051210
This new NR human trial showed a reduction in fatty liver and ALT liver enzymes.

The Basis human trial results didn’t measure glutathione or catalase but it did show a decrease in liver enzymes ALT and AST.
https://www.nature.c...1514-017-0016-9

Though neither trial measured glutathione, the results demonstrate that NR is safe from a hepatic perspective at moderate dosages.

Its an interesting outcome, brings back the topic of dosing.

Been giving some thought to the original swim till exhaustion study observations and was thinking results might have more to do with red blood cell oxygen transport capacity than muscle health.  This followup mentioning observed changes in anti-oxidant levels of that study subject's erythrocytes further supports these cells being a focus.  And suggests to me that a 21-day dosing period may be insufficient to draw meaningful conclusions given that the normal life-span of erythrocytes are 3.5 months or so.  Glucose level impacts on A1C generally take 3 to 6 months to stabilize because of this and assume that the erythrocyte life-span is a constant.  If NR causes alteration in erythrocyte life-span, count, and/or oxygen transport capacity, longer duration study may be needed, particularly to draw any inferences about longevity.

 

Howard

Edited by hav, 22 July 2018 - 05:57 PM.

Possibly it works like this: NR, NMN and NAM can produce a high NAD+/NADH ratio, which results in the fissioning of mitochondria. Fissioned mitochondria are less efficient at producing ATP and thus the young mice had reduced exercise capacity. But for old mice, fissioning results in mitophagy of defective mitochondria and the restoration of vitality.

Possibly it works like this: NR, NMN and NAM can produce a high NAD+/NADH ratio, which results in the fissioning of mitochondria. Fissioned mitochondria are less efficient at producing ATP and thus the young mice had reduced exercise capacity. But for old mice, fissioning results in mitophagy of defective mitochondria and the restoration of vitality.

 

+1. I am amazed at your discernment. You have studied a lot of information on mitochondria. 

Edited by Kentavr, 19 August 2018 - 05:06 AM.

The researchers have now published the results of the dissection of the rats. The abstract:

 

 

 Nicotinamide riboside is a recently discovered form of vitamin B3 that can increase NAD(P) levels. NAD(P) play key roles in energy metabolism and their main function is the transfer of electrons in various cellular reactions. Research in aged or diseased mice reported that nicotinamide riboside increases NAD(H) levels, reduces morbidity and improves health and muscle function. We have recently shown that in healthy young rats, chronic administration of nicotinamide riboside decreased exercise performance by 35% (p=0.071). As a follow-up to this finding, we analyzed samples from these animals, trying to reveal the potential mechanisms driving this adverse effect, focusing on redox homeostasis and bioenergetics. Thirty eight Wistar rats were divided into four groups: control (n=10), exercise (n=9), nicotinamide riboside (n=10) and exercise plus nicotinamide riboside (n=9). Nicotinamide riboside was administered for 21 days (300 mg/kg body weight daily). At the end of administration, the exercise and the exercise plus nicotinamide riboside groups performed an incremental swimming performance test until exhaustion. Nicotinamide riboside supplementation increased the levels of NADPH in liver (P=.050), increased the levels of F2-isoprostanes in plasma (P=.047), decreased the activity of glutathione peroxidase (P=.017), glutathione reductase (P<.001) and catalase (P=.024) in erythrocytes, increased the levels of glycogen in liver (P<.001) and decreased the levels of glucose (P=.016) and maximal lactate accumulation in plasma (P=.084). These findings support the prevailing idea that exogenously administered redox agents in heathy populations may lead to adverse and not necessarily to beneficial or neutral effects.

 

They mainly point to overexpression of NADPH when supplementing healthy animals. Since in another thread Michael pointed to possible deleterious effects of too much NADPH I think it is useful that anyone can read the full text. See below.

 

 

Pretty hefty dosing 300mg/kg rat weight. HED is about 50mg /kg human. Person weighing 70kg means 3.5gram

Or adding nam / nr drives atp production until all the adenine is used up. At which point it creates an imbalance. The body responds to the low atp by fissioning mitochondria but that doesn't work and energy levels fall off anyway. Recovery still depends then upon restoration of adenine so ribose can be added to it to produce adenosine and eventually atp. Just a theory....sources of adenine are scarce and not sure it is safe to consume...but looking into it...


Giving rats high doses of adenine causes kidney issues, but I suspect the human dose for our purposes would be much smaller

https://journals.plo...al.pone.0192531
Edited by zorba990, 29 August 2018 - 02:43 AM.

This doesn’t make sense to me.

 

They gave NR at 300 mg/kg a day to young mice for 21 days.  1/2 of those getting NR also got exercise.

 

They found 35% DECREASE in exercise performance (apparearantly for both exercised and sedentary)

 

 

“In healthy young rats, chronic administration of nicotinamide riboside decreased exercise performance by 35%”

 

 

 

Sinclairs study published in March gave NMN to young mice at 400 mg/kg.  

 

They found no impact on exercise performance of the young mice from NMN alone.

 

They found a significant INCREASE in exercise performance for those receiving NMN + exercise.

 

 

“ NMN did not alter the capillarity or exercise capacity of sedentary animals younger than 12 months (not shown), consistent with overexpression of Nampt, an NAD biosynthetic gene (Fred- erick et al., 2015). There was a strong effect, however, in young mice on NMN after endurance training for 1 month, resulting in 70% more capillaries than untreated sedentary mice, more than twice the effect of NMN alone (Figure 6I). To test if NMN works by sensitizing ECs to VEGF, we treated mice with axitinib, an inhibitor of VEGF signaling (Figure S6O) and saw no effect of NMN on capillary density and exercise capacity (Figures 6J and S6P).”

 

 

 

 

 

 

 

Is there really that much difference in the effects of NR vs NMN on endurance in YOUNG mice, or am I misreading something?  Or perhaps there is a flaw in this current study we are discussing?

 

This doesn’t make sense to me.

 

They gave NR at 300 mg/kg a day to young mice for 21 days.  1/2 of those getting NR also got exercise.

 

They found 35% DECREASE in exercise performance (apparearantly for both exercised and sedentary)

Sinclairs study published in March gave NMN to young mice at 400 mg/kg.  

 

They found no impact on exercise performance of the young mice from NMN alone.

 

They found a significant INCREASE in exercise performance for those receiving NMN + exercise.

Is there really that much difference in the effects of NR vs NMN on endurance in YOUNG mice, or am I misreading something?  Or perhaps there is a flaw in this current study we are discussing?

 

Of course, we don't know w/o direct testing, but note that the Greek study didn't use 5 m.o. mice , but 4 m.o. rats. So as we've discussed before, there are at least two different possible explanations for the differences in findings in the Kourtzidis et al studies vs. most of the mouse work based on the differences in choice of model organism:

 

First, as I noted in response to a prior question of yours, Sinclair's study used C57BL/6J mice, which have the NNT mutation and thus might benefit from megadose NAD+ boosting supplements while organisms with intact NNT genes (like rats and humans) might suffer oxidative stress and related problems, such as those seen here.

 

Second, remember that while a 5 m.o. mouse is a young adult, stefan pointed out that a 4 m.o. rat is really still a juvenile; in an animal that already is at the peak of NAD+:NADH and redox tone, an NR-driven redox imbalance seem more likely than such an effect in older organisms with flagging NAD+ (tho', contrariwise, a young animal might also have less tendency to throw off potentially deleterious metabolites, and exercise might help mitigate those, as we've been discussing).

Edited by Michael, 30 August 2018 - 12:08 AM.

Ah, gotcha, thanks for reminder.    

 

I thought you discounted the relevance of the NNT mutation after finding the Mills study showed benefit using mice that were not C57BL/6J ?

 

Maybe its just a 5 mo mouse vs 4 mo rat thing.

Ah, gotcha, thanks for reminder.    

 

I thought you discounted the relevance of the NNT mutation after finding the Mills study showed benefit using mice that were not C57BL/6J ?

 

I will give you another reminder of what I actually said, then .