Conclusions
HD NR supplementation increased plaque thickness, as well as IL-6 and LDL-C plasma levels, moderate NR dose had neutral effects. Elevated hepatic expression levels of CD38 and decreased SIRT1 may at least in part explain the atherosclerotic phenotype. Thus, HD NR supplementation in mice does not decrease but worsen atherosclerosis and induce systemic inflammation. A cautious approach should be considered when applying NAD+ boosting in patients with atherosclerotic disease.
As people will know I prefer HDAC inhibition to HDAC boosting. Sirtuins are HDACs.
This is an interesting paper which argues that harm can arise from NAD boosting (in mice so not necessarily carried forward to humans).
This study was done on ApoE KO mice which are known to have cholesterol issues and develop arteriosclerosis easier than normal mice. Not sure how valid the risks are for a regular variety of mouse. I guess NAD boosting makes a bad situation worse, but it’s hard to draw any real definitive conclusions.
On the other hand, NAD boosting isn’t showing all the promise that it was supposed to have. Maybe it’s best just to forget this class of supplements and move on to other things
I think the problem as people get older is the kynurenine pathway starts going wrong (the usual long genes sort of thing) which does cause a shortage of NAD. However, what we are not trying to do is to actually speed up the activity of HDAC Class 3 (the Sirtuins). Hence for an old person or old mice a bit of NAD boosting might help, but seriously speeding up the deacetylation of the histone potentially causes senescence (through blocking differentiation).
To me the key objective is improving both transcription (of DNA to mRNA) and translation (or mRNA to proteins). Personally I think that delivers results.
Part of the latter is more efficient mitochondria which is where Rapamycin comes in.
One of Micheals videos shows that to high NAD levels boosted by NMN actually has a negative effect on blood aging markers. I think this NMN/NR thingy is a double edged sword. Better of with Niacin or similar that are below in the NAD ladder.
I don’t know. I still take a big dose of Niacin and accordingly it should raise NAD and make things worse. I think I’ll cut it down to about 50 or 100 per day. I’m counting on cyclodextrin now.
The high NR dose for these mice was very high, at 2.4g/kg/day, equivalent, roughly, to about 12g for typical person. Combine that with mice susceptible to heart disease, and I don’t think there is too much concern for anyone who isn’t double ApoE.
I think that David Sinclair says he takes NMN every day and that he’s personally been taking a daily statin for decades due to genetic hypercholesterolemia. I know he’s not everyone’s cup of tea around here but I thought it was worth mentioning.
Whereas there is a good argument that there are many substances where a large dose is harmful, but a smaller dose has merit, it is useful to know what harm may be caused by a large dose. This then raises the question as to what effect a smaller dose has. Does it cause a small amount of atherosclerosis? We don’t know.
However, what it does say is that NAD Boosting is not necessarily good. It raises some doubt.
It can help certain people with different issues. For instance, it improves my healthspan. I rarely feel fatigued or tired anymore and I don’t get jetlagged anymore. It does wonders for me but may not work the same for others.
I will try to dig these up later, but I think I recall that in other mouse studies there have been a U-shaped curve for NAD+ levels. Extremely high levels were detrimental and extremely low levels were detrimental. I think the level of NR supplementation that started to become detrimental was the human equivalent of 1.5 grams a day. The human equivalent of 500-750mg was the sweet spot. I’ll see if I can find those studies again. They were for functional measures, not lifespan.
For now, i stopped taking NMN (1.200mg) as it increased my LDL, APOB. The last think i wish is to put another STENT ( one i have is enough). But i will measure my NAD for future assessment if return or not to NMN again…
@Goran, maybe I’m susceptible, but niacin gave me a nasty case of gout, which I treated with prednisone and colchicene. The latter, by the way, is toxic above sub-milligram doses. I recently read of an MD working in poison control who killed his wife with colchicene. He demanded that there be no autopsy, which raised suspicions. Apparently he was after her life insurance.