An Investigation of Adverse Effects of Nicotinamide Riboside Supplementation

Nicotinamide riboside is so far the only approach to NAD+ upregulation for which there is published human trial data, though other trials for other approaches are underway at the present time. NAD+ declines with age, for reasons that remain comparatively poorly understood, and this has a negative impact on mitochondrial function. Thus there is considerable enthusiasm at the moment for intervening in this known manifestation of aging by tackling the proximate causes, raising NAD+ levels, but without addressing underlying causes.

Researchers here find the potential for adverse effects on glucose metabolism and white adipose tissue function to result from nicotinamide riboside supplementation, but there are a great many details involved: dietary differences and genetic differences in mice appear important as to whether problems arise, and the final sections of the discussion in the paper are worth reading closely. It is hard to say whether or not the discoveries made in mice that are reported in this open access paper will apply to humans, but the specific details suggest that investigation is warranted.

Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor vitamin. The scarce reports on the adverse effects on metabolic health of supplementation with high-dose NR warrant substantiation. Here, we aimed to examine the physiological responses to high-dose NR supplementation in the context of a mildly obesogenic diet and to substantiate this with molecular data. An 18-week dietary intervention was conducted in male C57BL/6JRccHsd mice, in which a diet with 9000 mg NR per kg diet (high NR) was compared to a diet with NR at the recommended vitamin B3 level (control NR). Both diets were mildly obesogenic (40 en% fat). Metabolic flexibility and glucose tolerance were analyzed and immunoblotting, qRT-PCR, and histology of epididymal white adipose tissue (eWAT) were performed.

Mice fed with high NR showed a reduced metabolic flexibility, a lower glucose clearance rate and aggravated systemic insulin resistance. This was consistent with molecular and morphological changes in eWAT, including sirtuin 1 (SIRT1)-mediated PPAR╬│ (proliferator-activated receptor ╬│) repression, downregulated AKT/glucose transporter type 4 (GLUT4) signaling, an increased number of crown-like structures and macrophages, and an upregulation of pro-inflammatory gene markers. In conclusion, high-dose NR induces the onset of WAT dysfunction, which may in part explain the deterioration of metabolic health.



9000 mg NR per kg is insanely high compared to current supplementation strategies.
From that I know daily recommended doses range between 100mg-1000mg total (not per kg)

Posted by: Yaniv at November 5th, 2019 6:01 AM

you have difficulties understanding English language (like a lot):

"High Dose of Dietary Nicotinamide Riboside Induces Glucose Intolerance and White Adipose Tissue Dysfunction in Mice Fed a Mildly Obesogenic Diet"

if you do NOT understand what the study says, ask somebody who understands it, and it will translate it for you.

Posted by: z at November 5th, 2019 11:07 AM

I can give you some anecdotal, personal experience with the Sirtuins (NR and AMPK). I starting using these around 2015-2016. I developed a persistent cough over the next three years. I read somewhere on the longecity forums that one of the side effects of excessive NAD+ boosting is increased histamine production, which produced the return of my allergies and, hence, my cough. I stopped taking NR and AMPK activator about 3 months ago. My cough has largely disappeared. I also read that excessive NAD+ boosting my also interfere with proper clearance of senescent cells, necessitating the greater use of senolytics. The interesting thing about the first symptom is that it would not have occurred if NAD+ boosting did not work at all. In my particular experience, I did not need much of it at all.

In short, I think NR and the other Sirtuins are useful. But they must be used judiciously while keeping in mind the idiosyncrasies of one's own molecular biology.

Posted by: Abelard Lindsey at November 5th, 2019 11:08 AM

The study states reason for using high dose NR here: "Since we did not observe beneficial effects of an NR dose of 900 mg per kg of diet (900NR in [19]), which is at the low end of the dose range that displayed NAD+ boosting or beneficial effects on metabolic function in other studies [3,4,5,13,14], we here imposed a dose of 9000 mg NR per kg diet (high NR), which is one order of magnitude higher and just at the high end of this dose range."

Posted by: August at November 5th, 2019 11:19 AM

So..Did I make a big mistake by getting a 4 hour intravenous infusion of NAD+ ??

Posted by: August at November 5th, 2019 11:20 AM

Possibly of interest is this recent paper --

"Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice"

Posted by: L Pagnucco at November 6th, 2019 2:28 PM

Every time I have tried NAD+ I have felt terrible. Niacin interferes with b vitamin methylation and I have a genetic variant that already reduces my methylation considerably. I do take methylated B-12 and folate, and I find that I need B1 and B2 daily to feel my best. I also avoid B complex vitamins like the plague. They really pile on the niacin in those things which for me makes them worse than useless.

Personally I think that NAD+ messes up methylation.

Posted by: John Whitling at November 11th, 2019 6:52 AM

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