Niagen, Niacin, Nicotinamide, and NMN (Current State of Anti-Aging Research)

In the last twenty years or so, research has emerged that supports the idea that boosting levels of NAD+ (the oxidized form of nicotinamide adenine dinucleotide) in animals (including mammals) can slow or even reverse many aspects of biological aging, either by activating sirtuins (proteins that regulate key biological pathways), by facilitating cell-to-cell and intracellular communication, and/or by other means. NAD+ levels can be boosted by orally supplementing with NAD+ precursors, including nicotinamide riboside (patented and marketed as Niagen, abbreviated as NR), and nicotinamide mononucleotide (abbreviated as NMN). To a much lesser extent, NAD+ can be increased by supplementing with plain old niacinamide/nicotinamide (NAM), and niacin/nicotinic acid (NA).

NAD+ can also be increased by fasting (including intermittent fasting), saunas/heat shock, exercise, and anything that increases sirtuin activity and/or AMPK activity. Inhibiting the enzyme C38 (with quercetin and/or apigenin) can also increase NAD+.

The topic is complex, and its understandable if you found the above paragraphs to be gobbledygook. But I’ll try to break it down into bite-sized chunks.

NMN Mouse Research, and What David Sinclair Takes

Research on mice conducted in Sydney, Australia in David Sinclair’s lab demonstrated that oral supplementation with nicotinamide mononucleotide (NMN) doubled exercise capacity in older mice, primarily via neo-vascularization (growth of new blood vessels) without increasing cancer risk. Additional research demonstrated other anti-aging effects from NMN supplementation, including “enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle.”

NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle.

So should we all be taking NMN? In Sinclair’s research, only older mice benefited from NMN supplementation; apparently the younger mice had enough NAD+. Sinclair himself currently takes 750mg of NMN per day, along with a gram of resveratrol (the stuff in red wine that activates sirtuins), and 500mg metformin (a medication used to control blood sugar).

Unfortunately, taking that much NMN is expensive. Using this source on amazon, 750mg would cost you $5.50/day.

Resveratrol is relatively cheap, and has been shown (also by Sinclair) to activate sirtuins and have anti-aging effects. However in humans, resveratrol blunts the effects of exercise, effectively acting as a vasoconstrictor and inhibiting the growth of new blood vessels. The same goes for high doses of vitamin C and vitamin E; it seems too many antioxidants are a bad thing, blunting positive adaptations to exercise.

But moderate doses of resveratrol (maybe less than 100mg per day) probably do more good than harm, and the early evidence for NMN supplementation is very promising. The use of metformin for non-diabetics deserves its own post.

https://www.youtube.com/watch?v=3qvQKmRl8_w

Niagen/Nicotinamide Riboside

Nicotinamide riboside (patented and sold as Niagen) has recently been shown to increase NAD+ in humans. At the recommended dose (250mg/day) it’s much less expensive than NMN, costing about $1/day. However the human experiment linked above used 1000mg/day, which would quadruple the cost.

Which is more effective, nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN)? Niagen’s sale page claims that there is more human research with NR, which is true. But Alive by Nature’s sales page lists a number of studies where NMN was more effective than NR.

There are some interesting anecdotal reports of people using Niagen. This person claims Niagen cured their IBS and restless leg syndrome. This person has been taking 500mg/day of Niagen (twice the recommended dose) along with pterostilbene (found in blueberries) for several years and is claiming full-on reverse aging (hair regrowth, reduced wrinkles, return of youthful energy, etc.).

I’ve just started experimenting with Niagen in the past few months, at a low dose of 125mg/day, with some breaks. So far I’ve noticed slightly better sleep and mood. I may increase the dose over time.

Methyl Depletion?

There are some anecdotal reports of an energy boost when starting Niagen (NR), followed by an energy crash days or weeks later. There is also this experiment with rats that showed NR supplementation reduced exercise capacity by 35%.

Chris Masterjohn points out that processing excess vitamin B3 (in any form, including niacin, niacinamide, and nicotinamide riboside) requires methyl groups, and that methyl depletion can lead to reduced creatine production (and therefore reduced exercise performance) as well reduced production of choline and regulation of some neurotransmitters, possibly leading to mood issues or even depression. Masterjohn suggests supplementing with TMG (trimethylglycine) in conjunction with B3 to provide additional methyl groups. This may not be necessary if your diet is high in meat (which provides methyl groups via methionine) and/or you have a fully functional version of the MTHFR gene (I don’t).

TMG is the same thing as betaine, but not the same thing as betaine Hcl (the latter increases stomach acidity and is used to improve digestion, but could lead to gastric discomfort or worse in people who have adequate stomach acid). Masterjohn recommends supplementing 1mg of TMG for each 1mg of B3 (NA, NAM, or NR) that you take. TMG is generally regarded as a safe supplement, and provides other benefits, but higher doses come with side effects.

So far I’ve only noticed positive effects from Niagen, but I’m also using a relatively low dose. If I increase my Niagen dosage I’ll probably add in TMG for methyl support. I suspect my current metabolic/epigenetic state might actually be overmethylated, leading to high neurotransmitter levels and a recent bout of insomnia. B3/NR supplementation is probably helping me balance out at the moment by sopping up excess methyl groups.

Does NMN metabolism also deplete methyl groups? I couldn’t find an answer for this. If you can find any research that answers this question, please comment below. According to the Niagen site, NMN is not a form of B3 (unlike NA, NR, and NAM).

Niacinamide (NAM)

Supplementing with niacinamide (which is the same thing as nicotinamide, both abbreviated as NAM) has multiple benefits, some of which I’ve discussed in this blog. NAM can reduce anxiety, prevent infections, and of course prevent pellagra (as can any form of B3). Niacinamide is also used by the body to produce NAD+, but high doses of NAM inhibit sirtuin activity, at least in vitro, so it probably isn’t an ideal anti-aging supplement.

I still use niacinamide (up to 100mg/day) in addition to Niagen, especially in the evening if I’m having trouble relaxing and getting sleepy.

Niacin/nicotinic acid (NA)

Niacin, the kind of that makes you flush bright red if you take too much, has it’s own uses. For decades therapeutic levels of niacin have been used to reduce high cholesterol levels, boost NAD+, improve circulation, and protect the heart. However megadosing with niacin can lead to serious health issues in some cases, including high blood sugar, gastric distress, and even ulcers.

Mega-dosing niacin to boost NAD+ is not very effective and could result in potentially dangerous side effects. But using low doses will help support healthy NAD+ levels. Other intelligent uses of niacin include using sub-flush doses to improve hand and foot circulation. It’s also worth noting that some people experiencing schizophrenic or other mental healthy symptoms have noted significant improvements using niacin.

What I’m Taking

Currently I’m taking 1 pill (125mg) of Niagen daily. I’ll probably double this dose at some point, adding TMG as needed. I’ll probably take a break from Niagen and experiment with NMN as well. In addition I’m experimenting with low doses of SIRT/AMPK activators such as quercetin, pycnogenol, resveratrol, and berberine.

I sometimes also take niacinamide to help me relax and get sleepy in the evening, and small doses of niacin on colder days to improve circulation in my hands.

My long-term health goals are to feel and look younger, to reduce my resting heart rate, to maintain or improve my insulin sensitivity, and to generally improve my healthspan (and possibly my lifespan as well). I think there’s enough evidence if terms of the safety and effectiveness of NAD+ precursors such as NR and NMN that it makes sense for me (and probably most people over 40) to start carefully experimenting with NAD+ precursor supplementation (and other ways of boosting NAD+ levels).

Update: Chris Masterjohn recently posted a persuasive video re: why he favors nicotinamide riboside (NR) over nicotinamide mononucleotide (NMN).

Additional Resources

Ben Greenfield podcast on Niagen and interview with Dr. Brenner

Interview with Dr. Sinclair and news about upcoming human NMN trials

Financial Disclosure

I purchased a small amount of Chromadex stock (the company that sells Niagen) a few months ago, which I plan to hold long-term.