Niacin as an anti-aging and life-extension drug

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Niacin prevents heart disease

Vitamin B3 comes in two forms, niacin (also known as nicotinic acid; no relation to nicotine) and nicotinamide (niacinamide), and has been widely used in recent decades for the prevention of hyperlipidemia, and thus cardiovascular disease. (Note that niacin can cause skin flushing, a benign but slightly unpleasant effect; nicotinamide does not do this.) Niacin raises levels of HDL cholesterol and lowers LDL levels; meta-analyses have found that it significantly lowers the risk of cardiovascular disease, by about 25%. The lipid-lowering action of niacin leads directly to another of its effects, an increase in autophagy. Since autophagy declines with age, and animals that have been genetically engineered to have higher levels of autophagy live longer, niacin and nicotinamide have the potential to slow aging and prolong lifespan.

Acipimox, a niacin derivative

A niacin derivative called Acipimox was developed in Europe that would lower lipid levels but not produce flushing. (It’s not approved by the FDA for the U.S., so you can’t obtain it here.) Due to its action in lowering free fatty acids in the blood, Acipimox also lowers insulin levels by about 50% in obese patients literally overnight. Sounds almost like a miracle drug. Keep in mind that the only apparent difference between niacin and Acipimox is that the latter does not cause flushing.

Acipimox, like niacin, also promotes autophagy, which is probably linked with its insulin-lowering action. Insulin and IGF-1 tightly and negatively regulate autopahgy, so lowering insulin levels increases autophagy. In an experiment, rats were either fasted every other day, fasted once a week, fasted once a week and given Acipimox, or controls fed ad lib. As they aged, the control rats developed decreasing activation of autophagy, which declines with age, and increased levels of dolichol, which is a biomarker of aging. The animals that were fasted every other day, and those that were once weekly fasted and received Acipimox, showed none of the changes that aging ad lib fed animals did; the animals that fasted once weekly but without Acipimox had beneficial changes, but not as strongly. Therefore it seems clear that fasting once a week with Acipimox means the equivalent in health benefits as every other day fasting does, which is remarkable. In the words of the study:

It is concluded that life-long weekly-repeated transient inhibition of insulin secretion by antilipolytic drugs may have an anti-aging effect, additive to the anti-aging effect of a milder caloric restriction. Speculation is that transiently lower plasma insulin levels might stimulate the anti-aging cell-repair mechanism autophagy, which has longer lasting effects on cell housekeeping.

What we know so far is that the niacin derivative Acipimox essentially boosts the effects of intermittent fasting by raising autophagy levels and, in at least some aspects, inhibits aging. Now what we want to know is whether niacin or nicotinamide can do the same.

Nicotinamide promotes autophagy

It’s been found that levels of NAD+, a key metabolite, decline with aging and that restoring NAD+ levels can have a profound anti-aging effect. I first became interested in nicotinamide several years ago when I read about this, and soon discovered that it raises NAD+ levels, and by doing so increases autophagy as well as preserves mitochondrial integrity. Mice that were engineered to be susceptible to Alzheimer’s had improved cognitive performance and suppressed Alzheimer’s pathology with several months treatment with nicotinamide.

In the present study we determined whether improving neuronal bioenergetics via provision of the nicotinamide (NAM) would enhance autophagy and ameliorate neuronal dysfunction and degeneration in experimental models of AD. NAM, an amide of vitamin B3, is the essential precursor of β-nicotinamide adenine dinucleotide (NAD+) in mammalian cells (Belenky et al., 2006). NAM is converted to NAD+ through the activity of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in NAD+ biosynthesis.

NAM [nicotinamide] moves rapidly (within minutes) across the blood-brain barrier by facilitated diffusion and is converted to NAD+…. We previously found that NAM preserves cellular NAD+ levels and improves cell survival under conditions of metabolic and excitotoxic stress in neurons and in a rodent model of stroke…. We show that the benefit of NAM in AD [Alzheimer’s disease] mice involves elevation of NAD+ levels and increased resistance of mitochondria to oxidative stress, and enhancement of the autophagy-lysosome process.

Nicotinamide, by raising NAD+ levels, improving mitochondrial function, and increasing autophagy, acts as an anti-aging drug.

A recent review article, Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers, mentions a number of chemical inducers of autophagy which are effectively calorie restriction mimetics. As calorie restriction is the most robust anti-aging process known, these chemical inducers of autophagy have real anti-aging potential. Among those listed are resveratrol, curcumin, EGCG, and… nicotinamide, which “are highly efficient inducers of autophagy in vitro and in vivo, in rodents. Another common characteristic of these agents is their capacity to reduce aging-associated diseases and to confer protective responses against ischemia-induced organ damage. Hence, we classify them as “caloric restriction mimetics” (CRM).”

In Antiaging Therapy: A Novel Target for Antilipolytic Drugs, the authors state:

Functioning of autophagy may decline in well fed adults and is almost negligible at older age. Induction of autophagy may result in “cleaner cells” lower in oxidative status and more resistant to injury and disease. The administration of antilipolytic drugs to fasted animals was shown to intensify autophagy in a physiologically appropriate manner, to enhance submaximal antiaging effects of low level of caloric restriction, to rapidly rescue older cells from the accumulation of altered mtDNA and older peroxisomes, to increase urinary 8-OHdG levels, and counteract the age-related hypercholesterolemia in rodents. In conclusion, benefits of long-lasting stimulation of autophagy and protein and organelle turnover shows that antilipolytic drugs might find a novel therapeutic application in antiaging medicine.

While there’s likely a lot more to be discovered, niacin and nicotinamide look quite promising for anti-aging.

 

Update: I had some questions via comments and email about dose of nicotinamide (also called niacinamide so as not to scare the ignorant). At this point there’s a lot of guesswork, but I take NOW Niacinamide 500 mg Carlson Niacinamide when fasting. It is similar to the dose of Acipimox that lowered insulin levels by half.

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29 comments
Allan Folz says March 21, 2015

Very interesting post. Unlike some of the other supplements that have growth-promoting and anti-aging properties, and over which I have concerns about long-term side-effects, B3 I would harbor no reservations.

Apologies if you’ve mentioned previously, but what are your thoughts on dosage and timing. Big dose all at once to induce maximal autophagy? On the other hand, if there is a limit on our uptake capacity, I don’t want to have half of it go in one end and right out the other. 😉 Oh, and I ain’t getting up for a dose at 1:00 AM like those poor bastard diabetics. My pancreas functions quite well, thank you very much, and uninterrupted night’s sleep, I feel, is my quite just reward.

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    P. D. Mangan says March 22, 2015

    Hi Allan, as you saw, those diabetics got 3 doses of 250 mg each of Acipimox, and I’ll assume that by weight it’s similar to nicotinamide. The Alzheimer’s mice got 40 mg/kg body weight nicotinamide, which would amount to 1000s of mg for a 70 kg man. I have some 500 mg nicotinamide tablets, and I’ve begun to take one during my fast, for example yesterday I fasted until dinnertime from the previous night, so hopefully my nicotinamide boosted my autophagy.

    I didn’t mention in the original post that when I first read about NAD+ and longevity, I bought some nicotinamide and started taking it, and actually thought that I felt more energy. But then I had doubts about whether nicotinamide really raised NAD+ levels, since a number of anti-aging researchers and companies are promoting nicotinamide riboside, an NAD intermediate, for raising NAD+ levels. Finding references that state that NAM raises NAD+ proved hard to find, but lately I’ve seen them all over the place. For instance, here’s one that I didn’t manage to get into the post: Nicotinamide enhances mitochondria quality through autophagy activation in human cells:

    Nicotinamide (NAM) treatment causes a decrease in mitochondrial respiration and reactive oxygen species production in primary human fibroblasts and extends their replicative lifespan. In the current study, it is reported that NAM treatment induces a decrease in mitochondrial mass and an increase in membrane potential (ΔΨm) by accelerating autophagic degradation of mitochondria. … Furthermore, in the NAM-treated cells… mitochondria experienced dramatic changes in structure from filaments to dots or rings. This structural change is required for the decrease of mitochondrial mass indicating that NAM accelerates mitochondrial autophagy, … All these changes were accompanied by and dependent on an increase in the levels of GAPDH, and are blocked by inhibition of the cellular conversion of NAM to NAD+. Taken together with our previous findings, these results suggest that up-regulation of GAPDH activity may prolong healthy lifespan of human cells through autophagy-mediated mitochondria quality maintenance.

    Pushing nicotinamide riboside looks to me motivated by money, and maybe scientific novelty, unless it really raises NAD+ much more and with fewer side effects than NAM, but I doubt whether anyone knows that at this point.

    I assume that you’ve heard of Dr. Abram Hoffer, who has used doses of niacin in the several grams range to treat schizophrenia and other mental health problems. http://www.doctoryourself.com/review_hoffer_B3.html

    I’d bet the mechanism of action is raising NAD+ levels and thus energy levels in neurons.
    Here’s a short article by Hoffer stating that he used nicotinamide as well as niacin.
    http://www.encognitive.com/node/6344

    Reply
The Man says March 22, 2015

Have you ever looked into nadph oxidase inhibitors? Apocynin/C-Phycocyanin found in spirulina

Examine.com review seems very positive: http://examine.com/supplements/Spirulina/

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    P. D. Mangan says March 22, 2015

    Thanks for that. I did actually take spirulina at one time when I had CFS, and for that reason, that it inhibits NADPH oxidase.

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Dusan says March 24, 2015

What about side effect of niacin? Especially for people who suffers from diabetes?
Tnx

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Intermittent Fasting Boosters / Autophagy Enhancers - Rogue Health and Fitness says April 8, 2015

[…] on this blog we recently discussed nicotinamide, a version of vitamin B3. (I’m not using the editorial “we”, it’s that I […]

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Joshua says April 9, 2015

I would note that niacin (aka Vitamin B3) is found in large quantities in most meats and seafoods. Assuming one already eats a lot of those foods, I can’t help but wonder if additional supplementation is really necessary. I suppose the question hinges on whether or not it’s necessary to ingest niacin WHILE fasting, or if you just need to generally have a good quantity of it in your system during those times that you fast.

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    P. D. Mangan says April 9, 2015

    Joshua, thanks for commenting, we may be talking 2 different effects here. One is raising NAD+ levels, which would happen over a slightly longer term, say days to weeks to months. One study I saw gave rats nicotinamide for several weeks I think it was, then measured NAD+. As for inducing autophagy, that seems to require a relatively high blood level, and nicotinamide and niacin have relatively short half-lives. Niacin, e.g., when taken for lipid control, is taken 3 times a day. The effects of Acipimox are manifested starting in a matter of minutes and seem to fade after a few hours. That’s why I believe that taking nicotinamide for autophagy enhancement should be done with the fast. Over a longer term, NAD+ levels will also rise. Anyway, that’s my theory, hopefully backed up by the data.

    Reply
      Joshua says April 10, 2015

      Thanks for the reply. After reading your blog lately, I’m starting to feel like I need a way to figure out which supplements to prioritize! So many interesting ideas, so little mental energy to track supplements… 🙂

      Reply
        P. D. Mangan says April 10, 2015

        I’m starting to feel like if I add another supplement, I’ll need to get rid of one.

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Anonymous Coward says April 12, 2015

Mr. Mangan,

Take a look at this chap’s experience:

http://ctheblog.cforyourself.com/2008/12/overdosing-on-niacin-side-effects.html

There may be cause for concern with long term usage.

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    P. D. Mangan says April 12, 2015

    Thanks. Lots of anecdotes, and anyway he was taking much more than I advocate, as well as niacin, not nicotinamide.

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      Cloudswrest says May 7, 2015

      I’ve been taking 1000 mg of Niacin once a day in the evening for a year or more with no side effects other than flushing. I get regular blood tests and my liver is fine. The trick with niacin is your liver is much better able to handle it on an “impulse” basis. Fast dose once or twice a day. The same daily dose in a slow or time released form has the potential to trash your liver. None of the “low flush” forms ever did squat for my cholesterol levels, but Nicotinic acid does wonders. See http://www.lifeextension.com/magazine/2007/3/atd/Page-01

      Reply
        P. D. Mangan says May 7, 2015

        Thanks for that link, Cloudswrest, great article by Dr. William Davis of Wheat Belly fame.

        Reply
Bob McBob says May 23, 2015

Niacinamide, being a SIRT inhibitor, is pro-aging.

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Drifter says December 2, 2015

As an interesting anecdote (interesting to me anyway) is that when I took 1500 mg of real niacin per day for a week or so, it seemed to significantly increase my cold tolerance, which persisted for at least two weeks after I stopped taking it. I only flushed the first day so it was not due to flushing. It seems to be consistent with improved blood flow and/or higher metabolic rate.

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louis sir says June 30, 2016

I guess I misread this. I should take this everyday or on days I intermittent fast.

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    louis sir says May 5, 2017

    Did I miss this, the niacin has been taken off the recommended supplements page?

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      P. D. Mangan says May 5, 2017

      I think I removed it out of lack of interest. No one ever bought any.

      Reply
        Bill says May 5, 2017

        PD I had an interesting experience this week here in Oz. I have been taking Niacin ( 1000 mg ) each day for the past 2 months to raise my HDL-C. And it works by the way. A 40% increase in that time according to blood tests.

        I ran out & went to my local chemist and there was none of the brand I use on the shelf. A staff member said “Oh no we don’t stock that ‘Faulding’ any more. Here buy this “Nature’s” own instead”.

        The ‘instead’ was double the price and only half the amount ! That is it was 4 times the price effectively.

        I said this her quite loudly and she got embaresed and replied it was not her decision.

        I went to 3 other chemists in my home town. None had it. All had the expensive half the dose brand.

        So I rang the company here in Oz. Yes it was still available and being produced. The company suggested I try at another chemist in a nearby town. I did this . It was not in stock but the pharmacist was helpful and courteous. He ordered it in for me. So I got double the quantity at the very cheap original price.

        But do I smell a conspiracy here re Niacin ( vitamin B3 )

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          Bill says May 5, 2017

          By the way a container of 60 Faulding 1000mg Vitamin B3, costs $7.50 Oz. retail. Very cheap !

          The alternative 60 by 500mg Nature’s Own cost $14.60 Oz. retail.

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          Bill says May 7, 2017

          PD, I have continued my checking out of B3 ( Niacin ).

          And today I found this science report on the role of HDL-C in longevity..
          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087084/

          Centenarians tend to have high levels of High .Density Lipids. And Niacin =B3 raises HDL-C levels in the blood. So maybe it is worth putting back in your list of supplements ?

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          P. D. Mangan says May 7, 2017

          High-dose, long-term niacin therapy can have unwanted side effects, for example see here. I don’t know what the current status of niacin as a lipid medication is, whether many doctors still use it or whether the mainstream recommends it. The article says it should not be routinely used. My suggestion of niacin as a longevity promoter is strictly for use during a fast, for instance once a week as in the experiments I cited, and not in gram amounts.

          Raising HDL with niacin could be ineffective – and according to the linked article, didn’t reduce the incidents of heart attack or stroke. HDL is a marker for insulin sensitivity, so raising it with a drug seems ineffective.

          Reply
ted says November 25, 2016

Here’s smth interesting – Nicotinamide/niacin/niacinamide/Vitamin B3 (I suppose they are the same thing) reverses damage and restores cognition in mice with Alzheimers!

http://www.earthclinic.com/supplements/niacinamide-for-alzheimers.html
A 2008 study published in the Journal of Neuroscience with demented mice showed that treatment with niacinamide reversed Alzheimer’s by causing a 60% reduction in one of the Alzheimer markers and increasing the number of microtubules that carry information inside the brain cells (1).

A 2012 study on lab mice reported that niacinamide restored cognitive functioning and synaptic plasticity (2).

A 2013 study concluded that niacinamide prevented cognitive decline in Alzheimer’s mice through improved neuronal activity and reduced breakdown of brain tissue (3).

Jonathon V. Wright, M.D. reviewed 2008 studies on laboratory mice and concluded that there was no reason to wait for ‘more research’ before administering niacinamide to Alzheimer’s patients (4).

Also this: http://www.life-enhancement.com/magazine/article/2049-nicotinamide-restores-cognition-in-alzheimers-disease

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ted says November 25, 2016

Niacin(B3/Niacinamide/nicotinamide) restores cognition and reverses damage in mice with Alzheimers:
http://www.earthclinic.com/supplements/niacinamide-for-alzheimers.html

A 2008 study published in the Journal of Neuroscience with demented mice showed that treatment with niacinamide reversed Alzheimer’s by causing a 60% reduction in one of the Alzheimer markers and increasing the number of microtubules that carry information inside the brain cells (1).

A 2012 study on lab mice reported that niacinamide restored cognitive functioning and synaptic plasticity (2).

A 2013 study concluded that niacinamide prevented cognitive decline in Alzheimer’s mice through improved neuronal activity and reduced breakdown of brain tissue (3).

Jonathon V. Wright, M.D. reviewed 2008 studies on laboratory mice and concluded that there was no reason to wait for ‘more research’ before administering niacinamide to Alzheimer’s patients (4).

And this too: http://www.life-enhancement.com/magazine/article/2049-nicotinamide-restores-cognition-in-alzheimers-disease

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charles grashow says January 25, 2017

Your thoughts

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962609/
Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B

http://perfecthealthdiet.com/2012/04/are-low-doses-of-niacin-dangerous/
Are Low Doses of Niacin Dangerous?

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    P. D. Mangan says January 25, 2017

    I don’t do long-term niacin treatment.

    Reply
Bill says May 7, 2017

Thanks for the reply PD. ..My reply is here because the ‘reply box’ was getting too long & skinny to use properly !
Niacin is definitely also an iron chelator. So that needs to be factored in – for good or bad as the case may be. In my case I need to watch my iron ferritin levels and not let them drop below about 30.

I also read the NBC report you linked in reply to my comment about Niacin. I note that the ‘patients’ in that study were all on standard cholesterol medications as well. Here’s what it says:
“…while adding niacin to standard cholesterol treatment did lower low density lipoprotein (LDL or “bad” cholesterol), it also was linked with a 32 percent increase in the rate of diabetes over four years.”

That’s curious as statins have the same side effects. So there is a major confounder here.

And I note that Dr Davis of Wheat Belly fame, in his June 28, 2015, article no longer sees the need to take Niacin to raise HDL-C levels, provided that a patient has adopted a complete very low carb. diet.

Thanks for clarifying how you suggest taking Niacin – only during a fast.

As for myself, I will not be taking it long term ( eg.4 years as stated in the NBC article ); probably just 6 months ! My intent is to raise by HDL-C to a protective ‘centenarian level’ as part of my anti-aging program after a long period on a vegetarian and sometimes vegan life style.

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Sasha says August 29, 2017

Thank you

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