It was disturbing to some readers when I characterized niacinamide as a pro-aging substance in the March 24 blog post SIRT1, mTOR, NF-kappaB and resveratrol, as it was disturbing to me when I first came to that realization years ago. In response to several blog comments I promised some readers to further research niacinamide and niacin for both health benefits and possible pro-aging hazards, and this blog post reports on that research. I will report on a number of research studies and finally I will give my opinions on how it all comes together and I will even disclose my past secret affair with niacin.
Niacin and Niacinimide
“Nicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid (vitamin B3/ niacin). Nicotinamide is a water-soluble vitamin and is part of the vitamin B group. Nicotinic acid, also known as niacin, is converted to nicotinamide in vivo, and though the two are identical in their vitamin functions, nicotinamide does not have the same pharmacologic and toxic effects of niacin, which occur incidental to niacin’s conversion. Thus nicotinamide does not reduce cholesterol or cause flushing, although nicotinamide may be toxic to the liver at doses exceeding 3 g/day for adults. In cells, niacin is incorporated into nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), although the pathways for nicotinamide and nicotinic acid are very similar. NAD+ and NADP+ are coenzymes in a wide variety of enzymatic oxidation-reduction reactions. (ref)”
Continuing, “Nicotinamide adenine dinucleotide (NAD) and its relative nicotinamide adenine dinucleotide phosphate (NADP) are two of the most important coenzymes in the cell. NADP is simply NAD with a third phosphate group attached – (ref). – NAD plays several key roles in metabolism. It “participates in many redox reactions in cells, including in glycolysis and most of those in the citric acid cycle of cellular respiration(ref).” And, as I have discussed previously, SIRT1 requires NAD for its actions(ref)(ref).
General information on dietary sources of niacin/niacinamide and problems associated with deficiency of vitamin B3 can be found here and here. “Niacin can be found in nuts, dairy products, lean meats, poultry, fish, and eggs. Some niacin is also supplied by legumes and enriched breads and cereals. The best dietary sources of vitamin B3 are found in beets, brewer’s yeast, beef liver, beef kidney, pork, turkey, chicken, veal, fish, salmon, swordfish, tuna, sunflower seeds, and peanuts. The body can synthesize niacin from the essential amino acid tryptophan, but the synthesis is extremely slow; 60 mg of tryptophan are required to make one milligram of niacin. For this reason, eating lots of tryptophan is not an adequate substitute for consuming niacin. As serotonin synthesis is reliant on tryptophan availability, inadequate dietary intake of vitamin B3 may also therefore lead to depression. The liver is the main storage area for this vitamin and absorption of vitamin B3 takes place in the intestines(ref).”
Further, “Niacin works closely with vitamin B1, vitamin B2, vitamin B6, pantothenic acid, and biotin to break the carbohydrates, fats, and proteins in food . – Vitamin B3 is essential in the metabolism of carbohydrates (to produce energy), fats, and proteins. It also aids in the production of hydrochloric acid, needed for proper digestion. Additionally, vitamin B3 facilitates the body’s ability to eliminate toxins.” – Vitamin B3 is required by the body for digestive processes, activating enzymes which nourish the brain, regulating blood pressure and regulating cholesterol levels.” “Niacin is a water-soluble vitamin that participates in more than 50 metabolic functions, all of which are important in the release of energy from carbohydrates. Because of its pivotal role in so many metabolic functions, niacin is vital in supplying energy to, and maintaining the integrity of, all body cells. Niacin also assists in antioxidant and detoxification functions, and the production of sex and adrenal hormones. Vitamin B3 (niacin, niacinamide, nicotinic acid) lowers cholesterol by preventing its buildup in the liver and arteries. Niacin moves fat from tissues for fat metabolism, burning it for energy. It promotes , the health of the myelin sheath (the protective covering of the spinal nerves), and good digestion, where it is also vital for the production of hydrochloric (stomach) acid. It is an aid in protecting the pancreas, and is necessary for the health of all tissue cells(ref).”
The government-recommended daily allowance (RDA) for niacin/niacinamide is 16 mg a day for men, 14 mg for women. The 95th percentile intake for both food and supplements is estimated to be 40-70 mg for both food and supplements(ref). Pharmacological doses of either form of B3 can range from 500mg to 2gm daily. There is a possibility of liver endangerment at the level of 3gms or more daily.
The case for niacinamide promoting health and longevity
B3 has been used now for over 40 years, often in large doses as a drug(ref). A major application has been control blood cholesterol levels. According to a 1986 publication: “The Coronary Drug Project was conducted between 1966 and 1975 to assess the long-term efficacy and safety of five lipid-influencing drugs in 8,341 men aged 30 to 64 years with electrocardiogram-documented previous myocardial infarction. The two estrogen regimens and dextrothyroxine were discontinued early because of adverse effects. No evidence of efficacy was found for the clofibrate treatment. Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). This late benefit of niacin, occurring after discontinuation of the drug, may be a result of a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfarction or a result of the cholesterol-lowering effect of niacin, or both.” Later it has become popular to combine niacin with a statin to control blood lipids. A 2009 study concludes: “ Combined use of extended-release niacin with atorvastatin was superior to atorvastatin monotherapy alone in lipid profile regulation. Combination therapy with niacin ER and atorvastatin was well tolerated and safe in patients with coronary artery disease.”
Several researchers think that pathways activated by niacin/niacinamide could offer hope for development of new drug treatments for several diseases, diabetes being prime among them, but further understanding of the complex metabolic pathways involved is a prerequisite.
The 2008 review article NAD+ and vitamin B3: from metabolism to therapies espouses this viewpoint. The 2008 publication Triple play: promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus, states “Here we discuss the novel application of nicotinamide, Wnt signaling, and erythropoietin that modulate cellular oxidative stress and offer significant promise for the prevention of diabetic complications in the nervous and vascular systems. Essential to this process is the precise focus upon diverse as well as common cellular pathways governed by nicotinamide.”
The 2010 publication Diabetes Mellitus: Channeling Care through Cellular Discovery comes to essentially the same conclusion “For these reasons, innovative strategies are necessary for the implementation of new treatments for DM that are generated through the further understanding of cellular pathways that govern the pathological consequences of DM. In particular, both the precursor for the coenzyme beta-nicotinamide adenine dinucleotide (NAD(+)), nicotinamide, and the growth factor erythropoietin offer novel platforms for drug discovery that involve cellular metabolic homeostasis and inflammatory cell control.”
Health and potential life-extending properties of niacin/niacinamide
“More recently, the health benefits of niacin have been shown to be far more extensive than previously appreciated — Numerous reports indicate niacin might help prevent atherosclerosis, diabetes and hypercholesterolemia. Niacin is effective in assisting burn-wound recovery, and in the prevention of cataracts and skin cancer. Unfortunately, the molecular basis for most of these health benefits remains unclear(ref).”
The 2006 e-publication Nicotinamide extends replicative lifespan of human cells reports “We found that an ongoing application of nicotinamide to normal human fibroblasts not only attenuated expression of the aging phenotype but also increased their replicative lifespan, causing a greater than 1.6-fold increase in the number of population doublings. Although nicotinamide by itself does not act as an antioxidant, the cells cultured in the presence of nicotinamide exhibited reduced levels of reactive oxygen species (ROS) and oxidative damage products associated with cellular senescence, and a decelerated telomere shortening rate without a detectable increase in telomerase activity. Furthermore, in the treated cells growing beyond the original Hayflick limit, the levels of p53, p21WAF1, and phospho-Rb proteins were similar to those in actively proliferating cells. The nicotinamide treatment caused a decrease in ATP levels, which was stably maintained until the delayed senescence point. Nicotinamide-treated cells also maintained high mitochondrial membrane potential but a lower respiration rate and superoxide anion level. Taken together, in contrast to its demonstrated pro-aging effect in yeast, nicotinamide extends the lifespan of human fibroblasts, possibly through reduction in mitochondrial activity and ROS production.
Another possible longevity contribution of nicotinamide is via autophagy as related in the 2009 publication 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 (DeltaPsim) by accelerating autophagic degradation of mitochondria.”
I note that these two studies as well as some others commenting on possible longevity benefits of niacin/niacinamide supplementation are in-vitro and the results may or may not apply in human bodies because of the many complex biochemical feedback loops involved.
The darker side of niacin/niacinamide supplementation
Turning now to the darker side, there is unquestionable evidence that niacinamide inhibits the expression of SIRT1 and its multiple health and longevity benefits discussed in three recent blog posts ( SIRT1, mTOR, NF-kappaB and resveratrol, Visit with Leonard Guarante, and .
The 2002 publication Inhibition of Silencing and Accelerated Aging by Nicotinamide, a Putative Negative Regulator of Yeast Sir2 and Human SIRT1 reported that in yeast at least nicotinamide inhibited Sir2 and decreased lifespan. “We show here that nicotinamide strongly inhibits yeast silencing, increases rDNA recombination, and shortens replicative life span to that of asir2 mutant.”
The 2005 treatise Vitamin B3 and sirtuin function is among the documents that makes the point via a comprehensive analysis: “Most notable with respect to the cellular regulation of sirtuins is their dramatic inhibition by nicotinamide.” – “Sirtuins are NADC-dependent protein deacetylases that are involved in transcriptional regulation, metabolism, apoptosis, differentiation and ageing. These unique enzymes are inhibited by nicotinamide, which is a form of vitamin B3. Recent studies have uncovered the molecular basis for nicotinamide inhibition, and provided the framework to understand the physiological processes mediated by sirtuins — .” SIR2 and its human counterpart SIRT1 produce many of their health and longevity processes via deacetylation reactions. “ SIRT1 targets transcription factors that are dynamically regulated by reversible acetylation.” — “Deacetylation by Sir2 requires NADC and yields the additional products nicotinamide and O-acetyl-ADP-ribose (OAADPr). Nicotinamide is a potent inhibitor of the reaction, but can be recycled back to NADC via a NADC-salvage pathway(ref).” – “Most notable with respect to the cellular regulation of sirtuins is their dramatic inhibition by nicotinamide. First analyzed in several kinetic studies [15–17] and recently by X-ray crystallographic analysis , nicotinamide and several of its derivatives are powerful mechanism-based inhibitors. The inhibition constants vary between homologs, but usually fall within the 20–200-mM range, which makes nicotinamide the most potent general inhibitor described to date. Accordingly, nicotinamide has been used to inhibit cellular sirtuins in a wide variety of experiments in yeast and mammalian cells.” The paper goes into the detailed biochemistry of the inhibition process.
An interesting point is that the acid form of niacin, nicotinic acid “displays almost negligible binding to and inhibition of sirtuins(ref).” The point is fairly moot in terms of what goes on in us mammals, however, since “Niacin is converted to nicotinamide and then to NAD and NADP in vivo. — “It is important to mention that, although only nicotinamide inhibits sirtuins, both nicotinic acid and nicotinamide lead to increased cellular NADC production. To help clarify these issues, a complete understanding of NADC metabolism with quantification of relevant metabolites and intermediates, and how these impinge on sirtuin-mediated pathways will be essential(ref).”
Going back to fruit flies, the 2008 study, Life span extension and neuronal cell protection by Drosophila nicotinamidase says that in Drosophila fruit flies, overexpression of nicotinamidase, D-NAAM significantly increases median and maximal fly life span. Nicotinamidase is an enzyme that promotes the breakdown of nicotinamide
The unknown effects of niacin/nicotinamide
After 50 or more years of use, researchers are starting to wonder exactly what large doses of niacin/ nicotinamide do in terms of activating cellular pathways. The 2009 publication The vitamin nicotinamide: translating nutrition into clinical care reports “Nicotinamide, the amide form of vitamin B3 (niacin), is changed to its mononucleotide compound with the enzyme nicotinic acid/nicotinamide adenylyltransferase, and participates in the cellular energy metabolism that directly impacts normal physiology. However, nicotinamide also influences oxidative stress and modulates multiple pathways tied to both cellular survival and death. During disorders that include immune system dysfunction, diabetes, and aging-related diseases, nicotinamide is a robust cytoprotectant that blocks cellular inflammatory cell activation, early apoptotic phosphatidylserine exposure, and late nuclear DNA degradation. Nicotinamide relies upon unique cellular pathways that involve forkhead transcription factors, sirtuins, protein kinase B (Akt), Bad, caspases, and poly (ADP-ribose) polymerase that may offer a fine line with determining cellular longevity, cell survival, and unwanted cancer progression. If one is cognizant of the these considerations, it becomes evident that nicotinamide holds great potential for multiple disease entities, but the development of new therapeutic strategies rests heavily upon the elucidation of the novel cellular pathways that nicotinamide closely governs.” I summarize this as “It is very interesting and potentially very useful stuff but we don’t know enough yet to be able to say exactly what it does.”
The same wondering tone is found in the 2009 publication Niacin status impacts chromatin structure, “Niacin is required to form NAD and NADP, which are involved in many essential redox reactions in cellular metabolism. In addition, NAD+ acts as a substrate for a variety of ADP-ribosylation reactions, including poly- and mono-ADP-ribosylation of proteins, formation of cyclic ADP-ribose, and the generation of O-acetyl-ADP-ribose in deacetylation reactions. These nonredox reactions are critical in the regulation of cellular metabolism, and they are sensitive to dietary niacin status. There are 4 known mechanisms by which ADP-ribosylation reactions directly regulate chromatin structure. These include the covalent modification of histones with poly(ADP-ribose), the extraction of histones from chromatin by noncovalent binding to poly(ADP-ribose) on poly(ADP-ribose) polymerase-1, poly ADP-ribosylation of telomeric repeat-binding factor-1 within telomeres, and deacetylation of histones by the sirtuins. These reactions produce a variety of localized effects in chromatin structure, and altered function in response to changes in niacin status may have dramatic effects on genomic stability, cell division and differentiation, and apoptosis.” Yes indeed they may. But do they, and if so what exactly are the dramatic effects?
The March 2010 e-publication Widespread effects of nicotinic acid on gene expression in insulin-sensitive tissues: implications for unwanted effects of nicotinic acid treatment summarizes the paradoxical effects of niacin supplementation. In mice, an infusion of niacin was shown to affect the expression of a great many genes. Some of the changes in gene expression produce wanted effects, others produce unwanted effects. “Nicotinic acid (NA; or niacin) has been used as a hypolipidemic agent for more than 4 decades. However, the mechanisms underlying the effects of NA treatment (wanted and unwanted) are still poorly understood. In the present study, we discovered that NA infusion in rats resulted in dephosphorylation (i.e., activation) of the forkhead transcription factor FOXO1 in insulin-sensitive tissues such as skeletal and cardiac muscles, liver, and adipose tissue. These NA effects were opposite to the effects of insulin to increase FOXO1 phosphorylation. Nicotinic acid had widespread effects on gene expression in all of the tissues studied, and the number of genes affected by NA greatly exceeded that of genes affected by insulin. — Some of the NA-induced changes in gene expression are discussed as potential mechanisms underlying wanted and unwanted effects of NA treatment.”
The literature suggests that either too little or too much (“pharmacological quantities”) of niacin/niacinamide can produce multiple, strange, and possibly unwanted effects. According to the 2009 publication Niacin status, NAD distribution and ADP-ribose metabolism, “Dietary niacin deficiency, and pharmacological excesses of nicotinic acid or nicotinamide, have dramatic effects on cellular NAD pools, ADP-ribose metabolism, tissue function and health. ADP-ribose metabolism is providing new targets for pharmacological intervention, and it is important to consider how the supply of vitamin B3 may directly influence ADP-ribosylation reactions, or create interactions with other drugs designed to influence these pathways. — A wide range of metabolic changes can take place following pharmacological supplementation of nicotinic acid or nicotinamide. As niacin status decreases towards a deficient state, the function of other types of pharmaceutical agents may be modified, including those that target ADP-ribosylation reactions, apoptosis and inflammation.”
There is a body of literature I am not covering here on the cosmetic use of nicotinamide in skin creams with purported anti-aging results. I might dig into this in another blog entry later.
How does it all come together?
Observation 1: The body absolutely needs to have an adequate supply of niacin or niacinamide available to make the amounts of NAD and NADP required for health. Further, this must come from dietary sources, foods or supplements.
Observation 2: The research literature related to therapeutic use of niacin/niacinamide is at first confusing expressing different viewpoints that have emerged during different periods of time and representing different ways of looking at the effects of substance. Some articles cite reasons why large doses of niacin may promote longevity, and other articles cite reasons why such use may shorten life.
Observation 3: For about 40 years large doses of niacin have been used for several therapeutic purposes. Many physicians currently prescribe large doses of niacin for lipid control and other purposes. Mild benefits seem to exist in some areas like raising HDL cholesterol. The long-term consequences of repeatedly taking large doses are unknown.
Observation 4: Large scale niacin dosage profoundly affects multiple genes through multiple pathways producing both wanted and unwanted results. While many researchers are excited by the possibilities of niacin-related therapies for a variety of conditions, the one thing they agree on is a need for further understanding of the pathways involved.
Observation 5: The sirtuin-related pathways involving the niacin metabolites NAD and NADP are among those related to niacin most intensely studied in recent years. Large doses of niacin/niacinamide inhibit the expression of SIRT1 and therefore prevent the health and longevity benefits associated with expression of SIRT1.
Niacin and my personal regimen I have been taking niacin included in a B-complex “B-50” pill taken twice daily, for a total of 100 mg daily. And added to this is niacin/niacinamide included in my breakfast cereals and other food, perhaps another 40mg. So, with food I have probably been ingesting 140 mg a day of B3. This is considerably over the minimum USRDA of 16mg and is possibly excessive for my optimal health. I am changing my personal regimen and my suggested anti-aging Supplement Regimen to include only one B-50 a day and am looking into different B-complex supplements. And clearly, I do not plan to take larger doses of either niacin or niacinamide.
Personal note on my affair with niacin
In the spirit of disclosure, I need to own up to the fact that I once had a torrid affair with niacin. And I really mean torrid because the stuff gives you hot flushes. In the late 1970s there were some psychiatric and medical practitioners prescribing megadoses of niacin for all kinds of conditions, including chronic hypoglycemia and what later has come to be called bipolar disease. It was a period where megavitamin therapy and orthomolecular medicine seemed to be the latest and best things for health. Proponents of this approach like Dr. Allan Cott were respected people to be paid attention to. I came under the influence of a New Hampshire medical practitioner who tested me and several of my sons for hypoglycemia, “evaluated” our mental states, and soon the whole bunch of us were taking megadoses of niacin, 1,000-1,500 mg a day. This at first may have actually benefitted one of my sons who had been having problems with his schoolwork. Reading some of the orthomolecular medicine literature of the day, I thought niacin was wonderful stuff. After about three years, however, two things happened that resulted in the affair with niacin ending. The first is that the son mentioned started taking larger and larger doses after he entered college, hoping it would help him cope with harder and harder schoolwork. He ended up being seriously ill with a very inflamed liver and had to be hospitalized. The diagnosis was overdose on Niacin. The second thing is that we learned that the New Hampshire practitioner was not really a medical doctor as he had represented himself to be. He was a fake. We stopped taking megadoses of niacin. In essence looking back, I think the spirit and intent of orthomolecular medicine was and continues to be a good thing, but that the scientific knowledge required to allow effective orthomolecular therapy to become a systematic practice is only now emerging.
Please see the medical disclaimer for this blog.