Silencing the Aging Gene: Another Look at Clinical Uses for Niacinamide
By Daniel J. Bourassa, D.C.Rodney Dangerfield’s famous whine ‘I can’t get no respect’ up until now could have been the banner call for niacinamide. Vitamin B3, in its niacinamide (nicotinamide) form, has often been a vastly under-appreciated supplement. The most widely recognized form of B3, niacin — also known as nicotinic acid, nicotinate, and pyridone-3-carboxylic acid — has almost achieved acceptance by traditional medicine for its dramatic role in reducing cholesterol and improving the overall lipid profile. Until recently, the value of niacinamide was not so well recognized.
Although niacinamide shares some characteristics of niacin, it has unique nutritional and pharmalogical properties of its own. The niacinamide form of B3 is literally required in hundreds of enzymatic reactions in the human body. Research has demonstrated its remarkable benefits for arthritis, asthma, diabetes, heart disease, stress, stroke and recently as an anti-aging nutrient.
Niacinamide is a component of two related coenzymes —nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The principle function of these enzymes is to facilitate oxidation and reducing reactions in the form of dehydrogenases. The traditional medical use of both forms of B3 is to treat the vitamin deficiency syndrome known as pellagra, a disease that occurs frequently among people who subsisted mainly on corn (maize). After the Spanish introduced corn to Europe, a condition began to be observed which was first called ‘Mal de la Rosa’ (redness of the rose) because of the red skin lesions frequently seen — one of the hallmarks of pellagra. In Italy, the condition was called pellagra, which meant rough skin. The name Pellagra was introduced into medical literature in 1771 by Frapoli.
Full-blown pellagra is a chronic wasting disease associated with dermatitis, dementia and diarrhea (the three Ds). Early symptoms include weakness, lassitude, anorexia, and indigestion. Mental changes include fatigue, insomnia, and apathy which precede encephalopathy, characterized by confusion, disorientation, hallucination, loss of memory and frank organic psychosis.
What’s in a Name?
The generic term ‘niacin’ has often been used interchangeably, especially regarding ‘niacin deficiency’ and ‘niacin activity’. While both forms of B3 (niacin and niacinamide) prevent deficiency symptoms, they have different pharmacologic action at high doses. One immediate and obvious difference is the absence of the ‘niacin flush’ with niacinamide, which invariably occurs when high doses of niacin are taken by someone who has not developed a tolerance for it. As many people enjoy the harmless niacin flush, this can be a boon or bane, depending on one’s perspective. Also, niacinamide does not provide the direct cholesterol-lowering benefits of niacin, nor is it directly effective in the treatment and prevention of atherosclerosis. However, those sensitive to the ‘flush’ can substitute niacinamide for nicotinic acid in many other nutritional therapies that require niacin.
Niacinamide is usually absorbed only in the small intestine, while nicotinic acid is absorbed in the stomach as well. Both niacinamide and nicotinic acid are present in blood plasma and are converted to the coenzyme form in the blood cells, kidney, brain and liver. Although niacinamide can be converted to nicotinic acid, there is no direct conversion back to niacinamide. Niacinamide is water soluble, and the body does not store a significant amount. Most of niacinamide is present in the tissues in the form of nicotinamide as NAD and NADP. Niacinamide converts twice as readily to NAD/NADP as does niacin. Tryptophan metabolism provides about two thirds of the nicotinamide the body utilizes (Fig. 1). A non-redox function involves transfer of the coenzyme to macromolecules that attach to ribosomes in mitochondria and in the nucleus where it affects the activity of DNA. The non-redox function is thought to account for the rapid turnover of NAD in the body.
Gene Silencing and Anti-Aging
Genes and gene therapy are proving to be a powerful tool in the latest frontier in the fight against aging. Genes are actually a small part of the DNA structure and cellular differentiation depends on not only gene expression but also on gene silencing. In other words, which genes are ‘expressed’ determines the cell purpose and activity. Recent research has identified genes that influence longevity. In particular, a gene labeled, Sir2, for silent information regulator 2, has been shown to produce a protein, Sir2p, that extends cell life. Recent research has shown that Sir2p is a NAD-dependent histone deacetylase that connects metabolism, gene silencing, and cellular life extension (Imai, et.al. 2000). Niacinamide, by increasing NAD, enhances Sir2p activity. Caloric restricted diets have long been known for their ability to extend the lifespan by slowing metabolism. NAD is essential in cellular metabolism. It was proposed by MIT researchers that by slowing metabolism NAD is spared, thereby enhancing Sir2p activity. Increasing intracellular NAD not only mimics the metabolic benefits of calorie restricted diets, but also helps maintain a balance of silent and active genes. Nutritional supplementation with niacinamide, as mentioned earlier, is an effective way to increase intracellular NAD levels. Additionally, Sir2 activity is also thought to have ADP-ribosyltransferase activity (Tanny, et al. 1999). Could it be that increased intracellular NAD positively influences ADP-ribosyltransferase activity in favor of Sir2p activity over nitric oxide synthase? This could explain the inhibition of nitric oxide and account for niacinamide’s benefit in the treatment of arthritis and diabetes, as well as protection of the brain.
Better for Arthritis than NSAIDS
Niacinamide has been known for over fifty years for its benefit in the treatment of arthritis. Niacinamide, glucosamine, SAMe, selenium and fish oil may all provide significantly superior alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs). These supplements act as modulators at multiple points in the signal transduction pathways that promote synthesis and mediate the activity of the cytokine interleukin-1 (IL-1). IL-1, so crucial to the pathogenesis of osteoarthritis, is also involved in B and T cell proliferation, cytokine production by macrophages and T cells, prostaglandin release, bone reabsorption and fever. IL-1 contributes to arthritis by stimulating nitric oxide (NO) production. Inhibiting NO has been proposed as a desirable therapeutic approach in osteoarthritis (Amin, Abramson 1998). NO is a highly reactive, cytotoxic (cell-killing) free radical. NO has long been implicated in a variety of tissue injury related diseases, and is thought to play a significant role in the breakdown of articular (joint) cartilage, resulting in osteoarthritis. Niacinamide blunts the anti-catabolic effects of IL-1 which is generated by the synovium (the membrane which surrounds the joint). IL-1 induces the production of increased nitric oxide synthase. Nitric oxide synthase, in turn inhibits chondrocyte synthesis of substances that are essential for the repair of cartilage. This results in the inefficient repair of articular cartilage. Niacinamide, by inhibiting ADP-ribosylation, is thought to suppress the cytokine-mediated induction of nitric oxide synthase by IL-1 (McCarty, Russell 1999). In fact, the progression of collagen II-induced arthritis is inhibited by niacinamide and this inhibition is enhanced when co-supplemented with N-acetyl cysteine (Kroger H, et.al. 1999).
Niacinamide and Diabetes
Niacinamide has three major benefits for diabetics. First, it reduces nitric oxide synthase which helps retard beta cell death. Beta cells are the pancreatic cells that produce insulin. Second, it enhances ox/redox function through restoration of NAD levels which help prevent cellular damage and improve regeneration. Third, it reduces glycosylated hemoglobin levels which reduces the peripheral organ and blood vessel oxidation load and damage from sugar metabolites. In type I diabetics, niacinamide supplementation may slow down pancreatic beta cell destruction (where insulin is formed) and enhance the cells’ regeneration. Niacinamide suppresses ADP-ribosylation reactions in beta cells as well as in immune cells and the endothelium. Cell death pathways and gene expression patterns are modified with high niacinamide doses leading to improved beta cell survival and an enhanced immunoregulatory balance (Kolb, Burkhart 1999). In another earlier study, nicotinamide supplementation was shown to result in lower glycosylated hemoglobin along with lower insulin doses. The authors concluded that niacinamide may be successful in improving metabolic control in recent onset type I diabetes, probably by increasing residual islet B-cell (beta cell) function (Pozzilli, et.al. 1989). Complete remissions of young adult type I diabetics lasting over two years are rare, yet a 1987 French study found two complete remissions out of seven patients given 3gm/day. They also found the mean dose of insulin was lower in the niacinamide-treated group than the placebo group. (Vague, et.al 1987) Niacinamide may also be of benefit in type II adult onset diabetes and chronic pancreatitis. Researchers observed improved glycemic parameters and other benefits by the addition of niacinamide to nutritional therapies of type II diabetics. It is reasoned that reduction of glycosylated hemoglobin and enhancement of beta cell survival and function is beneficial in Type II diabetes as well. In a study of alcoholics with chronic pancreatitis, niacinamide significantly increased basal secretion of insulin, slightly improved glucose-stimulated secretion and promoted reduction of hypercoagulation and time to remission (Loginov et.al. 1999). Niacinamide may also retard nephropathy in diabetics and reduce liver toxicity in drug therapies (Kroger, et. al. 1999). While high doses of B3 as nicotinic acid have been reported to worsen glycemic control, niacinamide’s positive effect on reducing glycosylated hemoglobin should be seriously considered. One to three grams of niacinamide per day is safely achievable. I have had only positive responses in my patients who use a multinutrient formula with large amounts of niacinamide. In addition, niacinamide works synergistically with other supplements such as vitamin E, calcium-AEP, chromium picolinate, vanadyl sulfate, lipoic acid and the herb Goat’s Rue (Galega officinalis) to reduce blood sugar and glycosylated hemoglobin, and regulate blood insulin. Studies show that control of glycosylated hemoglobin and insulin are key factors in management of Type I and II diabetes because both contribute heavily to the deleterious effects of the disease process. Dietary management is extremely important in the maintenance of glycemic control. Many Type II adult onset diabetics do not make adequate diet and lifestyle modifications and continue with dietary habits that contributed to their condition in the first place. When supplementing over 500mg/day of niacinamide, it is recommended that diabetics (both Type I and II) monitor not only blood sugar, but also glycosylated hemoglobin and insulin levels. They can then adjust their individual niacinamide dosing and diet accordingly to achieve an optimum reduction in glycosylated hemoglobin.
A Safe Alternative for Fighting Stress and Anxiety
Niacinamide reduces the psychological effects of stress and anxiety. Niacinamide has been shown to be effective in alleviating anxiety, elevating the aggressive reaction threshold, and decreasing fighting (Akhundov et.al. 1993). It may be an effective natural alternative to benzodiazepines. Niacinamide has demonstrated benzodiazepine-like actions (Mohler et.al. 1979). Niacinamide is thought to be an endogenous ligand for the benzodiazepine-GABA receptor complex. It potentiates the anticonvulsant effects of diazepam (Kryzhanovskii, Shandra 1985). Study participants report they sleep better when taking niacinamide. There now appears to be almost an epidemic of Ritalin prescriptions among school children. Unfortunately medicine has not fully considered Ritalin’s profound adverse effects on brain chemistry and energy. There is little focus on the role played by amphetamines and other mood-altering prescription or illicit drugs in childhood violence. Xenobiotic (synthetic) drug therapy, combined with biochemical imbalances resulting from situational stress and dietary induced nutritional deficiencies must be considered as a significant contributing factors in childhood violence. Niacinamide is a potentially highly effective treatment for many childhood and adolescent behavioral problems. Niacinamide helps maintain brain ATP/ADP ratios and thereby maintains brain energy and amine levels. Amphetamine-induced depletion of dopamine and energy stores can often be alleviated by niacinamide (Wan, et.al. 1999). Niacinamide, at the very least, would appear to be an inexpensive primary intervention tool due to its benefit of significantly reducing the aggression threshold. Niacinamide has yet another benefit for students. It was shown to have nootropic effects greater than piracetam! Niacinamide also beat piracetam as an antihypoxic, antiamnestic and anxiolytic (Akhundov, et. al., 1990). Perhaps administrators and psychologists should be dispensing niacinamide rather than amphetamines and mood altering xenobiotics in our schools.
Niacinamide’s Other Diverse Benefits
Niacinamide may have therapeutic benefit in a wide range of disease processes because of its potent anti-inflammatory and anti-tumor properties. In asthma, niacinamide supplementation reduced mast cell degranulation and histamine release. Niacinamide has consequently been recommended for relief of bronchial asthma and urticaria (Werbach 1987). Niacinamide may be beneficial in the fight against cancer. It has been shown to inhibit gene transcription of NF-kappa B, which regulates inflammation, and which in turn inhibits NF-kappa A and induces apoptosis of tumor cells (Pero, et.al. 1999). Niacinamide has been studied as a useful adjunct in the early treatment of stroke. If taken within two hours of onset of a stroke, niacinamide was shown to reduce the infarction in a dose dependent manner (Ayoub, et.al. 1999). Niacinamide has been shown to reduce damage in arterial occlusion largely by enhancing NAD+ (which increases ATP concentrations) and by inhibiting cell death through nitric oxide inhibition.
The most common side effect of high-dose niacinamide is sedation. High doses of niacinamide as well as timed-release niacin have raised questions about hepatotoxicity. This may be an overstated caution. Niacinamide at therapeutic doses of up to 3 grams a day for an adult and 100 - 500 mg for a child in 2-3 divided doses is usually well-tolerated. Lower levels of niacinamide were shown to actually protect against hepatotoxicity, as noted earlier. Two to three grams daily is recommended for an anti-aging program with a corresponding decrease in niacin. It should be given with a complete B complex or multivitamin. Niacinamide doses often can be reduced once therapeutic effects are achived if taken solely for stress and anxiety.
Niacinamide is very effective in alleviating the symptoms of diabetes, osteoarthritis, anxiety and insomnia, and for reducing the aggression threshold during stressful events. Arthritis patients report reduction in pain symptoms sooner when niacinamide is taken along with other substances like glucosamine, chondroitin, and MSM. Patients taking niacinamide for anxiety and stress usually report they soon feel ‘normal’ again and can ‘deal’ with their stress. They can reduce or stop niacinamide for a few days until the ‘pressure’ starts to build again. Niacinamide, along with a-lipoic acid, should be considered as an essential anti-aging nutrient. Its positive enhancement of Sir2p and longevity provides those seeking to slow and reverse the aging process a first-generation tool in genetic anti-aging therapy as well as a way to square the aging curve. Niacinamide also plays an important role in the Neuroendocrine Theory of Aging hypothesis. By blunting the effects of age-induced increase in IL-1 in the brain as well as its improvement of cellular ox/redox function and regeneration, it helps protect and maintain ‘set point’ sensitive neurons of the brain, and specifically in the hypothalamus. This ultimately may not only square the aging curve but may extend it as well. Niacinamide is a safe, effective, inexpensive supplement that should be considered an essential part in a nutritional program.
1. Imai S, Armstrong CM, Kaeberlein M, Guarente L; Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000 Feb 17;403(6771):795-800 2. Tanny JC, Dowd GJ, Huang J, Hilz H, Moazed D; An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing. Cell 1999 Dec 23;99(7):735-45 3. Kroger H, Hauschild A, Ohde M, Bache K, Voigt WP, Erlich W ; Enhancing the inhibitory effect of nicotinamide upon collagen II induced arthritis in mice using N-acetylcysteine. Inflammation 1999 Apr;23(2):111-5 4. Amin AR, Abramson SB; The role of nitric oxide in articular cartilage breakdown in osteoarthritis. Curr Opin Rheumatol 1998 May;10(3):263-8 5. McCarty MF, Russell AL; Niacinamide therapy for osteoarthritis —does it inhibit nitric oxide synthase induction by interleukin 1 in chondrocytes? Med Hypotheses 1999 Oct; 53(4):350-60 6. Kolb H, Bukart V: Nicotinamide in type 1 diabetes. Mechanism of action revisited. Diabetes Care 1999 Mar;22 Suppl 2:B16-20 7. Pozzilli P, Visalli N, Ghirlanda G, Manna R, Andreani D; Nicotinamide increases C-peptide secretion in patients with recent onset type 1 diabetes. Diabet Med 1989 Sep-Oct;6(7):568-72 8. Vague P, Vialettes B, Lassmann-Vague V, Vallo J; Nicotinamide may extend remmision phase of insulin-dependent diabetes. The Lancet Mar 1987 ltr 9. Loginov AS, Matiushin BN, Astaf’eva OV, Nilova TV, Vinokurova LV; [Nicotinamide in combined treatment of chronic pancreatitis]. Ter Arkh 1999;71(8):43-6 10. Kroger H, Hauschild A, Ohde M, Bache K, Voigt WP, Thefeldt W, Kruger D; Nicotinamide and methionine reduce the liver toxic effect of methotrexate. Gen Pharmacol 1999 Aug;33(2):203-6 11. Hoffer A; Schizophrenia: an evolutionary defence against severe stress. J. of Orthomol Med 1994; Vol. 9(4):205-221 12. Burns DM, Ruddock MW, Walker MD, Allen JM, Kennovin GD, Hirst DG; Nicotinamide-inhibited vasoconstriction: lack of dependence on agonist signaling pathways. Eur J Pharmacol 1999 Jun 18;374(2):213-20 13. Akhundov RA, Sultanov AA, Gadzhily RA, Sadykhov RV; [Psychoregulating role of nicotinamide]. Biull Eksp Biol Med 1993 May;115(5):487-91 14. Mohler H, Pole P, Cumin R, Pieri L, Kettler R; Nicotinamide is a brain constituent with benzodiazepine-like actions. Nature 1979 Apr 5;278(5704):563-5 15. Kryzhanovskii GN, Shandra AA; Effect of diazepam and nicotinamide on convulsive activity of various types]. Farmakol Toksikol 1985 Jul-Aug;48(4):21-5 16. Wan FJ, Lin HC, Kang BH, Tseng CJ, Tung CS; D-amphetamine-induced depletion of energy and dopamine in the rat striatum is attenuated by nicotinamide pretreatment. Brain Res Bull 1999 Oct;50(3):167-71 17. Akhundov RA, Zagorevskii VA, Voronina TA; [Nootropic activity of nicotinamide and its structural analogs]. Biull Eksp Biol Med 1990 Oct;110(10):384-6 18. Werbach M. Nutritional Influences on Illness, 2nd ed., 1993 pp 114-115, 117 19.) Pero RW, Axelsson B, Siemann D, Chaplin D, Dougherty G; Newly discovered anti-inflammitory properties of the benzamides and nicotinamides. Mol Cell Biochem 1999 Mar;193(1-2):119-25 20. Ayoub IA, Lee EJ, Ogilvy CS, Beal MF, Maynard KI; Nicotinamide reduces infarction up to two hours after the onset of permanent focal cerebral ischemia in Wistar rats. Neurosci Lett 1999 Jan 4;259(1):21-4 21. Paine AJ, Hockin LJ, Legg RF; Relationship between the ability of nicotinamide to maintain nicotinamide-adenine dinucleotide in rat liver cell culture and its effect on cytochrome P-450. Biochem J 1979 Nov 15; 184(2):461-3