Nicotinamide Improves Health and May Extend Life

Applying the Secrets of Caloric Restriction
By David Jay Brown

Many life-extension seekers have viewed the dramatic results from longevity studies involving caloric restriction as one of life's cruelest jokes. Calorically restricted animals (that receive all their proper nutrients) develop fewer diseases in general and are known to live significantly longer than animals that are allowed to eat as much as they like. Numerous animal studies - dating all the way back to the 1920s - have shown this to be the case with worms, flies, mice, and monkeys.1

While living longer by adhering to a partial-starvation diet may not seem particularly appealing to most people, the results of these studies have been so impressive that anyone seriously interested in life extension has to be more than a little intrigued.

Caloric restriction doesn't just increase average lifespan in animals; it also increases maximum lifespan - dramatically so. This means that animals on calorically restricted diets live significantly longer than the longest-lived members of their own species that are not calorically restricted. Many things increase average lifespan in animals - a healthy diet, nutritional supplements, exercise, good genes, etc. - however, increasing maximum lifespan is a whole new ball game. The maximum lifespan for a human being is somewhere between 110 and 120 years. The longest-lived human ever documented was a French woman who died in 1997 at 122 years. The rodents in the calorie-restriction studies lived to be the human equivalent of 140 to 160 years!3


Rhesus monkeys used in the NIA caloric-restriction study had much lower incidence of cancer and other diseases involving cell proliferation.

LESS CANCER AND PROLIFERATIVE DISEASES
The primate studies involving caloric restriction suggest that these results probably apply to humans as well, and exciting new research suggests that the life-extending benefits of caloric restriction may be available without having to struggle with a near-starvation diet. New evidence from a recent study at the National Institute on Aging in Bethesda, Maryland sheds some light on the mechanism involved in caloric restriction and suggests that nicotinamide supplements (with the proper cofactors) may mimic the benefits of caloric restriction.

Recently, Mark Lane, Ph.D., Angela Black, Ph.D., and colleagues at NIA revealed that calorically restricted monkeys develop fewer proliferative diseases (such as cancer and endometriosis) than controls.4 The NIA study, which followed 120 rhesus monkeys for more than a decade, found that monkeys who consumed 30% fewer calories than controls had fewer chronic diseases in general, but, more specifically, they had a much lower incidence of diseases involving cell proliferation. "I think the main implication for potential human application of this would be that it's going to reduce the incidence of age-related diseases, in particular cancer. Cancerous tumors in the animals were noticeably reduced," said Dr. Lane. This finding is not unique to the NIA study. It has been generally accepted that caloric restriction - the practice of undernutrition without malnutrition - doesn't just slow the progress of cardiovascular disease; it slows cancer too.

CALORIC RESTRICTION MECHANISM UNKNOWN
Although there have been hundreds of studies on caloric restriction, the exact biological mechanism responsible for the increase in longevity and the reduction of proliferative diseases remains a mystery. However, a number of important clues are now available. "Caloric restriction reduces insulin, insulin-like growth factor-1 (IGF-1) [a measure of growth hormone release], and other growth factors in the body. That's been shown many times. So that would have obvious effects on proliferative or runaway-growth kinds of diseases. That may be the proximate mechanism here, but we really don't know that for sure," said Lane. However, most longevity researchers agree that caloric restriction probably extends animal life because fewer calories means less energy production, less wear and tear, and less oxidative damage.5

THE GENE-SILENCING THEORY
MIT researcher Leonard Guarente, Ph.D., offers an alternative explanation.6 His gene-silencing theory proposes that caloric restriction reduces the overall metabolism of an essential cofactor called nicotinamide adenine dinucleotide, or NAD for short. NAD is normally shunted into the breakdown of glucose in cellular energy production. But when increased in availability through caloric restriction, there is an abundance of NAD beyond that needed for cellular energy production. This extra NAD is available to act as a catalyst for an enzymatic protein called silent information regulator no. 2 (Sir2p). NAD increases the effectiveness of Sir2p, and the result disables the transmission of certain genetic messages that ultimately lead to cell death.

The mechanism involves a process called deacetylation, in which acetyl groups are removed from a substance called chromatin, which normally fits around the chromosomes like a loose sleeve. However, once deacetylated, the chromatin tightens itself snugly around the DNA. This blocks the DNA from broadcasting genetic instructions that would ultimately have devastating consequences for the cell and are thought to be responsible for a cellular aging process. When the chromatin tightens itself snugly around the DNA, the instructions that would eventually lead to the cell's death are squelched. When NAD is abundant, the effectiveness of Sir2p is increased, and cell life is preserved. Thus, NAD helps prevent the expression of certain genes responsible for a cellular aging process involving damage to DNA molecules.

When NAD is abundant, Sir2p prevents the release of circular DNA fragments that proliferate inside cells during the aging process. These replicating rings of genetic "noise" accumulate to the point where they eventually strangle the cell from within. However, when NAD and Sir2p join forces, the possibility of this happening is significantly reduced because of gene silencing. If caloric restriction helps increase longevity by decreasing the incidence of cancer, runaway cell proliferation - the mechanism of cancer - is likely to be fueled by more, rather than fewer, calories.

THE "CANCER-SILENCING" LINK
"A link between aging and cancer is suggested by the delay of cancers in calorically restricted mice," write Drs. Leonard Guarente and Cynthia Kenyon (also an aging-gene researcher, but at University of California, San Francisco), "and by the striking correlation between physiological age and the likelihood of cancer in animals with very different lifespans. This suggests that any treatment that slows the aging process, whether it acts directly on hormone signaling, gene silencing, or oxidative stress, may have the potential to delay cancer and possibly other diseases of aging."7

Understanding the mechanism of slowing the aging process leads one to predict that caloric restriction might be most effective in slowing down the incidence of runaway cell growth and proliferative disease, and this is exactly what Lane and Black found in their most recent study.

THE RACE FOR CALORIC-RESTRICTION-MIMICKING DRUGS
These findings have stimulated an aggressive search for drugs that mimic the process of caloric deprivation. Lane is currently studying a synthetic molecule similar to the sugar glucose. He has demonstrated that cells take up this glucose analog as if it were glucose, but they cannot metabolize it to obtain energy, as they do from glucose.

In rodent studies, administering this synthetic molecule produces some of the same responses as caloric restriction, such as reducing body temperature and lowering the amount of insulin in the blood.4 Lane and his colleagues at NIA are now testing whether these treatments will extend the lifespans of rodents.

ALTERNATIVES TO CALORIC RESTRICTION?
"By disrupting the normal metabolic pathway for the metabolism of glucose with a glucose analog," Lane explained, "we were able to reproduce many of the biological effects of [caloric] restriction - such as a reduction in insulin levels, a reduction in body temperature, and even a slight reduction in body weight. Those animals did not exhibit any significant reduction in food intake, so they were essentially eating as much as they wanted of a diet with this glucose analog in it. . . . We think that caloric restriction has many of its effects by acting as a metabolic stressor on the body. You're basically reducing metabolic output of the cells by inhibiting glycolysis, and this is what this glucose analog also does."

THE LIMITATIONS OF DRUGS
It’s unfortunate that the glucose analog that Lane is studying has significant drawbacks; at high doses it's toxic throughout the body and can kill brain cells. But there may be less toxic alternatives to mimicking the effects of caloric restriction. "There are other compounds that inhibit glycolysis as well that may not have these toxic effects," said Lane. "Right now we're focusing on really trying to study the mechanism using this glucose analog because it's well characterized and well studied in other model systems. Once we get a better handle on its workings, and if indeed it is mimetic of caloric restriction, then we're going to move into developing other compounds. The end point of this research would be to develop other compounds that are not toxic - that have these inhibitory effects on metabolism, by creating the metabolic stress that I described, and mimicking the effects of caloric restriction, including the effects on lifespan. More importantly, I like to call these effects on 'health-span,' that is, improving the quality of life in later years - healthy living versus just extension of the lifespan."

CAN NUTRIENTS MIMIC CALORIC RESTRICTION'S BENEFITS?
It also seems reasonable to suspect, however, that these health-span effects can be achieved as well, if not better, through nutritional supplements that increase the amount of NAD in the body. The body converts the nutrient niacin (vitamin B3), in the form of either nicotinic acid or nicotinamide, into NAD. It is also known that, although both nicotinic acid and nicotinamide produce NAD in the body, the rate of synthesis from nicotinamide is twice as great as that from nicotinic acid. In addition, the conversion of nicotinamide (but not nicotinic acid) into NAD is accelerated significantly by inorganic phosphate.8

OTHER ADVANTAGES FROM TAKING NICOTINAMIDE
Nicotinamide may have other benefits besides increasing levels of NAD. In addition to acting as a catalyst to Sir2p, NAD has been shown to reduce general damage to genetic material, and it protects against stress-induced apoptosis (cell suicide). In addition, NAD guards against autoimmune damage and protects pancreatic beta cells in Type 1 diabetes. It may even stave off diabetes in prediabetics.9 Many people who take nicotinamide supplements also report that they simply feel better and have more energy. This makes sense, because its traditional use, written about by Linus Pauling and others, has been effective in alleviating severe psychiatric symptoms when it is given in the range of 1.5-18 grams/day, along with 3 grams/day of ascorbic acid (vitamin C).10

The current caloric restriction research suggests that future possibilities for life extension in the area of genetics appear to be especially promising. But fully understanding the role that the Sir2 genes - and all the other genes - play in the aging process is still years away.

NAD INHIBITS METABOLISM'S DOWNSIDE
"Many people are focusing on genetic approaches," said Lane, "and my own particular feeling on that is that aging is very complex. Richard Weindruch - a real leader in the field of caloric restriction - looked at about 10% of the genes in a mouse and showed that around fifty-some genes were altered by caloric restriction. So imagine, if that's only 10% of the mouse genome, and you multiply that by ten, you're talking about hundreds of genes that are altered during aging and may be affected by caloric restriction. So I think a pure genetic approach is a long way from yielding potential results. Our approach is to use this metabolic inhibition to get at the mechanism."

NAD OFFERS THE POSSIBILITIES OF EXTENDED LIFE
Through the use of a high-potency nutritional supplement with nicotinamide and the proper cofactors to produce abundant NAD, you may be able to elevate the levels of NAD available in your cells, thereby enhancing Sir2p's role in gene silencing. When this happens, it is possible to reduce the deleterious messages, prevent runaway proliferation, and "get at the mechanism" - and you can do it today, so you're more likely to be around tomorrow, when the really big genetic breakthroughs occur. Perhaps nicotinamide and those cofactors offer the benefits of caloric restriction without the sacrifice of near-starvation.

References

  1. Pugh TD, Oberley TD, Weindruch R. Dietary intervention at middle age: caloric restriction but not dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence in mice. Cancer Res 1999 Apr 1;59(7):1642-8.
  2. Weindruch R. The retardation of aging by caloric restriction: studies in rodents and primates. Toxicol Pathol 1996, Nov-Dec;24(6):742-5.
  3. Walford R. Secrets of Long Life: Dr. Roy Walford's Plan to Live to 150. http://www.walford.com/lifextin.htm.
  4. Black A, Lane M, et al. Calorie restriction reduces the incidence of proliferative disease: preliminary data from the NIA CR in nonhuman primate study. Gerontological Society of America Annual Meeting, November 17, 2000, Washington, D.C.
  5. Sohal RS, Weindruch R. Oxidative stress, caloric restriction,and aging. Science 1996;273:59-63.
  6. Lin SJ, Defossez PA, Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 2000; 289(5487):2126-8.
  7. Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature 2000 Nov 9;408(6809):255-62.
  8. Micheli V, Simmonds HA, Sestini S, Ricci C. Importance of nicotinamide as a NAD precursor in the human erythrocyte. Arch Biochem Biophys 1990;283(1):40-5.
  9. Pozzilli P. Prevention of insulin-dependent diabetes mellitus. Diabetes Metab Rev 1998;14(1):69-84.
  10. Pauling L. Orthomolecular psychiatry: varying the concentrations of substances normally present in the human body may control mental disease. Science 1968 Apr 19;160(825):265-71.

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