New Gene Supplements
May Extend Your Life

By Will Block

The arrival of gene-support supplements opens a view to the world not foreseen.

f all the reasons to take nutritional supplements, the most compelling is the extension of life. There lies the Holy Grail, the "sacred" quest of all serious health seekers. This is because life extension embraces all the strategies of good health, which principally include:

  • Putting the brakes on degenerative decline so that (at first) health levels are maintained.
  • Enhancing energy, both mental and physical.
  • Improving restorative powers for better immune function and healing.
  • Restoring all functions of mind and body to what they were (or should have been) at their optimum.
  • Raising the banner of a new optimum, beyond the heights that may have been achieved by a few individuals, or never achieved by anyone.

It doesn't take a rocket scientist to tell that the future of life extension lies in the genes. Without a doubt, in the long run our health will be determined by what we do about our genetic programming. Indeed, the strategies of life extension outlined above apply also to DNA and our entire genetic integrity. In this realm, we must first prevent DNA damage and brake the momentum of genetic decline, especially in those mechanisms that govern the production, utilization, and conservation of energy. Next, we must express those genes that are involved in immune/healing functions. Finally, we must restore our genes' programming "defaults" while seeking new optimal "settings." Paraphrasing John Lilly, M.D., we must reprogram, or override, the human biocomputer that resides within each of us.

But for now, it is said, gene strategies are impractical because they are so complex and there is so much yet to learn. While that may be true - personal gene engineering may be far down the line - there are other ways to intervene. To a certain degree, we can enable our genes with nutrient supplements that serve to help prevent and reduce damage to them. By the intelligent use of nutrients, we can also make sure that our genes have the right materials they need to execute their instructions. This gets us on first base and moving forward to develop a body of knowledge that can help us to do the proper housekeeping. But there is exciting work beginning to appear on the horizon.

We must reprogram, or override,
the human biocomputer that
resides within each
of us.

Recent breakthroughs in understanding the mechanisms of gene action now allow us to see that the application of this knowledge, through "gene care," may lead to an extraordinary outcome. It may, for example, be possible to gain the life-extending benefits of caloric deprivation to date this is the only repeatedly studied way to extend the maximum lifespan of laboratory animals (and probably humans) without the need to live a life of self-deprivation. All that may be required is a higher level of care for our genes.

In a recent, heavily footnoted (26 references) letter to the editor of the journal Nature,1 researchers from the Massachusetts Institute of Technology offer evidence to explain why lower-calorie diets may help people live longer. They report that a gene present in every organism from yeast to humans may very well provide the explanation for the extended lifespan observed in lower animals and probably primates, including humans.

Previously, in experiments with yeast cells, the researchers had found that when the protein coded by this gene is absent from the cells, lifespan is shortened. Conversely, when an extra copy of the gene is contained in each cell, their lives go on: they live much longer. Stated in genetic terms, when the gene that codes for production of that protein is expressed, longevity is conferred. The gene in question is known as Sir2 (for silent information regulator no. 2), and the protein is called Sir2p. Through a process called "gene silencing," Sir2p controls the rate of aging by suppressing production of waste genetic material that would normally clog the cells.

Sir2 may be the first longevity
gene we can use right
now to extend life.

Since all cells of a given organism have the same set of DNA instructions, individual cells can function properly if they invoke only those genes that pertain to their unique character and purpose. (Recall that every gene is just a particular segment of a DNA molecule, and a gene's molecular structure represents the code for producing a particular kind of protein that is unique to that gene.) Therefore, selective silencing of genes is required. Otherwise, there would be no cell diversity or identity that determines whether a cell is a brain cell or a bone cell. This genetic control differs from gene expression, which is the full use of the information in a gene via transcription and translation, leading to production of a protein.

Professor Leonard Guarente, one of the article's authors, said that some genes "need to be silenced, and some need to be active."

How gene silencing occurs is not entirely clear, but it seems to involve the material with which DNA is clad, known as chromatin because it absorbs colored stains. When the variety of this material known as heterochromatin has its acetyl groups (a part of the molecular structure) removed in some places, as Sir2p is capable of doing, it tightens around the DNA beneath it, thus preventing access to the cell's messaging system (gene transcription) in that portion of the DNA. The result is that gene-directed activity (gene expression) is blocked.

Silencing the messages that genes carry requires a complex series of interactions between proteins, regulatory sites, and origins of replication. Sir2p orchestrates this task by attacking the chromatin in certain regions, thereby repressing gene expression. But, as the MIT research team points out, while Sir2p removes the acetyl groups and silences the genes, it does so only with the assistance of a special chemical partner, a compound intimately involved in cell metabolism.

In investigating the activity of the protein Sir2p, Guarente and his colleagues discovered that its activities, including its gene-silencing ability, depend on a molecule, common to all cells, that breaks down food and is involved in cellular energy metabolism. That molecule is nicotinamide adenine dinucleotide (NAD). While plentiful throughout the body, in all likelihood NAD is most abundant when the energy requirements of the cell are low.

What does this have to do with the genetic link between caloric intake and aging, as the MIT researchers vigorously propose? Based on other studies they conducted with both yeast and mice, they conclude that Sir2p's activity depends upon metabolism. Caloric restriction lowers metabolism.

As mentioned earlier, caloric restriction has been shown repeatedly to extend lifespan in laboratory animals. Most scientists agree that it works because fewer calories mean less energy production, less wear and tear, and less oxidative damage. However, the MIT researchers offer an alternative explanation: cutting calories slows metabolism, which frees up more NAD. In turn, the greater availability of NAD keeps Sir2p working properly, and that means extending cell life. Moreover, keeping Sir2p in good shape should help maintain the balance of silent and active genes, thus promoting the health of all body cells. According to Guarente, "If you lose silencing over time, you could get inappropriate gene expression, and these changes could be responsible for some of what we see in aging."2

Guarente and colleagues have found a related protein in mice that performs a similar function, suggesting that the Sir2 gene plays the same role in other mammals as well. They believe that, if additional animal studies support this thesis, their findings will not only lend support to the value of a lower-calorie diet, but also initiate a research race in which the protein Sir2p could become a drug target how about a nutrient target? for helping prevent some age-related degenerative diseases, and for extending life. Keeping Sir2p active, whether by drug or by nutrient, may help protect against immune-function decline or help increase muscle building. To be realistic, any drug or nutrient that aids Sir2p would probably not be a ticket to longevity, but instead could help people "square the aging curve," thereby allowing aging to stop, and help maintain vitality to stay in the race the human race.

Is there a way to increase NAD in the body? Fortunately, there is a direct precursor, the nutrient niacin (vitamin B3), in the form of either nicotinic acid or nicotinamide, which has a long history of use as a nutrient supplement.3 The result of one study showed that, although both of these compounds produce NAD, the rate of synthesis from nicotinamide is twice as great as that from nicotinic acid under physiological conditions. Moreover, the conversion was stimulated significantly by inorganic phosphate, but only for nicotinamide.

Heterochromatin, the highly condensed material that envelops the DNA strand and probably makes it transcriptionally inactive.

Other studies have shown that nicotinamide helps prevent DNA fragmentation. Independently of NAD's role, this can help protect mice from the oxidative stress associated with various neurodegenerative, age-related diseases. In one study, nicotinamide was found to produce neuroprotective effects via the elevation of NAD levels, which were increased by 50% in the mouse brain.4 It is believed that nicotinamide helps prevent the critical depletion of NAD, thus enabling it to repair DNA.

Apoptosis is a characteristic form of cell death (often called "cell suicide") that has been implicated in nerve degeneration. In another mouse study, apoptosis and DNA fragmentation were induced in vivo (in the body) by a potent free-radical neurotoxin that damages dopaminergic (motor-mechanism) neurons in the substantia nigra of the midbrain.5 Nicotinamide, again noted as a precursor of NAD, was able to block the induced apoptosis. As well, it was seen to quench some of the free radicals formed by xanthine oxidase.

Nicotinamide has also been found to help protect against DNA damage induced by radiation, especially when the cells to which it was directed were repair-deficient, but not so deficient as to be defunct.6

The susceptibility to a strong chemical oxidant that causes DNA damage in most regions of the brain was found to be age-dependent.7 As measured by cell suicide (apoptosis), older mice (24 months) were found to have significantly more DNA damage than younger ones (8 months). This type of DNA-implicated nerve degeneration is observed in both Alzheimer's and Parkinson's disease patients. Nicotinamide was able to prevent DNA fragmentation damage when it was coadministered with the chemical toxin in older mice.

The nutrient nicotinamide enhances
the protective activity of Sir2p,
the longevity gene's protein. 

Lymphocytes - white blood cells that fight infection and disease - from old mice show a lower level of DNA repair than lymphocytes from young mice.8 After in vitro (in a test tube) treatment with nicotinamide, UV-induced DNA repair was increased in resting lymphocytes from both young and old mice, but the effect was more dramatic in old mice, showing a twofold relative increase in repair. However, the presence of chemicals that inhibited the production of NAD limited DNA repair activity, demonstrating the importance of nicotinamide as a precursor of NAD and not some other substrate.

In 56 recently diagnosed, insulin-dependent diabetic patients, 25 mg per kg of nicotinamide (2.0 g for a 175-lb individual) or a placebo was given over 12 months. The results showed that nicotinamide can be added to insulin in these patients to help prevent insulin-producing beta-cell destruction.9 Researchers currently believe that nicotinamide may be able to help prevent insulin-dependent diabetes in susceptible individuals10 (at least one trial is currently underway). This has been shown to be true in mice.11 Since the byproducts of diabetes help accelerate the aging process,12 it might be a good idea to take nicotinamide supplements as a preventive.

As a bonus, nicotinamide has been found to be beneficial in osteoarthritis and rheumatoid arthritis. A recent pilot study found nicotinamide to reduce erythrocyte sedimentation rate (the creation of red-blood-cell waste material) by 22% and increase joint mobility by 4.5 degrees, vs. controls.13 It also improved joint flexibility, reduced inflammation, and allowed for a reduction in standard anti-inflammatory medications.

The chemically reduced form of NAD, called NADH, has become popular as a supplement because studies have shown that it may be able to enhance brain and body functions for Alzheimer's disease, Parkinson's disease, and chronic fatigue syndrome. When the MIT researchers studied NADH, they found that it did not promote a significant level of gene-silencing by Sir2p, as did NAD. Apparently NADH diverts from some enzymatic step needed to amplify Sir2p's silencing effects.


NAD (nicotinamide adenine dinucleotide), the ubiquitous coenzyme needed for oxidation/reduction reactions during food breakdown, regulates the protein Sir2p to maintain and increase the "housekeeping" functions of cells, thus helping to extend life, according to MIT researchers.

Unfortunately, genes are not exempt from the assault of free radicals. It is thus encouraging to know that certain antioxidants can help defend against DNA mutations, which may lead to cancer. In a survey of men in their fifties living in the northeast of Scotland, smokers were initially found to show significantly more oxidative damage to the DNA of human lymphocytes than nonsmokers.14 Lymphocytes are white blood cells that fight infection and disease. While initially correlations between DNA damage and plasma concentrations of various antioxidants were generally negative and not statistically significant, this changed following a 20-week supplementation diet with vitamin C (100 mg/day), vitamin E (140 IU/day), and beta-carotene (25 mg/day). The results showed a highly significant decrease in oxidative damage to the lymphocyte DNA of both smokers and nonsmokers. Also of importance was that the lymphocytes of antioxidant-supplemented subjects showed increased resistance to oxidative damage when challenged in vitro with hydrogen peroxide.

In another Scottish study, 21 healthy, nonsmoking males (median age 29 years) were divided into two groups. One group consumed a diet containing 5% polyunsaturated fatty acids (PUFA), which are highly susceptible to oxidation, for 4 weeks. After a 10-week washout period (when no PUFA diet or vitamins were taken), they were switched to a 15% PUFA diet for another 4 weeks.15 The other group followed an identical protocol, but in reverse order. The diets were provided to the subjects either with or without an additional 80 mg of vitamin E per day.

When lymphocytic damage as well as endogenous DNA damage was measured, there was a significant decrease after consumption of the 5% PUFA diet , but a significant increase after consumption of the 15% PUFA diet for subjects not taking vitamin E. However, these changes were abolished by the vitamin E, indicating that, although high dietary levels of PUFA may adversely affect some indices of DNA stability, vitamin E can ameliorate the damage.

In a study conducted in Amsterdam, N-acetyl-L-cysteine (NAC) has been shown to be of value in the treatment of oral, laryngeal, and lung cancer.16 Experimental data have shown its ability to exert antimutagenic effects and to inhibit genotoxicity, the deleterious effect of free radicals. NAC's ability to protect DNA has also been shown in other studies. It has even alleviated chromosomal damage in animal experiments. Moreover, as a supplement it is easy to take, judging from good compliance in treated patients and a low frequency of side effects.

Sir2p slows aging by reducing
mutational damage and halting
cell death which occurs due
to the runaway accumulation of
a lethal form of DNA.

In other studies, NAC has inhibited both spontaneous mutagenicity and that induced by a number of chemical compounds and complex mixtures.17 It significantly decreased the incidence of neoplastic (abnormal new growth, such as a tumor) and preneoplastic lesions induced by several chemical carcinogens in rodents (mice, rats, hamsters), e.g., in lung, trachea, colon, liver, mammary gland, Zymbal gland (a sebaceous tissue associated with the ear duct of certain rodent species), bladder, and skin. NAC achieved this through multiple mechanisms, including inhibition of carcinogen-caused DNA adduction or damage, inhibition of "spontaneous" mutations, and protection of enzymes that operate in the cell's nucleus.

There are other nutrients too that can have a positive effect on DNA, including zinc, arginine, and conjugated linoleic acid (CLA). Zinc is an essential cofactor in a variety of cellular processes, including DNA synthesis, reproduction, bone formation, wound healing, and immune function. As well, a recent study has found that zinc plays an instrumental role in regulating DNA replication and repair.18

The amino acid arginine is also involved in many of the same processes as zinc, as well as many others. It is an excellent inducer of growth-hormone release and the precursor of nitric oxide, both of which play an important role in improving immune function, enhancing DNA synthesis, and regulating gene transcription.19 CLA (see Introducing Conjugated Linoleic Acid (CLA): CLA Reshapes Your Body - February 2000) has been found to alter gene expression, which probably accounts for its inhibitory effect on carcinogenesis and atherosclerotic plaque formation.20

The future will undoubtedly be a world in which genes, with a capital G, will dominate every aspect of our lives, but most importantly, where our health buck hits the table. With this in mind, it is wise to make peace with the programming within, the DNA machinery that issues death warrants or a future of life extension and all the good that it can bring.

For the present, while it seems that the MIT researchers are hot on the trail of the Holy Grail, there is no downside risk to gene supplements such as nicotinamide. On the upside, gene supplementation, such as it now is, could be the real start of everything for which we've hoped and worked. Then we would be able to say goodbye to calorically restricted misery and put back the juice of life for toasting the prospect of forever.


  1. Imai S-I, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000;403:795-800.
  2. Strauss E. New clue to age control in yeast. Science 2000;287:1181-2.
  3. Micheli V, Simmonds HA, Sestini S, Ricci C. Importance of nicotinamide as an NAD precursor in the human erythrocyte. Arch Biochem Biophys 1990 Nov 15;283(1):40-5.
  4. Klaidman LK, Mukherjee SK, Hutchin TP, Adams JD. Nicotinamide as a precursor for NAD+ prevents apoptosis in the mouse brain induced by tertiary-butylhydroperoxide. Neurosci Lett 1996 Mar 8;206(1):5-8.
  5. Mukherjee SK, Klaidman LK, Yasharel R, Adams JD Jr. Increased brain NAD prevents neuronal apoptosis in vivo. Eur J Pharmacol 1997 Jul 2;330(1):27-34.
  6. Riklis E, Kol R, Marko R. Trends and developments in radioprotection: the effect of nicotinamide on DNA repair. Int J Radiat Biol 1990 Apr;57(4):699-708.
  7. Mukherjee SK, Adams JD Jr. The effects of aging and neurodegeneration on apoptosis-associated DNA fragmentation and the benefits of nicotinamide. Mol Chem Neuropathol 1997 Sep-Dec;32(1-3):59-74.
  8. Licastro F, Walford RL. Modulatory effect of nicotinamide on unscheduled DNA synthesis in lymphocytes from young and old mice. Mech Ageing Dev 1986 Jul;35(2):123-31.
  9. Pozzilli P, Visalli N, Signore A, Baroni MG, Buzzetti R, Cavallo MG, Boccuni ML, Fava D, Gragnoli C, Andreani D, et al. Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study). Diabetologia 1995 Jul;38(7):848-52.
  10. Pozzilli P. Prevention of insulin-dependent diabetes mellitus 1998. Diabetes Metab Rev 1998 Mar;14(1):69-84.
  11. Beales PE, Burr LA, Webb GP, Mansfield KJ, Pozzilli P. Diet can influence the ability of nicotinamide to prevent diabetes in the non-obese diabetic mouse: a preliminary study. Diabetes Metab Res Rev 1999 Jan;15(1):21-28.
  12. Thorpe SR, Baynes JW. Role of the Maillard reaction in diabetes mellitus and diseases of aging. Drugs Aging 1996 Aug;9(2):69-77.
  13. Jonas WB, Rapoza CP, Blair WF. The effect of niacinamide on osteoarthritis: a pilot study. Inflamm Res 1996 Jul;45(7):330-4.
  14. Duthie SJ, Ma A, Ross MA, Collins AR. Antioxidant supplementation decreases oxidative DNA damage in human lymphocytes. Cancer Res 1996 Mar 15;56(6):1291-5.
  15. Jenkinson AM, Collins AR, Duthie SJ, Wahle KW, Duthie GG. The effect of increased intakes of polyunsaturated fatty acids and vitamin E on DNA damage in human lymphocytes. FASEB J 1999 Dec;13(15):2138-42.
  16. De Vries N, De Flora S. N-acetyl-L-cysteine. J Cell Biochem Suppl 1993;17F:270-7.
  17. De Flora S, Cesarone CF, Balansky RM, Albini A, D'Agostini F, Bennicelli C, Bagnasco M, Camoirano A, Scatolini L, Rovida A, et al. Chemopreventive properties and mechanisms of N-acetylcysteine. The experimental background. J Cell Biochem Suppl 1995;22:33-41.
  18. Park JS, Wang M, Park SJ, Lee SH. Zinc finger of replication protein A, a non-DNA binding element, regulates its DNA binding activity through redox. J Biol Chem 1999 Oct 8;274(41):29075-80.
  19. Yamashita S, Ong J, Melmed S. Regulation of human growth hormone gene expression by insulin-like growth factor I in transfected cells. J Biol Chem 1987 Sep 25;262(27):13254-7.
  20. Moya-Camarena SY, Belury MA. Species differences in the metabolism and regulation of gene expression by conjugated linoleic acid. Nutr Rev 1999 Nov;57(11):336-40.

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