The Gene Supplement Nicotinamide

The Secret to Longevity Is
Hidden Deep in the Gene Pool

Genes that have remained unchanged through evolutionary history
may hold the key to life extension

bumper sticker you may have seen reads "Everyone out of the gene pool!" It sounds funny even if you don't know exactly what a gene pool is. And just in case you don't, a gene pool is the sum of all the genes in all the DNA in a given population of organisms. It represents the entire genetic potential of the organisms in question - everything they are, or could ever become. We humans - all 6 billion of us - have a gene pool, of course, and so do weasels and worms and all other living things. If you could "pool" the gene pools of all the different species of life on earth (there are many millions), it would be a veritable gene ocean.

OF PEOPLE, WEASELS, AND WORMS
In terms of reproduction, the gene pools of different species generally do not overlap, and that is what keeps all species distinct from one another. Humans, for example, cannot mate with weasels or worms (although some of us, on occasion, have been known to behave like weasels or worms).


Nicotinamide has turned out to
play a longevity-related role in our
physiology that no one could have
imagined just a few years ago.

But this does not mean that humans don't have many genes in common with weasels and, to a lesser extent, worms. The truth is, we do. Some genes, in fact, are common to virtually all animals, and they are therefore said to be evolutionarily conserved. In other words, the structure and function of such genes have remained essentially unchanged (conserved) during the evolution of modern organisms from primitive ancestors that inhabited the earth many millions of years ago.

OUR PLACE ON THE TREE OF LIFE
Over the last four billion years, biological evolution has taken place in the manner of a tree that first grows a few mighty branches, then a number of smaller branches, then many still smaller ones, and so on until it ends in millions of twigs - each one a different species - bristling from all those branches. And that is what our species, Homo sapiens, is: one tiny twig, way up at the top of the tree, as far from the root as it is possible to be. Beneath us on the tree of life are millions of less advanced species with whom, surprisingly, we have much more in common than meets the eye - thanks to those conserved genes.

One of the greatest surprises in this regard is the recent discovery that some of those genes may regulate the aging process.1 This runs counter to the conventional wisdom that aging is a random kind of process in which all bodily systems gradually deteriorate toward states of increasing molecular disorder, culminating in death. The idea that aging is actually subject to regulation by certain genes that allow lifespan to be extended significantly (in various lower organisms, at least) means that it is not as random and haphazard as it has always seemed. And it means that if we can figure out how to manipulate those genes within ourselves, we may be able to extend the maximum human lifespan well beyond what it is now (about 120 years).

SUPPLEMENTING WITH NICOTINAMIDE PRODUCES NAD
Until that day comes, we can do something that might help extend our lifespan right now: we can take extra amounts of nicotinamide, also known as niacinamide, a close relative of niacin (vitamin B3).* Now, we've always known that vitamins are good for us - they are essential, in fact, by definition - but nicotinamide (which has vitamin activity comparable to niacin's) has turned out to play a longevity-related role in our physiology that no one could have imagined just a few years ago. Actually, it is a chemical derivative of nicotinamide, called nicotinamide adenine dinucleotide, or NAD, that does the trick, once it is produced in our bodies.


*Nicotinamide does not cause the notorious "flushing" response associated with large doses of niacin.

And what is the trick? It is that NAD assists in a cellular process by which a certain gene acts to extend lifespan by silencing the activity of other genes that may act to shorten lifespan. (This process is called gene silencing.) Put simply, NAD is a key player in a sort of "good gene/bad genes" drama. The "good gene," called Sir2, is related to longevity: the more active it is, the longer the organism tends to live. (Right here we must say that this effect has not been observed in humans, but only - so far - in certain yeasts and worms, so it is still purely speculative in humans.) The "bad genes" are not really bad - it's just that, with age, they tend to become more active than is desirable because they are not adequately silenced, and the net result of all this activity is deleterious to the health, and thus the lifespan, of the organism. It is part of the aging process.

THE MIRACLE OF LIFE
But what is gene activity, exactly? What do genes do? They do just one thing: they act as the repository of coded information for the synthesis of proteins, of which there are tens of thousands of different kinds, serving tens of thousands of different functions, all adding up to what we call life. The trick with proteins is to maintain just the right balance of all the right kinds of proteins in all the right places at all the right times.


Put simply, NAD is a
key player in a sort of 
"good gene/bad genes" drama.

This task is stupendously complex, and the fact that it can be accomplished at all, let alone as beautifully as it is in human beings (and other creatures too), is one of the main reasons that we speak of the "miracle" of life. We know from the theory of evolution, of course, that this miracle did not come about overnight. It is the end product of billions of years of molecular trial and error, guided by the principle of natural selection.

Thus, when we speak of genes becoming too active, it means that too many of the proteins they code for are being produced, because normal control mechanisms are breaking down.

THE DUAL, VITAL ROLES OF NAD
The protein that the Sir2 gene codes for is called Sir2p, and it is this protein that goes about the task of silencing various other genes - meaning that it inhibits the ability of those genes to transmit their coded information, thus inhibiting the synthesis of the proteins that they code for. But there is a catch: the Sir2p protein can perform this task only in the presence of adequate amounts of a vital cofactor, another molecule that is indispensable to the process. And that molecule is NAD, which, as we have seen, is derived from our old friend nicotinamide.2

Now, NAD serves other functions in the body as well, and chief among them is being a facilitator in the process of cellular energy metabolism, the sequence of chemical reactions by which glucose is oxidized ("burned") to produce the energy that life processes depend on. And here is where an interesting problem arises: the more our supplies of NAD are needed for energy metabolism, the less they are available to collaborate with the Sir2p protein in gene silencing. This suggests that if our NAD were needed less for metabolism and were therefore more available for gene silencing, we might live longer.

HOW ONE GENE AFFECTS LIFESPAN
The only way to reduce the need for NAD in energy metabolism in our cells is to eat less - specifically, to take in fewer calories. By doing so, our digestive tract produces less glucose for delivery to our cells (the delivery is facilitated by the hormone insulin, which causes channels in the cell walls to open up and admit the glucose molecules). And when this caloric restriction - eating less, by up to 30% - is imposed on experimental animals, the result is . . . increased lifespan!

Wow - a molecular mechanism for enhancing longevity, all tracing to a single gene!* But is it really that simple? Almost certainly not, because there are other reasons why caloric restriction may slow the aging process. The most obvious of these is the decreased assault on our cells by damaging free radicals, which are produced in huge numbers by the chemical reactions involved in energy metabolism. The slower the metabolism, the fewer the free radicals, and the more our antioxidant defense systems can be brought to bear on other sources of free radicals, including outside sources such as solar radiation and air pollution.


*For more on this subject, see "Nicotinamide Links Calories, Genes,and Antiaging" in Life Enhancement, September 2001.

CALORIC RESTRICTION AIDS SURVIVAL
In nature, caloric restriction is a common phenomenon. Scarcity of food can be caused by a variety of adverse environmental conditions: natural disasters such as fire or drought, competition from other, stronger animals, or just the natural cycle of the seasons. And when food is scarce, animals go hungry or even starve to death, with only the fittest surviving to reproduce and pass on their genes to the next generation.


Wow - a molecular mechanism
for enhancing longevity,
all tracing to a single gene!

In laboratory experiments with young worms of the species Caenorhabditis elegans, caloric restriction causes the worms to enter a state called dauer (from the German word for "to last") in which metabolism and other physiological functions are slowed, and growth and development are suspended. The worms stop moving and also become infertile, because reproducing when there is little food for their offspring to eat would be disadvantageous, not just to the offspring but also to the very survival of the species. In addition, the dauer worms become resistant to oxidative stress, another apparent survival mechanism.

Is Evolution "Just a Theory"?

Charles Darwin couldn't stand the sight of blood, so he dropped out of medical school. Medicine's loss was biology's gain, as Darwin went on to create one of the towering achievements of science: the theory of evolution. After decades of acute observation of nature and profound thought about what he saw, he brought forth a concept so magnificent in scope and power that it utterly transformed the way people thought about the world and all the living things in it - including, of course, themselves.

The concept of evolution has proved to be one of the most successful and productive in our intellectual history. Some people, however, are skeptical of evolution because it is called a "theory," which suggests to them that it is still an unproved idea. Although it is true that in science the word "theory" can mean an important idea that appears to have merit but that is still unproved, there is another, quite different, meaning of the word, which most laymen are not familiar with. Therein lies the confusion.

In science, "theory" can also mean a substantial body of knowledge and understanding based on one great unifying principle whose validity has been proved beyond any doubt. The acid test for such a theory is that it must be able not only to explain a wide variety of known phenomena but also to predict - accurately - phenomena that have not yet been discovered.

Science is replete with theories of this kind. For example, one of the cornerstones of the physical sciences is the kinetic-molecular theory of gases, the validity of which has been proved so thoroughly, in so many ways, that no scientist has the slightest doubt about it. It is called a theory not because it's an unproved idea but because it represents a solid (indeed splendid) intellectual edifice - like quantum theory and relativity theory, both of which have also passed the burden of hard scientific proof in countless ways.

The theory of evolution is that kind of theory, as is universally recognized by bona fide scientists.

CALORIC RESTRICTION PROLONGS LIFE
When conditions improve, i.e., when food again becomes abundant, the worms emerge from the dauer state to become fertile again, with normal lifespans - which is to say, their total lifespan is longer than normal, because it is extended by the length of the dauer period. Further growth and development are stimulated by activation of an evolutionarily conserved signaling pathway for the insulin system, which plays a key role in the rate of growth and aging - and hence of lifespan - of organisms up and down the evolutionary tree.3

A signaling pathway is a cascade of information, carried via chemical reactions, from the outer membrane of a cell to the cell's nucleus, in response to an outside stimulus. An extracellular signaling molecule, such as insulin, binds chemically to a receptor site on the cell membrane; this triggers the signaling pathway, which ultimately controls the activity of certain genes contained in the DNA within the nucleus.

CAN HUMAN LIFESPAN BE EXTENDED TOO?
Experimentally induced mutations in certain genes that are involved in the insulin/IGF-1 signaling pathway can produce the dauer state even when abundant food is present, and other mutations can allow the worms to grow to adulthood but remain youthful much longer than normal, living up to twice as long as the average worm. Like the dauer worms, some of these mutant worms have low metabolic rates, and all of them exhibit resistance to oxidative stress. Remarkably, it is possible to produce long-lived mutant strains that, with one exception, do not have the dauer traits at all: they move about normally, have normal metabolism, are fully fertile, etc.

This has led Cynthia Kenyon, of the University of California, San Francisco, one of the foremost researchers in this field, to say,1

The fact that these long-lived mutants can appear so normal makes one optimistic that if this system exists in humans, then by perturbing it in the right way, it may be possible to extend normal youthfulness and lifespan.

WHY ANTIOXIDANTS ARE IMPORTANT
We mentioned that there was one exception - one dauer trait that all the long-lived mutant worms do have - and that trait is a high resistance to oxidative stress, i.e., an enhanced ability to counteract the damaging effects of free radicals. Kenyon says, "Thus, it is possible that the ability to detoxify reactive oxygen species is what extends lifespan." In other words, if you can not produce a long-lived mutant with normal resistance to oxidative stress, then it could be that oxidative stress (caused by free radicals) is the main factor in the aging process.


With growing insights from both
evolutionary biology and molecular
biology, we may yet be able to
achieve what the lowly worm has
achieved: a way to live longer.

This comes as no surprise to those who have long argued in favor of the free radical theory of aging, but it is gratifying to see experimental evidence that seems to support it. And it underscores the importance of bolstering the body's antioxidant defenses in every way possible. Indeed, it has been found that certain antioxidants are known to extend the lifespans of the worms, and also of fruit flies.4,5 And in this case, what is good for worms and flies is probably good for people too.

In this scientific arena, however, nothing is simple. For example, it has been found that, unlike in the case (can?) of worms, there can be long-lived mutants of fruit flies that do have normal resistance to oxidative stress, which means that this form of stress resistance is not necessarily the main factor in the aging process after all - at least not in fruit flies. Clearly, much more research is needed to shed further light on this complex question.

THE VALUE OF EVOLUTIONARY CONSERVATION
All complexities notwithstanding, there are striking similarities among the regulatory systems affecting aging and longevity in the lower organisms used in these experiments, which suggests strongly that these systems arose early in the evolutionary history of life on earth and have been essentially conserved - albeit with increasing levels of refinement - ever since.6,7

The value of such systems in terms of natural selection is enormous, because they allow organisms to survive hard times without losing their ability to reproduce and propagate their species. If the organisms did not have such regulatory systems, they would die of starvation during times of food shortage or other hardships, or they would produce offspring that would die - either way, not good.

WHERE DO WE GO FROM HERE?
How all this knowledge (which is still in a primitive state) might be applied to human beings is still an open question - but a burning one, for obvious reasons. With growing insights from both evolutionary biology and molecular biology, which complement each other in many and marvelous ways, we may yet be able to achieve what the lowly worm has achieved: a way to live longer.

Meanwhile, a good way to stay healthy is to take a scientifically formulated spectrum of vitamins, minerals, and antioxidants, including nicotinamide.

References

  1. Kenyon C. A conserved regulatory system for aging. Cell 2001 Apr 20;105: 165-8.
  2. 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.
  3. Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature 2000 Nov 9;408(6809):255-62.
  4. Melov S, Ravenscroft J, Malik S, Gill MS, Walker DW, Clayton PE, Wallace DC, Malfroy B, Doctrow SR, Lithgow GJ. Extension of life-span with superoxide dismutase/catalase Science 2000 Sep 1;289(5484):1567-9.
  5. Sun J, Tower J. FLP recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the life span of adult Drosophila melanogaster flies. Mol Cell Biol 1999 Jan;19(1):216-28.
  6. Kenyon C. Ponce d'elegans: genetic quest for the fountain of youth. Cell 1996 Feb 23;84(4):501-4.
  7. Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001 Mar 8;410:227-30.

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