Nicotinamide Links Calories,
Genes, and Antiaging

New research explains connection between caloric restriction and life extension

rom information generated by the Human Genome Project, scientists now know that human DNA contains about 30,000 genes. That came as quite a surprise, because it was formerly believed that there were about 100,000 genes in our genome. It seems that we're not as complex as we thought we were. Still, 30,000 is a lot, and trying to deduce the role of each of those genes inhuman biology is going to take a long time. In this article we will see how progress is being made toward understanding just one of those genes - the antiaging gene called Sir2 - and the critical role played in the antiaging drama by a familiar nutrient, nicotinamide.

Every aspect of our bodily structure and function, both inside and outside, is programmed by a given gene or a group of related genes. From the shape of our nose to the efficiency of our pancreas, from the strength of our bones to the ways in which we utilize boron, we can thank our genes (or blame them) for everything - including our expected lifespan.


A key player in the
molecular drama of
antiaging has turned out to
be a close relative of
niacin, or vitamin B
3.

We have all heard of people who ate sensibly, exercised regularly, didn't smoke or drink, and died young anyway. And we've heard of folks who lived well past a hundred on a diet of tobacco and booze. The secret has to be in their genes. If only we knew which genes and how they worked, and how to make something of that knowledge, we would live longer. The day when we will know all that is surely coming, now that the human genome has been mapped.

OLD AND NEW WAYS TO EXTEND LIFESPAN
Meanwhile, we are discovering how some lower organisms - yeasts, worms, flies, and even mice - can be made to live longer. One way has been known for decades, actually, and is decidedly low-tech, whereas the other is at the cutting edge of modern science.

The old way of living longer is simple: just eat less - take in fewer calories, to be more precise. The method is called caloric restriction. Laboratory mice and rats live about 40% longer than normal if fed a nutritious, well-balanced diet with at least 30% fewer calories than normal - a very tough restriction, to be sure. The animals appear to be fit and healthy - except that they tend to be less fertile and to bear fewer young than normal - and they are notably free of age-related diseases. Separate studies have shown that restricting caloric intake to 70% of normal levels significantly extends the lifespans of yeast, roundworms, and mice, and possibly primates.

It has been noted, however, that not too many humans are willing to endure such deprivation voluntarily. And since locking them up in laboratory cages to see how well it would work is frowned upon, the question arises: is there an easier way to achieve the benefits of caloric restriction?

Yes . . . well, probably. It's too soon to say for sure. Rapidly mounting evidence, however, points to eventual breakthroughs in the new, cutting-edge field of human genetic engineering - the manipulation of our genes to achieve desired ends. That kind of research is complex and sophisticated, requiring deep knowledge in fields such as biochemistry, molecular genetics, and physiology. The breakthroughs, when they come, are likely to result in large part from the work described in this article.

NICOTINAMIDE - KEY PLAYER IN THE ANTIAGING DRAMA
Oddly enough - and this was totally unpredictable - a key player in the molecular drama of antiaging has turned out to be a close relative of a compound that most people are familiar with by name and that virtually everyone ingests daily: niacin, or vitamin B3. Niacin is absolutely essential for good health. Without this vitamin, we would get pellagra, a deficiency disease characterized by abnormalities of the skin, gastrointestinal tract, and brain. On the other hand, a high dose of niacin - about 3 grams per day will do for most people - is well known for its effectiveness in lowering cholesterol levels in the blood.

But those are not the aspects of niacin that interest us here. Niacin can be taken in the form of its derivative nicotinamide (also known as niacinamide), which also has vitamin activity but does not have the cholesterol-lowering ability of plain niacin. In our bodies, nicotinamide is converted to a much larger molecule, nicotinamide adenine dinucleotide, or NAD. And this is where the story becomes intimately involved with antiaging research. To pursue it, however, let us first climb way down the evolutionary ladder and mingle with yeasts and worms, because that is where most of the action in this field is. But there are strong connections with human biology as well, as we will see. (For more on these worms and related matters, see "Long-Lived Worms! Can People Be Far Behind?" in Life Enhancement, May 2001.)


When niacin is taken as
nicotinamide, our bodies convert it
to NAD. And this is where the story
becomes intimately involved
with antiaging research.

ENERGY METABOLISM DEMANDS NAD
In lower organisms such as yeasts and worms, NAD (yes, they have it too) is directly involved in two biological processes that compete for the available amounts of this vital molecule - with profound consequences for the organisms' lifespan. One process is energy metabolism, the means by which glucose derived from foodstuffs is converted to life-sustaining energy in the cells. Energy metabolism requires NAD, which is consumed (via chemical reactions) in the process. The more food the organism eats, the more glucose is delivered to its cells to be metabolized, and the more NAD it uses up.

GENE SILENCING DEMANDS NAD TOO
That's bad news for the other, competing biological process that needs NAD in order to work: gene silencing. This is a biochemical mechanism for keeping most of the genes in the cell's DNA inactive, or "silent," meaning that they are not engaged in synthesizing the proteins their structures code for. In all cells, some genes need to be active, or "turned on." Most genes, however, need to be silent (turned off) most of the time so that the genes that should be active can do their jobs without undue interference. Otherwise there would be total molecular chaos, like 30,000 people jammed into a small space, all talking at once.

As our cells age, genes that had always been turned off sometimes get turned on, causing problems that can lead to cell death. Scientists believe that this may explain many of the infirmities associated with aging of the body itself. Thus, because it is unhealthy to have too many genes active and "talking" at once, gene silencing may be critical to the cells' long-term integrity.

GENE SILENCING EXTENDS LIFESPAN
The scientists have discovered that one particular gene, Sir2, not only controls gene silencing but also has a dramatic impact on the organism's lifespan. If Sir2 is removed from the cell's DNA, lifespan is sharply curtailed. If an extra copy of the gene is inserted into the DNA, however, lifespan is extended, sometimes by as much as 50%. This is a spectacular result, made all the more intriguing by the realization that genes similar to Sir2 have been identified in many organisms, ranging from bacteria and fungi to humans.1

But, removing genes, adding genes - those are drastic interventions, done in laboratory experiments. What about real life? How does Sir2 affect lifespan when some scientist isn't messing with it? The evidence suggests that if Sir2 is relatively inactive, gene silencing is impaired, and so are the organism's health and longevity. But if Sir2 is fully active, gene silencing is efficient, and health and longevity are probably optimized.

LESS NAD FOR METABOLISM = MORE NAD FOR GENE SILENCING
The actual gene silencing is carried out by a protein, Sir2p, that the Sir2 gene codes for. Exactly how Sir2p does this need not concern us here, except for one crucial fact. It turns out that Sir2p can accomplish its appointed task only with the help of NAD! No NAD, no gene silencing. No gene silencing, no life extension - in fact, probably life curtailment.

Now think about it: if gene silencing requires NAD, but so does energy metabolism, and there is only so much NAD to go around, what situation would be most favorable for gene silencing? The answer is reduced energy metabolism, because the lower the metabolism, the less NAD would be required for that task, and, consequently, the more NAD would be available for gene silencing.


Sir2p can accomplish its appointed
task only with the help of NAD. No
NAD, no gene silencing. No gene
silencing, no life extension - in
fact, probably life curtailment.

So how do you achieve reduced metabolism? Simple: just eat less. Sound familiar? It's our old friend, caloric restriction! (We're starting to tie things together here.) You reduce your caloric intake by eating less food (or less calorie-rich food, at any rate). The less food you eat, the less glucose enters your cells and the less NAD is required for metabolism and the more NAD is available for gene silencing and the longer you will live probably. In a nutshell, the slower your metabolism (within reason), the longer you will live.

Finally, we have a simple, elegant explanation of why caloric restriction extends lifespan. It's because caloric restriction makes more NAD available for gene silencing. This is more of an hypothesis than an explanation, actually, because there is no real proof yet - just pieces of a puzzle falling into place in a way that's supported by the evidence and that seems to make sense, according to what we know of molecular biology.

NATURAL SELECTION FAVORS THE ABILITY TO SLOW THE AGING PROCESS


NAD, derived from nicotinamide, is the link between caloric restriction and gene silencing, which are intimately involved in antiaging research. 

An additional reason for believing that this hypothesis makes sense comes from another quarter: evolutionary biology, which is concerned with how and why living things acquired the traits they now possess. The guiding principle here is natural selection - the tendency for traits that confer some survival advantage on the organism to become prevalent over the course of countless generations, while those that are disadvantageous gradually die out.

In the animal world, fluctuations in food supply are common - there are times of plenty and times of scarcity. When food is scarce, it is a bad time to bear young, so the animals' best strategy is to forgo reproduction until conditions are more favorable. But if the wait is too long, they may get too old too soon and thus forfeit the opportunity to reproduce.

Thus, there would be an evolutionary advantage in the ability to slow down the aging process, through enhanced gene silencing, when a shortage of food imposed caloric restriction. Natural selection would favor those animals with that tendency, so they would be more likely to reproduce and pass that trait on to their offspring. Eventually, the trait would become common to all animals - as appears to be the case.

Do you see how this is all coming together? Remember how those lab mice and rats tended to become less fertile and bear fewer young when they were subjected to caloric restriction? It fits. The hypothesis seems so compelling, one wants it to be correct. Only time and more research will tell, however, and it's a sure bet that many surprises lie ahead.

IS AGING COMPLEX OR SIMPLE?
A very recent research paper published in Trends in Genetics discusses two opposing genetic theories of aging.2 One theory comes from evolutionary biologists, who have long held that aging is probably the net result of the deterioration of many bodily processes, under the influence of many different genes. If that's true, it is highly unlikely that any single biochemical or genetic intervention could significantly extend lifespan. The age-related decline in vitality would affect so many processes that singling out one of them would be like fixing one shingle while the roof was blowing away.

The other theory comes from molecular biologists, whose recent successes with the Sir2 gene incline them to think that aging may be a much simpler phenomenon, genetically speaking, than the evolutionary theorists believe. They hold that aging may be programmed to be under the control of just one or a few genes (like a roof made of just a few giant shingles), and hence relatively easy to modify. It is noteworthy that the Sir2 gene exists, in various forms, in virtually all animals, and it is astonishing that it can extend the lifespan of organisms as far apart on the evolutionary tree as yeasts (which are fungi) and worms.

AGING MAY BE COMPLEX AND SIMPLE
Yet a third genetic theory of aging, which seeks to reconcile the two extremes outlined above, is proposed by the paper's author, Dr. Leonard Guarente, a professor of biology at MIT and the leading researcher of the Sir2 gene. He proposes that the Sir2p protein, by virtue of its dependence on NAD as a coenzyme, may somehow be able to monitor the status of cellular energy metabolism, as reflected by the amount of NAD available. Sir2p then somehow "decides" how to use this information in respect to the regulatory mechanisms for aging that it controls in different organisms.

Although these regulatory mechanisms are distinctly different in yeasts and worms, their common denominator is that the team of Sir2p and NAD (as Sir2p's indispensable coenzyme) is required for governing them. There are reasons for believing that this same feature may extend across the vast reaches of the animal kingdom - all the way to human beings - even if there are many different ways in which the Sir2p/NAD team exerts its control.

Thus, if Professor Guarente's theory is eventually proved correct, it will indeed have bridged the gulf between the complexity of the evolutionary-biological theory of aging and the simplicity of the molecular-biological theory. The ultimate goal, of course, is to be able to control the aging process in humans. As Professor Guarente discreetly puts it,

It will be important to extend the link between Sir2 genes and longevity to mammals. Assuming mammalian Sir2 genes do regulate longevity, determining their function could well identify those processes that limit lifespan in mammals. . . . a specific and pervasive mechanism that links metabolism to the pace of aging would reconcile the evolutionary and molecular schools and augur well for the eventual possibility of intervention in the aging process to promote health benefits and longevity.

THE NAD CONNECTION - A TOTAL SURPRISE
It is both strange and gratifying to think that so familiar a substance as the B-vitamin nicotinamide - as the precursor to NAD - plays such a central role in controlling the aging process. As we said above, no one could have predicted it. And as Professor Guarente himself has said in this regard,3

The NAD connection came out of the blue, but it has an interesting implication: NAD could well be the signal for the metabolic status of cells. If an organism is starved for calories, the NAD level may go up. More NAD means activating Sir2, which silences sections of the genome and increases lifespan.

Will we eventually be able to genetically engineer ourselves into a longer-lived species? Probably, but who knows when? The research road ahead will surely be bumpy. Meanwhile, it is desirable to optimize our nicotinamide intake - not just to avoid pellagra, but to give ourselves whatever edge may be possible in the gene-silencing arena.

References

  1. Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001 Mar 8;410:227-30.
  2. Guarente L. SIR2 and aging - the exception that proves the rule. Trends Genetics 2001 Jul;17(7):391-2.
  3. MIT researchers uncover new information about anti-aging gene. MIT News, Feb. 6, 2000.

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