This vitamin derivative plays a key role in the molecular mechanism of antiaging
Undertaking interstellar voyages would require that astronauts be placed in suspended animation for very long periods. Our rudimentary knowledge of how this might become possible may be enhanced by current research on certain life-extending processes in lower organisms, in at least one of which NAD plays a key role.
A popular notion in science fiction movies about space travel is that of astronauts getting into gleaming metal and glass pods, sealing themselves in, and activating a high-tech mechanism that places them in a state of suspended animation. The idea is to allow them to survive - without growing older (not to mention being bored to death) - for the years, decades, centuries, or more that it will take the spaceship to reach some distant star system. At a preprogrammed time, the astronauts wake up, stretch and yawn, wipe out a few alien species, and conquer new worlds. Never mind that their grandchildren back on Earth may have died of old age long ago.
Sure, it sounds preposterous (and is there anyone who would actually be willing to do that even if it werepossible?), but so did space flight and genetic engineering and the Internet, not so long ago. So, in fact, did almost everything that we now take for granted in the realms of high technology. So let's keep an open mind, shall we? Especially because there exist, in nature, creatures that are already way ahead of us in the field of suspended animation. And no, they're not alien beings from a superior civilization on the planet Xenix, they're right here on earth - well, maybe in the earth, because they're . . . worms.
We Have Much to Learn from Worms
That's right, worms. We could learn a lot from worms, and we're trying hard to do just that. We're trying to understand, for example, how a certain kind of tiny roundworm, Caenorhabditis elegans, enters the dauer state, stays there for some time, and then emerges again to resume the rest of its normal lifespan without, in effect, having grown any older during its time in the dauer state.
I know what you're thinking: what the heck is the "dauer state"? Well, dauer comes from the German word for "to last," and it describes a state of suspended animation (sort of) that certain worms enter as a response to unfavorable environmental conditions, such as lack of food. When we humans are deprived of food long enough, we starve to death, period. But not these worms - they say, "No problem, we'll just do the dauer thing until food becomes plentiful again, and then resume everyday life as if nothing had happened." They can stay in the dauer state for months on end, even though their normal lifespan is only about 18 days!
There exist, in nature, creatures
that are already way ahead of us
in the field of suspended
animation. And no, they're not
alien beings from another planet,
they're right here on earth.
Is that cool or what? The mind boggles. But it's true, and it raises an obvious question: If worms can do it, why can't we? Better yet, why can't we figure out a way to extend our lifespan without having to enter the dauer state or some kind of suspended animation?*(It's so hard to party when you're totally zonked out.) Well, maybe we can, because those same darned worms can do that too - with a little help from scientists who know a lot about genetics and molecular biology. Among them are Heidi Tissenbaum and Leonard Guarente of MIT, who recently published a paper that serves as the source material for this article.1 (For previous Life Enhancement articles on this subject, see the May, September, and November issues from 2001.)
*For true longevity, nothing beats bacteria, some of which have been brought back to life after tens of millions of years in suspended animation (trapped in fossils). In many higher organisms, the appearance of suspended animation is given by hibernation (which is practiced not only by bears but also by many other species of mammals and reptiles). It is characterized by a sharp drop in metabolic activity and is of great interest to scientists, for obvious reasons.
Sir2 Is a Longevity Gene
So how do those worms manage to live longer than normal (much longer than normal - several times their normal lifespan, in fact) even without entering the dauer state? By having certain genes in their DNA overexpressed, which means that the genes are activated to a greater extent than usual, such that the effects they normally produce become enhanced (the effects are actually brought about by the proteins that the genes code for). Well, if the overexpression of a certain gene (i.e., the overproduction of that gene's protein) causes an extension of lifespan - and, conversely, if the underexpression of that gene causes a shortening of lifespan - then that gene must be playing a role in regulating lifespan. It must be, in effect, a longevity gene of some kind.
There are many different longevity genes, as it turns out, acting in different ways on different aspects of cellular function in different organisms. One that stands out as particularly interesting, however, is a gene called Sir2. Among the reasons why scientists are most intrigued by this gene are that:
- Its overexpression promotes longevity in organisms as radically different from each other as yeasts and worms, which are far apart on the evolutionary tree of life. This is astonishing.
- It is known to exist (in variable forms) in the DNA of higher organisms, including humans, making it impossible not to wonder whether it might promote longevity in us too.
- In lower organisms, it is known to be intimately involved in the one strategy - caloric restriction (sharply reduced food intake) - that is known to be successful in promoting longevity in higher organisms, such as mammals.
NAD Is Required for Sir2p to Extend Lifespan
Those are good reasons to pursue research on Sir2 intensively, and many scientists are doing so. Another reason to be interested in this gene has to do with an important molecule called NAD (nicotinamide adenine dinucleotide). NAD is a derivative of nicotinamide, which is, in turn, a derivative of the common vitamin niacin (vitamin B3). Nicotinamide has vitamin activity similar to that of niacin and is, in fact, sometimes used as a substitute for niacin in vitamin formulations. Although this forfeits some of the nonvitamin benefits of niacin, notably its cholesterol-lowering action, nicotinamide has the advantage of being more readily converted to NAD in the body than niacin is, because it's already halfway there, so to speak. (See the June 2002 issue of Life Enhancement for the article "Nicotinamide Induces Rejuvenation in Human Cells.")
The greater the cellular level of
NAD, the greater the activity of
Sir2p, and the greater the gene
silencing that promotes longevity.
But what is the connection between Sir2 and NAD? It's this: the Sir2 gene - or, more accurately, the protein it codes for, called Sir2p - is dependent on NAD as a vital cofactor for helping it carry out its longevity-promoting function, a process called gene silencing. No NAD, no gene silencing by Sir2p; no gene silencing by Sir2p, no lifespan extension attributable to Sir2. To put it another way: the greater the cellular level of NAD, the greater the activity of Sir2p, and the greater the gene silencing that promotes longevity.
NAD Links Caloric Restriction and Longevity
Figure 1. Most of the NAD in our cells is needed for energy generation through glycolysis. When that demand is reduced, more NAD is available for gene silencing, which promotes longevity in yeasts and worms and . . . ?
All this came as a surprise to researchers when it was discovered. What really excited them, though, was the realization that NAD is no ordinary molecule (if there is such a thing): it's a key player in cellular energy metabolism, in which glucose molecules are broken down to produce the life-giving energy that every cell requires. This process is called glycolysis, and it requires an ample supply of NAD to keep it going. If glucose levels decline, however, the cells' available NAD reserves increase, because they're not being used in glycolysis. And that, of course, favors the increased activity of Sir2p in gene silencing (see Figure 1).
So when do glucose levels decline? Why, when food intake is sharply reduced - caloric restriction, which is known to promote longevity. Thus, scientists believe that caloric restriction increases lifespan because it increases the amount of available NAD, which increases the activity of Sir2p in gene silencing. A telling bit of evidence in support of this hypothesis is that when caloric restriction is performed on a strain of worm that lacks the Sir2 gene or that lacks the major biochemical pathway of NAD synthesis, there is no life extension.
The fact that caloric restriction does promote longevity in worms (normal ones) - which have more in common with humans, biologically speaking, than they do with yeast - is exceptionally interesting because it suggests that NAD levels may be relevant to the regulation of lifespan in higher organisms, including humans. In the words of the MIT scientists:1
It seems likely that fundamental principles, such as the coupling of aging rates to nutrient availability, will be universal. In support of this idea, it seems relevant that Sir2 determines lifespan in systems as diverse as yeast and worms, even though the mechanisms limiting their lifespans most likely differ. . . . It is possible that the determination of the functions of mammalian Sir2 proteins will lead to identification of the processes that limit mammalian lifespan.
Antioxidants Extend Lifespan
It has long been believed that one of the principal causes of aging is oxidative damage to our cells brought about by the cumulative effects of free radicals. These are unstable, highly reactive molecular species produced in great abundance by the chemical reactions involved in glycolysis, in which glucose is "burned" to produce the energy that life processes require.
All that prevents us from quickly succumbing (in a matter of minutes, in fact) to the overwhelming assaults on our health by free radicals is the defensive mechanism of antioxidants - primarily those that our bodies produce naturally, and secondarily those that are found in our food or that we take as nutritional supplements. (Among the most important are vitamins C and E, lipoic acid, and coenzyme Q10.)
Until recently, however, there was little hard evidence of a causal connection between oxidative stress and the rate of aging. If there were such a connection, the following two predictions would have to be true:
- Genetic mutations that affect oxidative stress should affect the organism's lifespan one way or the other.
- Interventions that reduce the levels of free radicals should increase the organism’s lifespan.
Recent studies on yeast and worms (those same roundworms, C. elegans, as used in the Sir2 research) have confirmed both of these predictions.1 Inducing mutations in a variety of genes that affect oxidative stress has been shown to increase or decrease lifespan dramatically (depending on the gene and the mutation). And the administration of certain antioxidant agents to the worms has been shown to increase both their average lifespan and their maximum lifespan by as much as 54%.
It's nice to know that our little worm friends can reap such great benefits from antioxidants - but what about us? Although there is no hard evidence that antioxidants extend human lifespan, there is abundant evidence of their benefits to many aspects of our health and well-being. And if they keep us healthier, then surely we live longer. Thus it is reasonable to suppose that, all else being equal, those who supplement aggressively with antioxidants live longer than those who do not.
- Tissenbaum HA, Guarente L. Model organisms as a guide to mammalian aging. Developmental Cell 2002 Jan;1:9-19.
NAD in the Longevity Sweepstakes
Whether or not Sir2 turns out to promote longevity in mammals and humans, as it does in yeast and worms, remains to be seen. The prospects appear promising, based on the worm research, but we must remember that it's still a very long way up the evolutionary tree from worms to humans, and only hard evidence, not wishful thinking, will tell the tale. Meanwhile, however, our increasing knowledge of the vital role that NAD plays in the longevity sweepstakes in those lower organisms gives us food for thought. So eat, drink, and be merry, and be grateful to the lowly worm for paving the way to what may be a brighter future for all of us.
The fact that caloric restriction
does promote longevity in worms
suggests that NAD levels may be
relevant to the regulation of
lifespan in higher organisms,
Nicotinamide is important as a precursor of nicotinamide adenine dinucleotide, or NAD, in regulating certain aspects of gene expression related to longevity.
Nicotinamide is also known as niacinamide. Niacinamide is a derivative of niacin, (vitamin B3). It does not, however, product the notorious "flushing" effect of niacin, and it is more readily converted than niacin is to the important molecule NAD in the body's cells.
- Tissenbaum HA, Guarente L. Model organisms as a guide to mammalian aging. Developmental Cell 2002 Jan;1:9-19.