Nicotinamide, the Longevity-Gene Cofactor

Long-Lived Worms!
Can People Be Far Behind?

The most exciting avenue in aging research - the quest for longevity genes -
is climbing the evolutionary ladder

n all the hoopla and controversy over the prospect of human cloning - which is now entirely possible and therefore virtually certain to occur soon - we tend to forget that the journey that brought us to this point has been a long one and had humble beginnings. It started decades ago with experiments on lowly creatures far less cuddly and photogenic than Dolly the sheep. Bacteria and fungi may not make exciting news copy, but they are invaluable to scientists taking the first, halting steps toward a distant, difficult goal.

Only a few years ago, the cloning of human beings still seemed like science fiction - a tantalizing but preposterous idea. Now we know we can do it, thanks to all those fungi, worms, frogs, etc., on up the evolutionary line, who gave their all in laboratories around the world so that science might advance toward this glorious (or tragic - we don't know yet) day.

SCIENTISTS EXTEND LIFESPAN BY UP TO 50%
Meanwhile, another scientific venture of epic import has begun and is slowly working its way up the biological ladder, species by species. It is the search for a genetic mechanism of aging. More specifically, it is a search for a means of extending maximum human lifespan through the manipulation of longevity genes, or antiaging genes, such as those that have already been discovered in primitive organisms.

In the laboratory of Professor Leonard Guarente of the Biology Department at MIT, this search has recently taken another leap forward with the discovery that a longevity gene previously identified in a certain kind of yeast (yeasts are unicellular fungi, by the way) also exists, in a similar form, in a certain kind of roundworm - and it has essentially the same effects.1 By inserting a duplicate copy of this gene into the worm's DNA, the researchers were able to extend its normally 3-week lifespan by up to 50%.

Wow - really old worms. OK, it might not sound all that exciting, but consider this: yeasts and worms are so far removed from each other on the evolutionary tree of life that this stunning similarity in their genetic makeup can hardly be a coincidence. There must have been a common origin. This suggests strongly that, if two such dissimilar creatures have a longevity gene in common, perhaps many other creatures - perhaps all creatures - have it in common with them. Wouldn't that be interesting?

THE SEARCH FOR A UNIVERSAL LONGEVITY GENE
In a variety of greatly dissimilar species, including higher ones such as mice, we already know about many genes that, when mutated, confer extended lifespan on the animal. That in itself is most exciting. These life extensions occur through different mechanisms that are apparently unique to a given species or animal group. But the Holy Grail of research in this field is to find a single such longevity gene, or a closely related family of genes, that occurs throughout the entire animal kingdom and acts similarly across that vast spectrum of biological types.

Such a revelation would indicate that there is at least one genetic mechanism of aging - and thus, perhaps, of antiaging - that is truly universal, a fundamental feature of life on earth. Such a mechanism would be of the greatest interest to scientists, because anything they could learn about it from studies on one species of animal would be more or less applicable to all other species - including, of course, ourselves.

Tiny roundworms (about 1 mm long) such as these live up to 50% longer when two copies of their longevity gene are inserted into their DNA. Will this feat someday be possible in humans?

This is the goal that Guarente and his associates are pursuing and toward which they have just taken their "worm step," on a tiny nematode worm with a big name: Caenorhabditis elegans. They have shown that, just as in the yeast (Saccharomyces cerevisiae), a gene called Sir2 regulates aging in the roundworms.

"The remarkable thing is that the same gene regulates aging in yeast and roundworms," said Guarente in an interview with Reuters Health. "The huge evolutionary divergence rendered it unlikely that Sir2 genes would be present in both organisms. This means that Sir2 is likely to regulate aging generally, including in mammals."

GENE SILENCING = LONGER LIFE
Among the intriguing, and confusing, aspects of this work is that there appear to be two different mechanisms by which Sir2 regulates aging in yeast.2 One of these is also found in higher organisms, and one is not, but both involve a process called gene silencing, from which Sir2 gets its name in the first place: Silent information regulator no. 2. In gene silencing, the protein that Sir2 codes for, called Sir2p, causes certain other genes of the organism to be inactivated, or silenced. (One might say that the Sir2p protein is the silencer, and those other genes are the silencees.)

The result is longer life, so gene silencing is definitely a good thing. "Longer life" in this case means either a lifespan optimized within the normal range or a lifespan extended beyond that range (but not ordinarily by the large factor mentioned above, which was accomplished through genetic engineering).

NICOTINAMIDE IS VITAL FOR GENE SILENCING
All this raises two interesting questions: (1) How does Sir2p silence the genes, and (2) How does gene silencing regulate aging?

The answer to the first question is complicated (insofar as it is understood at all), and it need not concern us - except for one extremely important factor, called NAD. That stands for nicotinamide adenine dinucleotide, a ubiquitous compound in the human body whose primary precursor is nicotinamide. And nicotinamide is just a common variant form of vitamin B3, also known as nicotinic acid or niacin, which we could all probably use more of than we typically get.

Now NAD, it turns out, is a vital cofactor to Sir2p in the latter's role as a gene silencer. Without NAD, Sir2p is virtually impotent: the process breaks down, and the genes don't get silenced. All the more reason that we should want plenty of nicotinamide, so as to optimize our levels of NAD.

The answer to the second question is: that's complicated too. In yeast, one way that gene silencing regulates aging is by suppressing the proliferation of circular bits of "rogue" DNA that accumulate in cells as part of the aging process, eventually choking the life out of them. But this process has not been observed in higher organisms, so it's irrelevant to humans, especially since there is another way in which yeast aging is affected - and that way may be universal.

Caloric restriction - taking in significantly fewer calories daily than is considered normal - appears to be a universally effective means for extending the lifespan of creatures from yeasts to higher animals, perhaps including primates (which includes us). Eat less, live longer - it's as simple as that. One way that gene silencing regulates aging in yeasts, and worms, and possibly ourselves, is by mimicking the effects of caloric restriction. How it does that is really complicated, and not well understood anyway, so we'll spare you the details.

TOWARD MAXIMUM LIFESPAN
Let us also not speculate on the implications of future genetic engineering techniques that might affect our maximum lifespan, except to say that this prospect is looking less like science fiction all the time, thanks to pioneering work such as that of Dr. Guarente. If we can clone human beings, perhaps we will soon be able to increase their maximum lifespan as well.

Meanwhile, supplementing with nicotinamide is a good way to ensure that we have plenty of NAD in our systems. Why should worms have all the fun?

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. Gems D. Yeast longevity gene goes public. Nature Mar 8;410:154-5.

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