Gene Yields New Insights Into Why We Age

February 22, 2000 - A gene known to govern the rate of aging in yeast cells has been found to be active in mice, yielding a new insight into why mice and people age and into possible ways of enhancing life span.

The gene's role is to "silence" DNA, meaning it seals off suites of genes and prevents the cell from gaining access to them.

Since every cell in the human body has the same set of DNA instructions, it is essential for each type of cell to activate only the genes needed for its own agenda and to ignore the rest.

The question of how access to the genes is controlled is still mysterious, but it must involve the versatile packaging material that clads the DNA, known as chromatin because it takes up colored stains.

The new finding, reported in the current issue of the journal Nature by Dr. Leonard Guarente and colleagues at the Massachusetts Institute of Technology, is that a gene first found in yeast cells, a common subject of laboratory study, silences the DNA by shaving off a certain chemical group from sites along the chromatin.

Loss of the chemicals, known as acetyl groups, makes the chromatin bunch up closer to the DNA, blocking access to the cell's gene-transcription machinery.

Biologists have long suspected that one of the cell's methods for controlling chromatin was adding acetyl groups to open the chromatin and removing the groups so as to repress the underlying genes. But the protein that shaved off the acetyl groups eluded discovery. A leading candidate, known as sir2 (for silent information regulator No. 2), showed no sign of fulfilling this role in test-tube studies.

Now Dr. Guarente has found that sir2 is indeed the cell's acetyl group remover, but it needs a special assistant that no one had guessed before: a chemical deeply involved in the cell's energy metabolism.

"This is an incredible insight," said Dr. C. David Allis, a chromatin expert at the University of Virginia. "It looks more and more like the cell is tweaking acetylation in a forward or backward way to create a balance that must be very fundamental to the business of the cell."

The evidence that the sir2 gene may be involved in human longevity is indirect. In 1997, Dr. Guarente discovered that sir2 controlled the rate of aging in yeast cells. When endowed with an extra copy of the sir2 gene, the yeast cells lived longer because the gene suppressed production of waste genetic material that would clog the cell.

This clogging mechanism of aging does not seem to operate in mammalian cells. But the sir2 gene occurs in mice and humans, and Dr. Guarente believes it may be linked with aging in mammals through a different mechanism, one that involves its newly found chemical assistant.

The chemical, known as NAD, for nicotinamide adenine dinucleotide, is an important intermediate in the cell's energy metabolism. NAD is the uncharged form of an energy-carrying chemical, and there is probably more of it around when the cell is in a state of low energy production.

The one intervention that is known to significantly prolong the life of laboratory rats and mice is to put them on diets with very few calories. No one knows why a calorically restricted diet prolongs life.

But Dr. Guarente's theory is that in caloric restriction the amount of NAD in cells may increase, spurring the activity of its partner sir2. Extra sir2 activity, he says, may prolong life in rats and mice just as it does in yeast.

"I think it is very interesting work because it provides a link between the energetic state of the cell and its ability to undergo gene silencing," said Dr. Tomas A. Prolla, an expert on the genetics of aging at the University of Wisconsin.

Dr. Cynthia Kenyon, who studies aging at the University of California at San Francisco, described Dr. Guarente's work as a "wonderful hypothesis that should stimulate a lot of research."

It is not yet known if caloric restriction -- a diet with 30 percent fewer calories but all necessary vitamins and minerals -- will also prolong life in humans. Monkey studies are under way but are not far enough advanced to interpret. Even if it turns out that humans do benefit, very few people are likely to be able to maintain such a difficult diet.

Dr. Guarente believes there should be a way to reap the benefit of caloric restriction without the pain, perhaps through a drug that affects the relevant genes, once these are discovered.

Is sir2 one of those genes? "I think we have a framework now to think about how mammalian aging might occur, and this hypothesis frames the next generation of experiments we will do," Dr. Guarente said. "And the first has to be, 'Can we make animals live longer with sir2?' "

He has engineered both mice and worms with extra copies of sir2, and is now measuring their life spans.

Evolutionary biologists have argued that aging is not the result of a deliberate genetic program but that it comes about as a sort of afterthought because natural selection cannot greatly favor genes that benefit an animal after the age of reproduction.

Dr. Guarente's assumption that there is such a program, and that it may be governed by the same set of genes in organisms ranging from yeast to mice to people, butts against this theory.

"I'm only a molecular biologist," he said, implying that deep evolutionary questions were beyond him. But he suggested that it might be useful for evolution to have a built-in longevity-controlling program to rely on in selecting organisms with life cycles adapted to different niches.

Dr. Guarente declined to say if his genetically engineered worms were living longer. Another scientist said a first batch of worms had lived longer, but had received many extra genes besides sir2. Such mutant worms can be bought off the shelf, whereas the ones with just an extra sir2 gene are a special order.


By NICHOLAS WADE
The New York Times on the Web: Science
http://www.nytimes.com/library/national/science/022200hth-aging-genetics.html

janet paterson
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