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Anti-aging gene's function may be tied to metabolism

MIT researchers reported in the February 17 issue of Nature that an anti-aging gene in yeast is an enzyme. This enzyme can turn off whole sections of the genome, slowing the organism's aging process. The million-dollar question is whether the gene, Silent Information Regulator, is a longevity factor in people.

The study by Professor of Biology Leonard P. Guarente, postdoctoral associate Shin-ichiro Imai and graduate students Christopher M. Armstrong and Matt Kaeberlein also points to a connection between slowing an organism's metabolic rate and slowing its aging.

Their results could shed light on separate studies that have shown that restricting caloric intake to 70 percent of normal levels significantly extends the life spans of yeast, earthworms, mice and possibly primates. "This is the first concrete indication that [genome] silencing and metabolism are connected," Professor Guarente said.

Specifically, the gene called SIR2 turns out to be a histone deacetylase -- an enzyme that activates proteins associated with DNA in chromosomes. "This would explain its ability to silence" or turn off whole sections of the genome, he said.

In each cell, some genes are active, or turned on, while others are silenced. Our skin cells, for instance, are genetically identical to brain cells, but each is programmed before birth to express certain genes and not others, much like striking different combinations of keys on a piano will result in different chords.

SIR2 can determine whether whole sections of the genetic "keyboard" are off-limits. This in turn could prevent age-related problems that surface late in an organism's life span, such as genome instability and inappropriate gene expression. As cells age, genes that had always been turned off sometimes get turned on, causing problems that can lead to cell death.

Professor Guarente and colleagues have been studying SIR2 for almost a decade. They found that organisms such as yeast that have been given an extra copy of the SIR2 gene have longer life spans than those who do not have an extra copy. If yeast is missing SIR2 altogether, the cells' life spans decrease.


The researchers also found that SIR2 needs nicotinamide adenine dinucleotide (NAD) to be activated. Made by all cells, NAD is a co-enzyme that helps transfer electrons and hydrogen in some oxidation-reduction reactions. (Anti-oxidants in food have been tied to lower cancer rates as well as slowing the aging process.) "Although NAD and NADH are frequent enzyme co-factors in oxidation/reduction reactions, this is the first example to our knowledge in which NAD drives a distinct enzymatic reaction," the authors wrote.

"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," Professor Guarente said. "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 life span."

Professor Guarente speculated that SIR2 taps into NAD levels in the cell to get a read on how metabolism is functioning, then "decides" what to do about silencing. If NAD levels are up, silencing takes place.

The next major test will be to try the calorie-reduction experiment on a population in which the SIR2 gene has been removed. If the organism's lifespans are not increased, this would indicate a strong link between SIR2 and calorie reduction.


Professor Guarente has found that there are changes in the nucleolus -- a section of the nucleus -- of yeast cells that are aging. He has found that in the nucleolus of older cells, some of the cell's genetic material, a circular piece of ribosomal DNA, pinches off from a chromosome. These coils accumulate in the cell, causing it to enlarge and eventually die.

By silencing sections of the genome, SIR2 seems to reduce this phenomenon.

Genes similar to SIR2 have been identified in many organisms, ranging from bacteria to humans. "All investigations led us to this gene," Professor Guarente said. The key now is to figure out what the gene does and exactly how it works. The hope is that researchers may one day be able to intervene in, and possibly inhibit, the aging process in humans.

"If we can keep SIR2 active for longer, we may slow down aging," he said.

This work is funded by the Human Frontier Science Program Organization, the National Institutes of Health, the Seaver Foundation, the Ellison Medical Foundation, and the Howard and Linda Stern Fund.

A version of this article appeared in MIT Tech Talk on March 1, 2000.

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