Gene Silencing and Anti-Aging

Shedding new light on the biology of aging, researchers recently reported a finding that may explain why a low-calorie diet prolongs healthy life in research animals. With this new insight, scientists may one day develop a drug that would allow humans to live in good health to the ripe old age of 170.

Scientists base this optimistic prediction on experiments in which laboratory mice live up to 40% longer when fed a nutritionally balanced diet that has 30% less calories than normal. The mice also remain free of age-related disease, although they are less fertile. Similar research with rhesus monkeys has not yet determined if a low-calorie diet has the same effect in primates. But even if caloric restriction can extend human life, very few people could endure such dietary deprivations. Scientists, therefore, hope to develop a drug that mimics the effects of low caloric intake. To create such a drug, one would first have to understand why, at a molecular level, caloric restriction leads to increased longevity.

Research with yeast has now provided that molecular understanding. Yeast are single-celled organisms that are widely used in research and that have many fundamental metabolic pathways similar to those of animals. In the September 22, 2000 issue of Science, Massachusetts Institute of Technology biologist Leonard Guarente reports that his experiments with yeast show that caloric restriction increases longevity by promoting gene silencing.

Gene silencing is one of the many ways to regulate the production of proteins. Genes are sequences of DNA that code for proteins, but if a gene is turned off, or silenced, its protein is not produced. Although some genes are expressed all the time because the cell constantly requires their protein products, other proteins are meant to be present only at certain times during the cell's life cycle. In fact, having the wrong genes activated at the wrong time can damage the cell. Many of the ravages of aging, Guarente says, may be explained by a breakdown of gene silencing.

In his research with yeast, Guarente found that caloric restriction stimulates gene silencing through the SIR2 gene pathway. SIR2 stands for silent information regulator No. 2, and, as the name implies, the SIR2 protein silences other genes. By switching off unwanted genes, SIR2 extends a yeast cell's life span. In Guarente's experiments, a mutant strain of yeast with super-strong SIR2 lived longer than other strains. Similarly, when the SIR2 gene was disrupted in normal yeast, the yeast expired earlier than usual.

Guarente realized the connection between caloric restriction and gene silencing when he discovered that SIR2 requires a cofactor called NAD to effectively turn off genes. A cofactor is a molecule or ion that a protein needs to carry out its cellular work. NAD also plays a vital role in breaking down food, so Guarente hypothesized that the SIR2 protein and metabolic proteins compete for NAD. According to Guarente, when an organism is eating a normal amount of food, most of the NAD in the body is assisting in breaking down this food. Consequently, little NAD is available for SIR2, and gene silencing activity is reduced. Conversely, when an organism has a low caloric intake, more NAD is free to aid SIR2 in silencing genes. This increased gene silencing, in turn, extends longevity by preventing cellular damage from accumulating. Therefore, through the SIR2 pathway, caloric restriction leads to a longer life span.

From an evolutionary perspective, the link between low caloric intake and longer life makes perfect sense, Guarente says. In the wild, during times of food scarcity, it would be advantageous for an animal to put off reproduction until conditions improved; activation of SIR2 and gene silencing provides this advantage by allowing an undernourished animal to live long enough so that it may eventually reproduce.

Guarente hopes that his new insight into aging may one day translate into a drug that activates SIR2 and limits age-related disease. Other biologists are skeptical, however, believing that aging is influenced by many genes and that targeting one gene cannot significantly reduce aging.

Sources

"Searching for Genes to Slow the Hands of Biological Time." Nicholas Wade. New York Times, September 26, 2000, page F1.

"A Pill to Extend Life? Don't Dismiss the Notion Too Quickly." Nicholas Wade. New York Times, September 22, 2000, page A20.