Geneticists Engineer Longer-Lived Mice

In a finding that may yield a sharp insight into the genetic reasons for death, a team of Italian scientists Wednesday reported discovery of a gene that exerts major control over the life span of mice. The effects of the corresponding gene in humans is unknown, but experts in aging called the findings a milestone that could someday lead to drugs that postpone the effects of aging.

The new gene fits into a pattern of other recent findings about aging that highlight the role of oxygen damage to the tissues as a major driver of the aging process.

Oxygen may be the breath of life, but in the body it creates chemical byproducts, free radicals, that can corrode the cell's working parts and corrupt the information in its DNA data bank. If the damage is too severe, cells are genetically programmed to self-destruct, a fail-safe mechanism to prevent damaged cells turning cancerous.

The gene studied by the Italian team makes a protein that triggers the self-destruct process in response to oxygen damage. Mice genetically engineered to lack the trigger protein turned out to live 30 percent longer than normal, with no apparent harm.

The gene's effect was discovered by Dr. Pier Giuseppe Pelicci of the European Institute of Oncology in Milan, together with scientists at the Institute of Pathology in Perugia, Italy and the Memorial Sloan-Kettering Cancer Center in New York. Their findings are reported in the journal Nature. Experts in aging described the report as a significant step, although all said the finding needed to be better understood, and extended to different strains of mice, before it could be considered decisive.

"This is a fascinating start on what could prove an incredibly exciting pathway for research," Dr. Steven Austad of the University of Oregon said. .TX .- "I think it is a milestone that we can alter a single gene in a mouse and make it live longer, without any obvious side effects," Dr. Leonard Guarente of the Massachusetts Institute of Technology said.

Guarente described the Italian research as "proof of principle that we will be able to dissect the aging process in mammals," and said that whether this or some other gene is the key to increasing longevity, "at least this says there is hope."

Despite the obvious differences, mice are quite similar to people at the genetic level and provide valuable insights into their fellow mammal. The new gene's role in protecting cells from oxygen-related damage is particularly striking because it fits in with findings from lower laboratory organisms like fruit flies and roundworms. Biologists who have made these animals live longer by genetic manipulation have found that their cells are less likely to die after oxygen-related damage.

Also, the single known treatment that makes ordinary mice and rats live much longer - severe restriction of the calories in their diet - is one that cuts down on their cells' metabolism of glucose and the associated oxygen-related damage.

The gene studied by the Italian researchers makes a protein that forces the cell to die when oxygen damage is detected. The mice that were genetically incapable of making the trigger protein presumably lived longer because their cells, even though suffering some degree of oxygen damage, were no longer being zapped by the hair-trigger self-destruct mechanism.

Pelicci said the trigger belongs to a class of proteins for which many inhibitory drugs are known, and that it should not be too difficult to tailor a drug to block it.

Caloric restriction seems to impede a whole set of aging processes, and drugs that inhibit the trigger protein might produce the same wide range of benefits as caloric restriction but without the pain, biologists said.

Few people are able to maintain a diet with 30 percent fewer calories than a normal diet. Should caloric restriction prove to increase life span in primates as well as mice - monkey studies are in progress - a drug that mimicked the effects of caloric restriction would be valuable.

A surprising aspect of Pelicci's work is that so far he has found no downside in blocking the manufacture of the trigger protein. In all other laboratory animals whose longevity has been enhanced, there have severe penalties, usually in the form of reduced fertility. Calorically restricted mice do not breed at all. Surprisingly, the fertility of Pelicci's mice appears to be normal.

There must be some deficit, however, because genes that do not benefit their owner are soon lost. Both Pelicci and other scientists expect he will find some adverse effect of losing the gene, perhaps a fertility effect too mild to have shown up yet or some disadvantage not evident in the protected conditions of a laboratory.

The expected downside is likely for evolutionary reasons to occur in the young. Experts on aging believe that if the gene works the same way in humans, with luck the downside of inhibiting it would not be a problem in treating older people.