By David N. Leff

Serendipity found a knockout mouse in Italy that lived 35 percent longer than its littermates. This unexpected longevity raised more questions than it answered.

"We were studying something else," recalled cancer biologist Pier Giuseppe Pelicci, at the European Institute of Oncology in Milan, "and we got into this problem absolutely unintentionally. More specifically," he explained, "in 1992 we discovered the human SHC gene, and found a protein encoded by this gene, which we called p52. That protein controls cell growth.

"Since we are a cancer research group," Pelicci observed, "we were very interested in this protein, because it's directly connected to Ras regulation - Ras being one of the most frequent oncogenes in tumors. After a few years," he continued, "we realized that the same gene encodes a second protein, p66, and that this protein is involved in aging. So we arrived at longevity by studying a cancer gene. And this discovery is posing more questions than answers."

He went on: "Now the first question becomes, 'Why does the same gene encode one protein that has to do with cancer, and a second one, which has to do with longevity?' This mystery explains why we are studying longevity right now. Since we are cancer biologists, it opens another question: Is there anything in common, genetically or functionally, between aging and cancer?"

Pelicci is senior author of a paper in today's issue of Nature, dated Nov. 18, 1999. It bears the title: "The p66^shc adaptor protein controls oxidative stress response and life span in mammals."

An adaptor protein is something like a molecular singles bar. "It's a protein," Pelicci explained, "that by itself has no enzymatic activity, but puts the right enzyme and the right substrate in the same place."

"Our paper in Nature," Pelicci told BioWorld Today, "reports a single experiment. We deleted the p66^shc gene in the germline of mouse embryos. That is, we generated a colony of mice lacking this gene. This, of course, is the standard approach to asking the question: What is the function of a given gene? The answer: Take it out and see what happens.

"What we saw," Pelicci went on, "was that these animals had no obvious defect. However, they lived longer. So the phenotype of this deletion mutation is increased longevity. Now, if we want to make the conventional type of conclusion, we should say that this gene's function is to induce aging. In fact, if we delete it, we prolong the animal's survival - its life span."

Did Evolution Intend A Longevity Gene?

"An immediate next mystery: Can we assign such a function - induction of aging - to a gene? We know that evolution selects genes, which should have a beneficial function for the individuals; otherwise we don't see any mechanism for gene selection. How can we hypothesize that aging is somehow beneficial?"

Pelicci's interpretation is that "the function of this gene is something else, and aging is the consequence of that function. This is our challenge now, to understand what the basic function of this gene really is, and why this function bears a cost so important as aging."

Picking up on this challenge, he and his co-authors looked hard at a universal burden that impacts life on earth - namely, oxidative stress.

He explained: "Our human organism, as well as each cell of our organism - as well as any organism in the world - is continuously attacked by oxidants. That's a real disaster, in the sense that this is the most important stress for any cells. Oxidative stress is the result of oxidants," Pelicci pointed out, "which are within the cell, as a consequence of mitochondrial activity - cell respiration - and as a consequence of the external environment, mainly diet and ultraviolet radiation - UV light.

"These are all very detrimental," he added, "in the sense that oxidants include damage to DNA, to lipids and to proteins. And the consequence of this damage is deterioration of the cell's function. This ultimately leads to what we know as the aging process, which is nothing else than malfunction. A cell that is stressed by an oxidant reacts to that stress. It's not just a matter of damage accumulation; there is a cellular response.

If It's Broke, Fix It - Or Commit Suicide

Pelicci made the point, "This p66 protein is among those that participate in the cellular response to stress. It is activated by oxidative stress. That response takes one of two forms, both aimed at final elimination of the stress. The first," he enumerated, "is repair, and the second, ultimate strategy is induction of cell death - apoptosis. This is the best and final way to eliminate a damaged cell, in order to prevent propagation of the damage to its daughter cells. And p66, we determined, is indeed part of the apoptotic response to stress."

The co-authors subjected homozygous p66^shc -/- knockout mice, along with their heterozygous p66^shc +/- littermates and wild-type p66^shc +/+ siblings, to injections of paraquat. This toxic chemical generates superoxide stress inside cells. It killed all wild-type (gene-carrying) animals in short order, while p66^shc -/- knockouts survived 35 percent beyond normal life spans.

Following up on this demonstration, Pelicci and his team are now actively pursuing four goals:

¿ Find the p66 protein's true function, which seems to be regulating cell metabolism.

¿ Find drugs that inhibit the kinases responsible for phosphorylating the protein; then screen for inhibitors.

¿ Find functions of the other genes in the family to which p66^shc - now patented - belongs: "Do they have something to do with aging, too, or what?" Pelicci asked rhetorically.

¿ Find commercial partners: "I hope that in the near future," Pelicci concluded, "there will be interest from big pharmas or biotech companies, to help me support my research activity. Right now this work has been entirely supported by the Italian Association for Cancer Research, the original idea being to study this gene because of its involvement in cell proliferation control."