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August 24, 2004
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  Long Life Gene    

In Search of the Secrets of Aging

"Of Mice and Men," an article about the use of mice in the study of genetics

Caloric Restriction Slows Aging, with information on how and why it works for humans

The Huffington Center on Aging at Baylor College of Medicine

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Long-lived mouse

The average human life span has never been longer, thanks to medicine and healthier living habits. But if new research on mice also applies to people, the secret of a long life may be found not in the gym... but in the genes.

Scientists have created a strain of genetically-modified mice that live 30 percent longer than their normal counterparts. The mice that lived longer are genetically different from normal mice by only one gene. In particular, the modified mice can no longer express the gene encoding the p66shc protein. This finding came quite accidentally: The research team was originally studying the gene because they believed it played a role in causing cancer. Instead, they found that mouse cells without this gene appear to be more resistant to environmental stresses, including those associated with aging.

"Little is known about the mechanism that controls how long we live," said Pier Paolo Pandolfi, one of the authors of the study (published in the journal Nature—the lead author was Pier Giuseppe Pelicci, of the Istituto Europeo di Oncologia in Milan, Italy) and a member of the human genetics department at the Memorial Sloan-Kettering Cancer Center in New York City. "This would be the first discovery to identify genes that can control life span in mammals."

So far, success with increased life span has proven to be a give-and-take situation. For example, the Ames Dwarf mice live longer than normal as a consequence of a single gene defect, but they are much smaller and develop more slowly. Non-genetic manipulations, such as caloric restriction (a severely restricted diet), can extend the life span of mice by more than 50 percent, but the affected mice are smaller and less fertile than normal mice.

The mice produced by Pandolfi and his colleagues, however, appear to be normal with respect to their size, development, intelligence and fertility. "I think it’s exciting," says Leonard Guarente, an expert on the genetics of aging in the biology department at the Massachusetts Institute of Technology, "because it’s the first time anyone has altered a mouse to make it live longer without there being some cost."

Do They Know Why This Accident Happened?

Scientists refer to the gene encoding the p66shc protein as "shick," but not much is known about its function. The researchers suspect, however, that the gene plays a role in oxidation, which can damage or kill cells.

Scientists have speculated on the relationship between aging and oxidative damage since Denham Harman, a researcher at the University of Nebraska, proposed the "Free Radical Theory of Aging and Disease" in the mid-1950s. More recently, Nobel Prize winner Linus Pauling strongly promoted the theory and advocated supplementing the human diet with antioxidants, such as Vitamins C and E. Until today, however, the theory lacked support from direct experimental findings.

"It is intuitive to all of us that if we are exposed to stress of any sorts, we might live shorter," says Pandolfi. "And therefore, the ability to cope with stress might prolong our lives. But this is a first demonstration that this is the case."

How Do You Erase A Gene?

Practical factors place restrictions on species that would make good gene "knock-out" targets for research purposes: Ideally, such species should reproduce quickly, have several offspring at a time, and live a relatively short life cycle. Consequently, much more is known about genetic mutations and aging in non-mammalian species such as fruit flies, yeast and worms.

Here is a technique for "knocking-out" a mouse’s gene:

Animation of a gene being knocked out of DNA.
  • The scientists must first isolate embryonic stem (ES) cells from a female mouse that has been pregnant for 3.5 days. ES cells are special, in that they are the unspecialized precursors of all other cells and are capable of turning into any kind of cell.

  • The scientists must next construct a strand of DNA that encodes for a desired gene. Somehow, this strand needs to switch places with the same region of DNA in the ES cell. A technique called homologous recombination makes such specific exchanges possible.

  • The ES cells with their modified DNA are implanted in a surrogate mother, with hopes that the cells will continue to develop as a normal pregnancy.

  • After birth, the scientists verify that the offspring’s DNA has been correctly modified and then they examine the animals for consequences of the mutation.

Would This Work In Humans?

image: AARP

Although optimistic, scientists also caution against speculating too far on the significance of this research to humans. "Oxidative damage is one mechanism thought to be important in human aging," says Guarente, "but it’s too early to tell what relevance this has to human aging."

Further research is necessary to determine whether this outcome is restricted to this particular strain of mice, or whether the disruption of this gene might have a similar effect in other strains, or even other species. The scientists now say they can begin to study people with unusually long lives to see if this gene is responsible.

But even with definitive proof that the gene is present in humans and can be safely manipulated, no one knows how to "knock-out" a gene in humans. Our ability to therapeutically manipulate the genome (for example, applying mutations to remedy a disease) awaits advances in gene therapy.

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