Study on Mice Could Shed Light on How Humans Age

A single genetic mutation in a mouse can cause it to age twice as fast as a normal mouse, scientists announced in a finding that might ultimately shed light on how and why humans age.

Mice usually live 2 1/2 to three years, but the ones with the mutation have an average lifespan of 14 months. A person who monitors two mice from the same litter might observe a normal one approaching mouse middle age at the same time that its genetically challenged brother gets gray hair and loses its hearing.

The genetic mutation was artificially induced by a research team led by Tomas Prolla, a geneticist at the University of Wisconsin- Madison and the lead author of the study published in the journal Science.

According to the team’s results, the process of aging seems to begin when enough defective products accumulate in a cell that the cell self-destructs. Destroyed cells get replaced, but for reasons not yet understood, the rate of replacement slows over time. Eventually cells die off faster than they’re replaced, resulting in symptoms such as decreased bone density and diminished muscle mass, characteristics typically associated with aging.

Prolla’s team tested this hypothesis by increasing the rate at which a mouse cell produced defects. The team targeted mitochondria, the cellular elements that power cells like tiny batteries.

Mitochondria are the only components of a cell that contain their own DNA. When a cell divides, its mitochondria and their DNA divide as well. As the DNA gets copied, a specific protein acts like a spellchecker, finding and correcting errors in the duplication process.

Prolla’s team re-engineered this process so the protein could find but no longer correct errors. That meant errors hence mutations accumulated in the cell over time, three to eight times more often than normal.

Prolla said scientists knew that even in normal mice, mutations in mitochondrial DNA build up over time

“What we didn’t know was, did this contribute to aging?” Prolla said. “So we took these (re-engineered) mice and didn’t change anything except their rate of (cellular) mutations, and they aged more rapidly than normal mice. So it’s likely this is one of the central mechanisms of aging.”

The research team compared the lifespans of 40 re-engineered mice with those of 40 normal mice. The mutant mice lived an average of 416 days while most of the normal mice are still alive more than 850 days later.

This research challenges earlier notions of the causes of aging, including the free radical theory that suggests that free radicals, which are by-products of normal biochemical processes, can damage healthy cells. As free radicals build up, the idea goes, more and more healthy cells are compromised. It was believed that the combined effect of free radicals and cellular mutations led to aging.

But Prolla’s team found no increase of free radicals in the prematurely geriatric mice.

“This doesn’t mean that free radicals aren’t involved in aging it just shows that in mitochondria, free radicals aren’t necessary to promote aging,” Prolla said. “Clearly the two are not necessarily linked.”

As researchers learn more about how aging works, they may be able to devise ways to slow the process, perhaps by preventing the signal that causes cells to self-destruct in response to mutations. But that’s a tricky process.

“Cells are kept in balance by cellular growth and death,” said Greg Kujoth, a UW-Madison geneticist on the team. “But if we prevent too much cell death, it’s likely to promote cancer.”

So is there a human benefit to this type of research? Sure, say the scientists, but it’s probably decades away. In the meantime, just having faster-aging mice gives other researchers a biological model on which to test anti-aging drugs. Instead of giving those drugs to mice with a three-year lifespan, scientists can now give them to mice with a one-year lifespan, thereby getting data and drawing conclusions faster.

George M. Martin, a professor emeritus of pathology at the University of Washington, said this research is a valuable piece in the puzzle of aging, but said aging is such a complex process that we are far from understanding. He also said he would have preferred that Prolla’s team do more post-death exams of the re-engineered mice.

This research might eventually help scientists answer a more basic question: Why do mice live for three years, dogs 10 to 12 years, humans about 80 years, turtles for 100? What’s different between the species?

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