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Elderly mice yield clues to the process of growing old

rks of aging -- including graying, hair loss and atrophied muscle and bone -- at a pace much faster than the typical laboratory mouse.

"It's like a broken spellchecker," says Prolla. "By introducing a malfunction in the (genetic) proofreading domain, these mutations accumulate much more rapidly."

The new work lends support to one of the two leading theories of how animals, including humans, grow old and die. It supports the theory that apoptosis or programmed cell death underpins aging. A competing theory holds that oxidative stress -- the body's reaction to oxygen and the production of reactive, cell-damaging molecules known as free radicals -- is responsible for the aging process.

According to the new Science report, markers of oxidative stress did not parallel the accumulation of mitochondrial genetic mutations. Instead, the group found evidence that indicated accelerated cell death, especially in tissues characterized by rapid turnover of cells, occurred as mutations mounted in the mitochondrial DNA.

"We found no evidence of oxidative stress," Prolla explains. In fact, the team noted less oxidative stress in some tissues - the liver, for example - which suggests that accumulated genetic mutations in mitochondria slow metabolism. In turn, that change prompts cells to produce fewer of the reactive free radical molecules.

The symptoms of aging become pronounced with the loss of some critical cells, notably adult stem cells from some tissues and that are essential for replacing cells that die. "If these stem cells are lost, tissue structure and the ability of tissue to regenerate are impaired," Prolla explains. "We have observed that in tissues like bone marrow, intestine and hair follicles."

The altered mice used in the study were created by manipulating mouse embryonic stem cells to produce mice with the defective DNA proofreading protein. The mice develop normally, but age rapidly and develop such things as age rela
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Source:University of Wisconsin-Madison


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