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Aging: Is it a power failure?

Researchers explore the role of mitochondria

They are the power plants within our cells, crucial for life, and concentrated in the tissues that often deteriorate the most as we age -- the brain, the heart, the muscles, the eyes. But are the mitochondria a driving force in aging?

Increasingly, researchers are focusing on the possibility that this tiny element of a cell may be a factor in failing memory, increasing weakness, thinning hair, and other symptoms of aging.

The evidence is piling up but not yet definitive. It is grounded in the knowledge that mitochondrial function deteriorates with age, that mitochondria generate damaging molecules called free radicals, and that mutations accumulate in mitochondrial genes, some of them caused by free-radical assault.

"It's one of the hottest areas of biology," said Simon Melov, director of genomics at the Buck Institute for Age Research who reviewed recent research in the October issue of Trends in Neuroscience.

Last spring, scientists in Sweden provided some of the strongest evidence yet. They shortened the life of mice and created signs of old age by injecting a small genetic defect into the mice's mitochondria.

Potentially harmful changes in mitochondria also have been discovered in age-related diseases, such as Alzheimer's, diabetes and the muscle-wasting condition called sarcopenia.

In addition, researchers are identifying natural changes in mitochondria that may promote longevity and protect against some diseases. For instance, scientists have discovered a particular mutation in mitochondrial DNA that occurs five times more frequently in centenarians than in younger individuals. Other researchers have identified segments of the world's population with mutations in their mitochondrial DNA that appear linked to both longer life and protection against Alzheimer's.

But not everyone is convinced.

"It's a very appealing theory," said David Finkelstein, who oversees research on metabolism at the National Institute on Aging. "Mitochondria are a source of energy and a lot of damage. But the body is designed to deal with a lot of this. I'd like to be a believer, but I also have to remain skeptical until we see rigorous proof."

Some of the key researchers working on mitochondria believe these tiny structures will turn out to be only one of several factors that explain aging.

Mitochondria, present in every cell of the body except red blood cells, are believed to have derived from bacteria that invaded more complex cells billions of years ago, bringing their own genetic code. They transform fat, sugar and oxygen into energy that can be used by the body. As a byproduct, they create free radicals, destructive oxygen molecules that can damage the mitochondria genes as well as the surrounding cells.

If mitochondria severely malfunction, humans eventually die -- from lack of fuel for the brain and heart, or from signals from the mitochondria that spur cell suicide. Inherited mitochondrial defects cause dozens of rare illnesses, and scientists are increasingly finding evidence of mitochondrial problems linked to more common diseases, which may shed light on the aging process.

For example, scientists at Yale University reported in Science magazine last month that they had found a mutation in mitochondrial DNA that caused high blood pressure, high cholesterol and low magnesium levels in four generations of an extended family. The work follows a study last year that linked a 40 percent decline in mitochondrial function in adults over 60 to insulin resistance, a major contributor to adult-onset diabetes. Since the symptoms of insulin resistance, high blood pressure, high cholesterol and obesity often cluster in aging adults, researchers suggest there may be a common mitochondrial cause.

"We need to explore this hypothesis directly," said Dr. Richard Lifton, chairman of the genetics department at Yale who conducted the most recent work.

Researchers also have found that mitochondrial mutations build up in the muscles of monkeys and rats with sarcopenia, an age-related loss of muscle mass. The damaged muscles have lost one-third to one-half of their mitochondrial genes, and thus a big part of their ability to generate energy to build muscle fiber, according to Judd Aiken, a professor of animal health and biomedical sciences at the University of Wisconsin in Madison who published the study last year. Aiken is now looking for the same mutations in human muscle cells.

Animal research on Alzheimer's also has implicated mitochondrial damage, finding that the disease's characteristic amyloid plaques increased as destruction caused by free radicals rose. In human brains, Douglas Wallace, a mitochondria researcher at the University of California at Irvine, found 63 percent more mutations in the mitochondria of those with Alzheimer's compared with healthy adults. And in the Alzheimer's patients, more of these changes were clustered in the portion of the mitochondria that controls its key functions.

While the links are accumulating, Finkelstein and others say there is still a big question about whether the mitochondrial changes cause the illnesses or are just another symptom.

That's why Dr. Nils-Goran Larsson decided to see if he could shorten the lifespan of mice and create age-related symptoms with a simple change in their mitochondria. The genetics professor and his colleagues at the Karolinska Institute in Stockholm disabled the ability of mice to correct errors in their mitochondrial DNA. As the mice aged and the mitochondria replicated themselves, errors built up. The mice began to show signs of premature aging, including weight loss, hair loss, osteoporosis and heart enlargement. All were dead nearly a year earlier than normal mice, which usually live about two years.

Looking at the reverse proposition -- extending life via changes in mitochondria -- Gary Ruvkun, a professor of genetics at Harvard Medical School, got roundworms to live 20 percent to 30 percent longer by genetically halving the efficiency of their mitochondria, which he theorized might have caused them to produce fewer damaging free radicals. But he's found that tinkering with the genes involved in regulating insulin, rather than mitochondria, can increase worm lifespan 200 to 300 percent -- suggesting that mitochondria may play a lesser role in aging.

Researchers can't experiment with human genes in the same way, but have found links to longevity in natural mitochondrial variations. Dr. Giuseppe Attardi, a biology professor at the California Institute of Technology, discovered an accumulation of mutations in mitochondrial DNA that was more prevalent -- though still not common -- in centenarians. He suggested that these mutations may help people survive under unfavorable conditions but can't yet explain the underlying mechanism.

Wallace has examined patterns of mitochondrial DNA around the world and found mutations he believes helped people adapt to living in colder climates -- and had the unexpected byproduct of extending lifespan and protecting against Alzheimer's and Parkinson's. According to a study he published in Science in January, the mutations directed the mitochondria to make more heat instead of energy, which led them to generate fewer free radicals and cause less damage to the body.

"We're very confident that these mutations are . . . protective of aging," he said in an interview.

Finkelstein said he finds the work of Attardi and Wallace provocative, but said the fact that mutations can affect lifespan doesn't mean they're the critical element.

"The bottom line: What controls aging is a big black box," he said.

Melov predicted that new research methods and a critical mass of researchers are coming together to bring some answers quickly.

"Evidence which will answer this question definitively will be published within the next few years." 

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