Power failure

           As mitochondria help fuel the body, are they also fueling the
           aging process?
           By Alice Dembner
           December 1, 2004

           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.
           Free radical connection

           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 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 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 a symptom.

           That's why Dr. Nils-Goran Larsson decided to see if he could
shorten
           the life span 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
           life span 200 percent to 300 percent ? suggesting that
mitochondria
           may play a lesser role in aging.

           Protective mutations

           Researchers can't experiment with human genes in the same way,
but
           have found links to longevity in natural mitochondrial
variations.
           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
life
           span 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 life
span
           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."