X-Message-Number: 26629
Date: Fri, 15 Jul 2005 20:12:58 -0700 (PDT)
From: Doug Skrecky <>
Subject: mitochondrial mutations may drive aging

[It is interesting that the free radical theory of aging seems to be
rapidly falling into disrepute. It is even more interesting that
mitochondria still enjoy center stage.]

---------- Forwarded message ----------
UF STUDY FINDS CELL MUTATIONS THAT LEAD TO APOPTOSIS MAY CONTRIBUTE
TO AGING IN MAMMALS
July 14, 2005
GAINESVILLE, Fla. --- A University of Florida study has found that
mutations in the mitochondria caused by obesity and lack of exercise
-- not oxidative stress from free radicals -- may be a key factor
in the aging process.
The study, published in this Friday's issue of Science magazine,
finds that accumulation of mitochondrial mutations that promote
apoptosis, or programmed cell death, may be a central mechanism
driving aging and may be unrelated to the release of free radicals,
previously thought to cause aging. This may be because of an
accumulation of DNA mutations in the mitochondria, the cellular
powerhouse that converts food to energy.
Results from the study may lead to more effective methods to prevent
aging and stress the importance of a healthy lifestyle, said Christiaan
Leeuwenburgh, an associate professor in the department of aging and
geriatric research in the College of Medicine and contributing author
of the study. He estimated that average maximum human lifespan could
be increased from the current 70 years to more than 100 years with
exercise and a proper diet.
"All the therapies have been targeted to reduce the free radical
production in the mitochondria, and now it looks like that doesn't make
complete sense," he said.
By breeding mice with the inability to detect and repair mistakes in the
DNA replication process, researchers discovered there was no increase in
oxidative stress despite an increased mutational load. However, there
was a significant increase in apoptosis, said Leeuwenburgh.
In mammals, uncorrected mistakes can cause genetic disorders, aging or
even death, said doctoral student Asimina Hiona, who was instrumental
in the biochemical analysis of free radicals and apoptosis in the study.
In the mutated mice, that ability was impaired so the cells could not
repair themselves.
The finding disproves the previously believed mitochondrial
"vicious cycle" theory of aging, which states that increases in
mitochondrial mutations increase oxidative damage, which is one
cause of aging.
"It was previously believed that the more mitochondrial mutations
you have, the more free radicals you're going to produce," said
Leeuwenburgh. "But that's one thing this paper shows, that that's
not necessarily the case."
The mice used in the study were bred by Thomas Prolla, an associate
professor and lead investigator of the paper, and Greg Kujoth, an
assistant scientist, both of the genetics department at the
University of Wisconsin.
"Mice with accelerated aging may be a useful system to discover
compounds that improve function in aging individuals and perhaps
retard or prevent some of the diseases associated with aging,"
Prolla said.
The researchers discovered that on average, the mutant mice lived
a third as long as normal mice. At just nine months of age, they
experienced significant loss of hair, hearing, bone mass, intestinal
lining and overall weight, conditions similar to those of an aging
human. Unaltered, the same mice normally live 30 to 32 months.
Also, no programmed cell death was observed between mutant and control
mice at 3 months of age. However, by the time the mice reached 9
months, significant levels of programmed cell death were found in
the testes, heart, thymus and other organs.
Although the mice were considered a "good model" of aging, they
lacked a chronic inflammatory component which can cause
cardiovascular disease, Alzheimer's and other health problems that
affect individuals as they age. Chronic inflammation is associated
with the increased production of free radicals produced by other
sources, such as white blood cells.
"As we get old, we become stiff and have pains and processes that
have inflammation," Leeuwenburgh said. He added that inflammation
may be prevented by maintaining an ideal body weight through
caloric restriction and exercise.
If people practice a healthy lifestyle, then stem-cell therapy,
nanotechnology and special exercise and dietary interventions will
be even more beneficial, he said.

Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in
Mammalian Aging
G. C. Kujoth, A. Hiona, T. D. Pugh, S. Someya, K. Panzer, S. E.
Wohlgemuth, T. Hofer, A. Y. Seo, R. Sullivan, W. A. Jobling,
J. D. Morrow, H. Van Remmen, J. M. Sedivy, T. Yamasoba, M. Tanokura,
R. Weindruch, C. Leeuwenburgh, and T. A. Prolla
Science 15 July 2005: 481-484


Restoration of mitochondrial function in cells with complex I
deficiency.
Ann N Y Acad Sci. 2005 May;1042:25-35.
  The mammalian mitochondrial NADH dehydrogenase (complex I) is the
major entry point for the electron transport chain. It is the largest
and most complicated respiratory complex consisting of at least 46
subunits, 7 of which are encoded by mitochondrial DNA (mtDNA).
Deficiency in complex I function has been associated with various
human diseases including neurodegenerative diseases and the aging
process. To explore ways to restore mitochondrial function in complex
I-deficient cells, various cell models with mutations in genes encoding
subunits for complex I have been established. In this paper, we discuss
various approaches to recover mitochondrial activity, the complex I
activity in particular, in cultured cells.

Rejuvenation Res. 2005 Spring;8(1):6-8.
Mitochondrial DNA gene therapy: a gene therapy for aging?
Mutations in mitochondrial DNA cause a group of diverse diseases
that affect an estimated half a million people worldwide. These
disorders are remarkably resistant to conventional treatments, and
thus several gene therapy approaches are being explored. As some of
these approaches develop towards maturity, one can't help thinking
that some day they may be used against a much more common health
problem currently affecting about 6 billion people- aging, which also
has been quite resistant to treatment. Unfortunately, we still do not
know whether mtDNA mutations significantly contribute to the aging
process or not. The prospect of success in mtDNA gene therapy makes
getting the answer a high priority.

J Neurochem. 2002 Jun;81(6):1273-84.
Age-dependent decline of DNA repair activity for oxidative lesions
in rat brain mitochondria.
Endogenous oxidative damage to brain mitochondrial DNA and
mitochondrial dysfunction are contributing factors in aging and in
the pathogenesis of a number of neurodegenerative diseases. In this
study, we characterized the regulation of base-excision-repair (BER)
activity, the predominant repair mechanism for oxidative DNA lesions,
in brain mitochondria as the function of age. Mitochondrial protein
extracts were prepared from rat cerebral cortices at the ages of
embryonic day 17 (E17) or postnatal 1-, 2-, and 3-weeks, or 5- and
30-months. The total BER activity and the activity of essential BER
enzymes were examined in mitochondria using in vitro DNA repair assay
employing specific repair substrates. Mitochondrial BER activity
showed marked age-dependent declines in the brain. The levels of
overall BER activity were highest at E17, gradually decreased
thereafter, and reached to the lowest at the age of 30-month (
approximately 80% reduction). The decline of overall BER activity with
age was attributed to the decreased expression of repair enzymes such
as 8-OHdG glycosylase and DNA polymerase-gamma and, consequently, the
reduced activity at the steps of lesion-base incision, DNA repair
synthesis and DNA ligation in the BER pathway. These results strongly
suggest that the decline in BER activity may be an important mechanism
contributing to the age-dependent accumulation of oxidative DNA lesions
in brain mitochondria.

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