New data contradict aging theory

Point mutations in mitochondrial DNA do not cause signs of aging in mice, according to a report in this week's Nature Genetics. The data, which contradict a prominent theory that mitochondrial mutations drive the aging process, show that mice with mitochondrial mutations 500 times higher than normal levels do not show signs of premature aging.

The finding "supports the idea that the accumulation of these mutations might be correlated with aging but [are] not causative," said Eric Schon of Columbia University in New York, who was not involved in the study.

Previous work has led to the mitochondrial theory of aging, which says that mitochondrial DNA mutations throughout life eventually cause the decline in tissue functioning associated with aging.

During the study, Marc Vermulst of the University of Washington in Seattle and his colleagues measured the accumulation of mitochondrial DNA mutations using a new technique -- an adaptation of the random mutation capture (RMC) assay, a quantitative PCR-based technique that amplifies single molecules to detect mutations but is not limited by polymerase fidelity.

They found that mutation frequency in mouse mitochondria is more than 10 times lower than that reported in previous studies, suggesting earlier work overestimated the rate of these mutations. "The technique we are using is much more sensitive" than previous assays, which had very high background levels, Vermulst said.

The authors compared the mitochondrial mutation frequency in wild-type mice to that in "mutator" mice with abnormally high levels of mitochondrial mutations. Mice homozygous for the mutant gene have 2,500 times the mitochondrial mutations as wild-type mice and also show reduced lifespan and several features of premature aging. However, mice with only one copy of the mutated gene showed no signs of premature aging, even though they have 500 times as many mitochondrial mutations as wild-type mice.

"The homozygous animals have crossed a certain threshold at which these mutations now cause premature aging syndrome," Vermulst said. "The heterzygous animals are below that but are still very high compared to wild-type animals," and still don't age prematurely. This suggests that wild-type animals, with their relatively small rate of mitochondrial mutations, could never accumulate enough to cause aging symptoms, premature or otherwise, he added.

Since their assay examined point mutations only, it remains possible that large deletions in mitochondrial DNA could still underlie aging, said senior author Lawrence Loeb, also of the University of Washington.

The study's result is "a problem for the mitochondrial theory of aging, at least with regards to point mutations," Schon told The Scientist. However, the mutator mice might not be perfect models for aging, he added. These mice begin accumulating mitochondrial mutations early in embryonic development, while normal animals don't accumulate them until after birth.

Given that mutated mice get an early start to these mutations, it's possible that embryonic cells in the mutator mice could "figure out a way to adapt to mutations that adult animals" could not tolerate, agreed Peter Zassenhaus of St. Louis University, who was not involved in the study. "We need to know what the mechanism is" through which mitochondrial mutations might influence tissue function, Zassenhaus told The Scientist. "Without really understanding how these mutations can cause a disease or pathology, it's hard to interpret the mutation frequencies by themselves."

The type of mutation induced in the mutator mice may also affect the results, according to Konstantin Khrapko of Beth Israel Deaconess Medical Center in Boston. These mice have defects in a mitochondrial DNA polymerase, which is not involved in naturally occurring mitochondrial mutations. "These mutations may accumulate in different cell types" than natural mutations, Khrapko told The Scientist in an Email.

These findings present a problem for researchers who believe that mitochondrial DNA mutations are "a central mechanism driving mammalian aging," noted Khrapko, who was not a co-author. But the results don't damage a "softer theory," he added -- that some types of mitochondrial mutations may affect aging only in certain tissues of certain species.

Melissa Lee Phillips
mail@the-scientist.com

Links within this article

M. Vermulst et al., "Mitochondrial point mutations do not limit the natural
lifespan of mice," Nature Genetics, published online March 4, 2007.
http://www.nature.com/ng/journal/vaop/ncurrent/abs/ng1988.html

S. Jay Olshansky et al, "What if humans were designed to last?" The Scientist, March 1, 2007.
http://www.the-scientist.com/2007/3/1/28/1

C.Q. Choi, "How mtDNA mutations cause aging," The Scientist, July 15, 2005.
http://www.the-scientist.com/article/display/22731/

Eric Schon
http://cpmcnet.columbia.edu/dept/genetics/faculties/Schon.html

A. Trifunovic, "Mitochondrial DNA and ageing," Biochimica et Biophysica Acta, March 31, 2006.
http://www.the-scientist.com/pubmed/16624248

J.M. Perkel, "DNA damage repair defect unifies theories of aging," The Scientist, December 20, 2006.
http://www.the-scientist.com/news/display/38218/

J.H. Bielas, L.A. Loeb, "Quantification of random genomic mutations," Nature Methods, April 2005.
http://www.the-scientist.com/pubmed/15782221


D. Zhang et al., "Construction of transgenic mice with tissue-specific acceleration of mitochondrial DNA mutagenesis," Genomics, October 15, 2000.
http://www.the-scientist.com/pubmed/11031098

A. Trifunovic et al., "Premature ageing in mice expressing defective mitochondrial DNA polymerase," Nature, May 27, 2004.
http://www.the-scientist.com/pubmed/15164064

Lawrence Loeb
http://depts.washington.edu/biowww/faculty/loeb.html

Peter Zassenhaus
http://medschool.slu.edu/mmi/faculty/zassenhaus.html

Konstantin Khrapko
http://research.bidmc.harvard.edu/research/ResearchPIInfo.ASP?Submit=Display&PersonID=1451