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Age-related genetic damage measured in mouse intestine, heart (7-17-00)

For the first time, scientists report they are able to measure specific genetic mutations that accumulate with age. Jan Vijg, Ph.D., and colleagues at The University of Texas Health Science Center at San Antonio (UTHSC) present their findings in the July 18 issue of the Proceedings of the National Academy of Sciences.

Dr. Vijg, professor of physiology at UTHSC and a participating scientist in the universityís Aging Research and Education Center, several years ago developed a so-called "transgenic" mouse equipped with a bacterial marker gene as part of the normal DNA present in each cell in its body. This gene enables the researchers to track mutations, which are changes in the DNA that alter the set of instructions it provides to the body to carry out its normal functions.

DNA, or deoxyribonucleic acid, is the molecule containing the genetic blueprint of life. DNA molecules are located in the cells of every living thing. As long ago as the 1950s, researchers proposed that damage to DNA in the form of slow natural accumulation of DNA mutations was the ultimate cause of aging. "Unfortunately, there were no methods available to verify if such a gradual accumulation of mutations actually occurred in the different organs and tissues of an aging animal or human," Dr. Vijg said. "This is what we have been able to accomplish.

"Using these mice, mutation accumulation can be monitored over the entire life span of the mouse in every organ and tissue," he said. "In our current article, with Martijn Dollé, Ph.D., as first author, we report that mutations do indeed accumulate with age in two tissues with totally different characteristics, the heart and the intestine."

The body undergoes cell division constantly, which is the reason that tissues such as fingernails, skin and hair regenerate. The researchers discovered a fairly rapid increase of mutations in the intestine, which is a tissue with high cell turnover. "In the heart, an organ composed of cells that are there for a lifetime and are not regularly replaced, mutations were found to accumulate, but at a slower pace," Dr. Vijg said.

The researchers found an average of about 400 mutations in the intestines of aged transgenic mice and about 200 mutations in the hearts of the same mice.

DNA is composed of about 100,000 genes, but scientists also break down the molecule into amino acid "base pairs." Each DNA molecule contains 3 billion of these base pairs arranged in precise sequence. The researchers took notice of a startling difference between the intestine and the heart mutations that accumulated in the mice. "While in the intestine only very small mutations, each involving one base pair out of the 3 billion base pairs, were found to accumulate, in the heart about half of those mutations were found to involve often millions of base pairs," Dr. Vijg said.

The researchers hypothesize that such mutations could cause "subtle functional deficits," he said, "which together might explain the decline in heart function during the normal aging process."

Dr. Vijg is director of the Department of Basic Research at the Cancer Therapy & Research Centerís Institute for Drug Development (IDD) and professor of physiology at UTHSC. Dr. Dollé has just been promoted from postdoctoral fellow to director of the Laboratory of Mutation Analysis at the IDD. Other co-authors are Wendy Snyder, a technician at the IDD, and Drs. Jan Glossen and Paul Lohman from The Netherlands.

"Although it is too early to conclude that aging in general is entirely due to this accumulation of mutations, this work offers the opportunity to at least further explore this possibility," Dr. Vijg said. His laboratory is comparing long-lived human individuals (centenarians) with control individuals of middle age for subtle differences in genes involved in DNA repair, one bodily function that protects the DNA against mutation.

Contact: Will Sansom