BioWorld International Correspondent

LONDON - A newly identified genetic mutation that leaves the body unable to deal with damage to DNA caused by ultraviolet radiation and other agents has provided a multitude of clues about the causes of aging.

A study of a 15-year-old boy who suffered frequent sunburn, and then developed premature signs of aging, including an old, wizened appearance, visual and hearing loss, and degeneration of many organs, showed that he lacked an enzyme that normally is involved in DNA repair. The boy died at age 16.

Mutant mice lacking a functional gene for the same enzyme die at 3 weeks instead of living for 2.5 years. Investigations by an international team of researchers have shown that the metabolic changes experienced by the mutant mice closely resemble those observed in normal aged mice, making them an excellent model for the study of aging.

Jan Hoeijmakers, professor of molecular genetics at Erasmus Medical Center in Rotterdam, the Netherlands, told BioWorld International that "Our work provides an important clue to the causes of aging - namely, that it is due in large part to DNA damage. In addition, if we want to identify compounds in food or in drugs that will prevent aging-related diseases, we need to have a reliable model system that will work within a reasonable time frame."

The mouse model he and his colleagues have identified should, he predicted, greatly speed up progress toward the goal. "We have shown that these mice are valid models of normal aging. Instead of experiments taking four years, they now take only a few weeks," Hoeijmakers said.

To exploit those findings, the Dutch team has set up a company, called DNage, which recently was acquired by Pharming, of Leiden, the Netherlands.

Hoeijmakers and his collaborators reported their findings in a paper Dec. 21 issue of Nature titled "A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis".

Genetic analysis of the 15-year-old patient showed that his DNA was homozygous for a mutation affecting the gene encoding an enzyme called XPF-ERCC1 endonuclease. The role of the enzyme is to repair damage that distorts the DNA helical structure, or that crosslinks the two strands of DNA.

The mutation had never been described before. Hoeijmakers's team called the condition XFE progeroid syndrome. Fortunately, mice lacking the murine version of the enzyme were available already. Those animals also show rapid onset of degeneration and die at about 3 weeks of age.

The researchers carried out a genome microarray analysis, to examine changes in activity of all genes in these mice during their lifetime. "We found that the profile of gene activity in the livers of these mutant mice at 15 days of age was very similar to that of normal mice, at the age of 2.5 years," Hoeijmakers said. "This shows that our rapid-aging mouse model has a striking resemblance to natural aging."

The team saw similar changes in control mice that were given the chemical mitomycin C to stimulate DNA damage.

Other experiments showed that DNA damage triggered a "survival response" that suppressed energy metabolism, by reducing consumption of glucose and fat, and upregulated cellular defenses.

Hoeijmakers added: "By suppression of growth and development and by investing in maintenance and repair mechanisms, the body attempts to slow down the process of aging, and we saw this with both accelerated and normal aging. We think that the aim of this shift, from burning energy to storing energy, is to reduce the amount of reactive oxygen species that are present in the body, because if you have a high metabolism, you have more reactive oxygen species and these can damage your DNA."

At DNage, Hoeijmakers uses the rapid-aging mutant mouse model to try to find compounds that will delay the onset of aging-related pathology. It might be possible to tell within two to three months whether adding a particular compound or food to the diet of the mice affects their propensity to age, he said.

Using conditional knockouts, it also would be possible to confine the aging characteristic to single organs, Hoeijmakers added. "We will be able to study the pathogenesis of aging in the brain, for example, while the body of the mouse remains normal. This approach has enormous potential for studying Parkinson's disease, Alzheimer's disease or neurodegeneration in general," he said.