Sci. Aging Knowl. Environ., 17 April 2002
Laid to Waste: Rare disease spawned by repair defect imitates aging (DNA repair; Premature aging)
Key Words: trichothiodystrophy XPD ERCC2 helicase TFIIH nucleotide excision repair progeroid
Abstract: Like buildings, bodies crumble if their maintenance crews falter. According to previous work, animals with a crippled ability to doctor DNA suffer an early demise. Now, new findings bolster the idea that rundown DNA promotes aging. Mice with a faulty DNA fix-it protein appear to grow old prematurely. What's more, when another repair molecule abandons its post, their ailments intensify. The work links the rare disease trichothiodystrophy (TTD) to aging and might supply a new animal model with which to study the process.
Hallmarks of TTD include brittle hair, flaky skin, and stunted growth. Severely affected children often die by age 5, which partly explains why TTD hadn't been considered a premature aging disorder. A defect in the gene XPD triggers about half of TTD cases. XPD encodes a protein with two functions: repairing DNA and copying it into RNA.
Several years ago, de Boer and colleagues engineered a mouse strain with the XPD mutation that causes TTD in humans. The mice develop normally but die young and have frayed fur. But de Boer didn't connect the symptoms with aging until he noticed that the animals were graying early. Now, the group has shown that the mice suffer from unusual amounts of wear and tear by 3 months of age, just past early adulthood. At that time, for example, they have lost weight and their bones are thin.
The researchers decided to probe for the root of the problem. As a first step, they asked whether compromised repair instigates the body's breakdown. In TTD mice, repair slows but doesn't stop, according to earlier work. If meager mending contributed to the animals' illness, turning it down further should make them sicker, the researchers reasoned. So they mated TTD mice with a strain that carries another disabled repair protein, XPA, to produce offspring severely impaired at patching DNA. The doubly deficient mice survived for 3 weeks and displayed heightened TTD symptoms. For example, they stopped growing after 2 weeks and their skin sloughed off more than that of their siblings with only the XPD mutation. "The study supports the notion that a buildup of DNA damage due to faulty repair or surveillance leads to the appearance of aging," says molecular gerontologist Vilhelm Bohr of the National Institute on Aging branch in Baltimore.
The TTD mice offer an ideal model for studying aging, given that some of their symptoms resemble those of humans, says oncologist Ronald DePinho of the Dana-Farber Cancer Institute in Boston. Still, any disease model has limitations. "It's simply impossible that a change in one component of DNA repair exactly mimics natural aging," says molecular biologist Jan Vijg of the University of Texas Health Science Center in San Antonio.
Although no one knows the mechanism by which deficient XPD fast-forwards aging, the authors propose that TTD-related DNA damage incites cell suicide. If they're right, the findings will strengthen the connection between cell death and aging (see "Death and Aging, Together at Last"). Indeed, if TTD simulates aging, studying the mice might reveal fatal cracks in the body's foundation.
J. de Boer, J. O. O. Andressoo, J. de Wit, J. Huijmans, R. B. Beems, H. van Steeg, G. Weeda, G. T. J. van der Horst, W. van Leeuwen, A. P. N. Themmen, M. Meradji, J. H. J. Hoeijmakers, Premature aging in mice deficient in DNA repair and transcription. Science, 11 April 2002 [e-pub ahead of print]. [Abstract/Full Text]
Citation: K. Morgan, Laid to Waste: Rare disease spawned by repair defect imitates aging (DNA repair; Premature aging). Science's SAGE KE (17 April 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/15/nw50
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