Sci. Aging Knowl. Environ., 29 January 2003
Vol. 2003, Issue 4, p. nw19
[DOI: 10.1126/sageke.2003.4.nw19]


Unraveling Chromosome Chaos

Trimmed telomeres might provoke premature-aging disease

Mitch Leslie;2003/4/nw19

Key Words: Terc • ataxia-telangiectasia mutated • apoptosis • intestinal crypts

Longer is better for swords, zoom lenses, and telomeres, the protective caps at the tips of chromosomes. A new study implicates shrinking telomeres in a fatal genetic disease marked by cancer vulnerability and symptoms of fast aging. The results suggest that keeping telomeres luxuriant might spare patients, and they bolster the struggling hypothesis that telomere decay provokes aging.

Children with ataxia-telangiectasia (AT) make a faulty version of the protein Atm, which normally detects broken DNA and halts cell division in response. Without Atm, which also helps spruce up the ends of chromosomes, telomeres fray, and chromosomes often break or stick together. AT patients--who show symptoms of cancer susceptibility, a flaccid immune system, and signs of accelerated aging--rarely survive past their early 20s. Some scientists have wondered whether dwindling telomeres contribute to this process. Researchers have tried to replicate AT in mice by knocking out the Atm gene (see Transgenic Mouse Entries: Strain 1, Strain 2, and Strain 3). However, these revised rodents suffer only mild symptoms. One possible reason is that mice have naturally long telomeres that might never shrink to a size that causes trouble.

To clarify the role of chromosome caps in AT, Wong and colleagues cut mouse telomeres down to size. Using a series of matings, they created animals that lacked Atm and telomerase, the protein that refreshes chromosome ends. Each successive generation carried shorter telomeres, and by the fourth one, the rodents displayed hallmarks of AT, such as premature graying and slow wound healing. Compared with control animals, the mice showed an increased incidence of cell suicide--a response to chromosome damage--in the bone marrow and the lining of the intestine. In addition, cells in the brain reproduced sluggishly. The high rate of cell suicide in fast-dividing tissues such as the intestinal lining and balky reproduction by brain cells suggest that failing telomeres decimate the body's stem cells, says co-author Ronald DePinho, a cancer biologist at Harvard Medical School in Boston. "The study shows that telomeres play an important role in the pathology of this enigmatic disease," he says.

The idea that shorn telomeres drive aging has taken a beating (see "More Than a Sum of Our Cells"), partly because many tissues that grow decrepit contain few dividing cells. But the new work "not only explains some of the symptoms of this disease, it also supports the idea that loss of telomere function is involved in normal aging," says cell biologist Peter Lansdorp of the British Columbia Cancer Research Center in Vancouver, Canada. However, molecular biologist Tej Pandita of Washington University in St. Louis, Missouri, cautions that telomere size could matter less than telomere structure does. Atm helps shape telomeres, which in turn affect the structure of the entire chromosome, so researchers should explore how the protein's loss warps telomeres, not just shortens them, he says. The link between telomere malfunction and AT deterioration suggests that shielding the chromosomes might stall symptoms, says DePinho. Finding a way to lengthen telomeres might stretch the lives of AT patients.

--Mitch Leslie

K.-K. Wong, R. S. Maser, R. M. Bachoo, J. Menon, D. R. Carrasco, Y. Gu, F. W. Alt, R. A. DePinho, Telomere dysfunction and ATM deficiency compromises organ homeostasis and accelerates aging. Nature, 22 January 2003 [e-pub ahead of print]. [Abstract/Full Text]

January 29, 2003 Citation: M. Leslie, Unraveling Chromosome Chaos. Science's SAGE KE (29 January 2003),;2003/4/nw19

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