As time goes by, mutant mice face problems.

Mice lacking an important enzyme go gray and lose their hair earlier than normal, frequently develop sores as they age, and have unusually short life spans. They also suffer more tumors than normal mice do, raising questions about a much-hyped idea for treating cancer.

These age-related conditions showed up in a new long-term study of mice that have a mutation in a gene for telomerase, an enzyme that affixes protective DNA segments to ends of chromosomes. Scientists know that if this enzyme doesn't work, the chromosomal tips, called telomeres, usually shorten whenever a cell divides, ultimately disappearing.

In 1997, Ronald A. DePinho of the Dana-Farber Cancer Institute in Boston, Carol Greider of Johns Hopkins Medical Institutions in Baltimore, and their colleagues described the development and surprisingly healthy early life of six successive generations of mice that lacked telomerase. Each generation had shorter telomeres than the previous one, and the sixth turned out infertile (SN: 10/11/97, p. 228).

Now, in the March 5 CELL, the scientists describe what happens as these mutant mice age and their telomeres shrink further in many cells. "Over the course of their 2-year lives, [the mice] walk this telomere plank into genetic instability, loss of cell viability, and so on," says DePinho.

A few scientists have speculated that many ravages of aging result because telomeres shrink over time in mammalian cells. Yet as the telomerase-lacking mice grew older, they didn't experience a greater-than-normal incidence of some age-related conditions, such as osteoporosis, cataracts, and atherosclerosis.

Nonetheless, telomere shortening may play a role in certain aspects of aging. In addition to premature graying and hair loss, the aging mutant mice have an increased rate of skin ulcers and are slower than normal to heal wounds--traits also common in elderly people. Moreover, when treated with blood-depleting agents, the mice have trouble recovering, an impairment resembling the difficulties that many elderly people face after chemotherapy or surgery.

In general, says DePinho, the mutant mice resemble aged individuals in their reduced ability to respond to physiological stresses. However, young sixth-generation mutant mice did not have the same impaired stress responses as 2-year-old third-generation mice, even though the groups had telomeres of similar length. Other, still undetermined, age-related changes in cells must combine with shortened telomeres for such symptoms to emerge, says DePinho.

Third-generation telomerase-lacking mice had an unusually large incidence of cancer, and the sixth generation showed a higher rate still. The lack of telomeres triggers chromosomal fusions and other genetic abnormalities that foster tumors, concludes DePinho.

The cancer finding adds a new wrinkle to the debate about whether depriving malignant cells of telomerase will prevent them from growing. John P. Murnane of the University of California, San Francisco and other scientists had previously found that cells can maintain telomeres through a mechanism not involving telomerase. Since this mechanism seems to depend upon chromosomal rearrangements, cancer cells employing it may undergo additional mutations that make them more malignant.

"You might actually make matters worse if you knock out telomerase in a tumor because you would select for cells that use the alternate mechanism," says Murnane.

Still, both Murnane and DePinho stress that mice sometimes poorly reflect human biology and that tests of telomerase inhibitors are warranted in people with cancer. Brief, localized use of the inhibitors may destroy or reduce the size of existing tumors without significantly increasing the risk of new cancers developing.