Rare Disease Offers Clues to Aging and Cancer

Mouse Model Indicates Genetic Connection

Preliminary research in mice suggests that a single protein may play a role in aging and cancer.

The findings, reported in the August issue of Nature Genetics, involve the protein WRN, which is responsible for the development of Werner's syndrome, a rare disease that causes premature aging.

"Given that most cancer occurs in the elderly, aging is the biggest risk factor for developing cancer in humans," says the study's lead author, Sandy Chang, M.D., Ph.D., assistant professor in the Department of Molecular Genetics at M. D. Anderson. "Now, with this animal model (genetically engineered mice), we can look at the common pathways that unify aging and cancer development."

Gene reveals clues to chromosome length

Werner's syndrome is an adult-onset disease that causes no symptoms for the first decade of life. As patients reach adulthood, however, they begin to rapidly develop signs of aging, including thinning hair, wrinkled skin, cataracts, osteoporosis and diabetes. Many often die in their 40s of cancer or heart disease.

Werner's syndrome is caused by a failing gene that produces the protein WRN, which helps maintain stability of a cell's genetic material. Patients with Werner's syndrome exhibit increased chromosomal aberrations, Chang says.

WRN is also implicated in telomere maintenance. Telomeres are repeat sequences on chromosomes that are necessary for genomic stability. Telomeres are closely associated with the aging process. Every time a cell divides, telomeres lose some of their length. Once telomeres become too short, the cell is programmed to stop dividing.

"We believe that loss of WRN accelerates telomere shortening and promotes premature onset of aging phenotypes in mice," Chang says. "If that is true, then studying this mutation may give us a handle to understand what normally happens during the aging process."

Genetically engineered mice test protein

Chang led a group of researchers from Harvard Medical School, Brigham and Women's Hospital in Boston, and the Massachusetts Institute of Technology in developing the mouse model to test the idea that symptoms of Werner's syndrome require telomere shortening.

They found that all cells in a mouse produce the enzyme telomerase, which prevents telomeres from shortening. In humans, only a few cells produce telomerase. Knowing that, Chang and his colleagues bred mice without WRN to mice engineered not to produce telomerase. They then allowed the offspring to procreate through several generations to progressively shorten the telomeres. In the first two generations, the mice aged normally.

In later generations, however, the mice with the shortest telomeres began to exhibit the classic symptoms of Werner's syndrome and died at a much younger age than normal. They also developed certain non-epithelial cell cancers, including osteosarcomas, soft-tissue sarcomas and lymphoma.

Thus, the mouse model shows that a deficit in WRN can lead to genomic instability that both accelerates aging and spurs cancer formation, according to the researchers. "The cancers these mice developed are fairly rare in the general human population, but are common in patients with Werner's syndrome," Chang says.

Chromosome length tied to cancer development

Results of the study open new avenues for exploration. Genomic instability also is the hallmark of epithelial cell cancers, which involve the layer of cells covering internal and external surfaces of the body such as the inner lining of the lungs, digestive tract and skin cells. These cancers are far more common in the general population. Their instability may also involve telomere length, Chang says.

For example, the p53 tumor suppressor gene senses when a cell's telomeres are too short and tells the cell to shut down. If p53 is dysfunctional, as it is in most cancers, the cell continues to divide.

Short telomeres increase genomic instability by promoting chromosomal fusions, which is a risk factor for cancer development in and of itself. But most human cancers keep their telomeres intact by turning on production of telomerase, thus ensuring that cells will remain immortal and continue to divide. "In fact, 90% of cancer cells use telomerase to keep the cells dividing," says Chang.

"The common denominator in aging and cancer appears in part to be the failure to maintain genomic stability, and how the p53 pathway senses this instability will ultimately determine whether a cell is programmed to stop dividing (aging) or progress to immortal growth (cancer)," he says. "Now we have a mouse model that will help us understand these links in detail."