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Researchers Boost Telomerase, Reverse Aging in Mice

http://online.wsj.com/article/SB10001424052748703785704575642964209242180.html

›Scientists Tweak a Gene and Rejuvenate Cells, Raising Hopes for Uses in Humans

NOVEMBER 28, 2010
By GAUTAM NAIK

Scientists have partially reversed age-related degeneration in mice, an achievement that suggests a new approach for tackling similar disorders in people.

By tweaking a gene, the researchers reversed brain disease and restored the sense of smell and fertility in prematurely aged mice. Previous experiments with calorie restriction and other methods have shown that aspects of aging can be slowed. This appears to be the first time that some age-related problems in animals have actually been reversed.

The study was published online Sunday in the peer-reviewed journal Nature.

"These mice were equivalent to 80-year-old humans and were about to pass away," says Ronald DePinho, co-author of the paper and a scientist at Dana-Farber Cancer Institute in Boston. After the experiment, "they were the physiological equivalent of young adults."

The institute is a teaching affiliate of Harvard Medical School. The first author of the study is Mariela Jaskelioff at Dr. DePinho's lab.

Although the finding is compelling, it remains to be seen whether the approach can slow the signs and symptoms of aging in people. The latest results were obtained with mice that were specifically altered to age prematurely. And while the animals showed no signs of tumors, there is a risk that the technique could trigger cancer.

The experiment focused on telomerase, an enzyme that makes small units of DNA that seal the tips of chromosomes. These DNA units, known as telomeres, act like the plastic caps at the ends of a shoelace, preventing the chromosomes from fraying and the genes inside them from unraveling. In 2009, three U.S. scientists won the Nobel Prize in medicine for illuminating the mysteries of telomerase.
Many different stimuli conspire and contribute to the aging process. The telomere is just one of them and likely not the most dominant. In normal tissue, telomeres get progressively shorter as part of the aging process, causing cells to stop dividing. As a result, stem cells go into a state of quiescence, organs atrophy and brain cells die.

As people age, low levels of telomerase are linked to the erosion of telomeres. Dr. DePinho and his colleagues wanted to see if by reactivating telomerase in mice they could halt—or possibly reverse—the shortening of telomeres, and thus turn back the clock on some aspects of aging.

The team made genetically engineered mice that aged prematurely. The animals had short, dysfunctional telomeres and suffered a range of age-related problems. Their spleens were atrophied, their intestines were damaged, and the sense of smell was impaired.

The brains were also shrunken, and the animals were incapable of growing new brain cells. Male mice had smaller-than-normal testes and produced depleted amounts of sperm.

"We stacked the deck against us and asked: Is there a point of no return?" said Dr. DePinho.

The researchers had devised an estrogen-based drug that would switch on the animals' dormant telomerase gene, known as TERT. The drug, in the form of a time-release pellet, was inserted under the skin of some mice. A similar pellet without the active drug was given to a separate group of control mice.

A month later, the treated mice showed surprising signs of rejuvenation. Overall, their telomeres had lengthened and the levels of telomerase had increased. This woke up the dormant brain stem cells, producing new neurons. The spleen, testes and brain grew in size.

In addition, key organs started to function better. The treated mice regained their sense of smell. The male animals' once-depleted testes produced new sperm cells, and their mates gave birth to larger litters. The treated animals went on to have a typical lifespan, though they didn't live longer than normal mice.

The reversals of age-related decline seen in the animals "justify exploration of telomere rejuvenation strategies for age-associated diseases," the paper concludes.

One worry is cancer. Tumors somehow turn on the telomerase gene, allowing cancer cells to divide continuously. Up to 90% of human cancers require certain levels of telomerase to do so. Indeed, many researchers are trying to deactivate telomerase as a cancer-fighting strategy.

Still, turning on telomerase for controlled periods of time might be useful. The strategy might one day have a role in treating rare genetic disorders that are linked to telomeres and cause premature aging, such as Werner's syndrome, according to Dr. DePinho.

The telomerase technique may also be relevant for people who age normally—provided it is clear that prolonged telomerase reactivation doesn't trigger tumors in later life.

Statistically, people with longer telomeres in their blood cells have an increased number of healthy years beyond the age of 60, Dr. DePinho said. And those over 60 with the shortest telomeres have higher rates of diabetes, cardiovascular disease and Alzheimer's.

Dr. DePinho said the next step was to try the technique on normally aged mice to see whether it can slow, halt or reverse signs of aging in them.‹