Age-related Degeneration Reversed In Mice For The First Time

Brain and testes growth, improved fertility and the recuperation of cognitive function were observed for the first time by scientists at Dana-Farber Cancer Institute, according to an article published in the scientific journal Nature. The laboratory mice were injected with a controllable telomerase gene - these genes maintain the telomeres - protective caps that shield the ends of chromosomes.

Low telomerase levels are linked to tissue degeneration and functional decline in elderly humans, due to erosion of telomeres.

Ronald DePinho, MD, and team generated prematurely aged mice with a telomerase switch. They then used the switch to reactivate the telomerase to find out whether the signs and symptoms of aging could be slowed down, or even reversed.

DePinho said it will be a few years before any human application is usable or approved. He added that some unusual genetic premature aging syndromes believed to be caused by shortened telomeres may eventually be treatable using their technology.

DePinho said:

"Whether this would impact on normal aging is a more difficult question. But it is notable that telomere loss is associated with age-associated disorders and thus restoration of telomeres could alleviate such decline."

In this experiment the scientists found that none of the mice developed cancer. Cancer cells activate telomerase to keep themselves alive virtually indefinitely.

To reduce the risk of cancer, the authors say that the telomerase can be switched on for short periods, perhaps days or weeks. They hope that this might be enough time to prevent fueling hidden cancers or setting off new ones.

DePinho said:

"If you can remove the underlying damage and stresses that drive the aging process and cause stem cells to go into growth arrest, you may be able to recruit them back into a regenerative response to rejuvenate tissues and maintain health in the aged."

Examples of the stresses DePinho quotes include the gradual shortening of telomeres, causing tissue and cells to fail.

When telomeres are lost, a cascade of signals within the body occurs, leading to a halt in cell division and even self-destruction, stem cells stop developing into anything, organs deteriorate, and brain cells start dying.

The authors wrote:

Generally, the shortening of telomeres in normal tissues shows a steady decline, except in the case of cancer, where they are maintained.

The laboratory mice had been specifically engineered to develop severe DNA and tissue damage as a result of abnormal, premature aging. They had short, telomeres that did not work properly. The mice had a range of age-related conditions and illnesses that was passed on to each generation progressively.

Some of the conditions experienced by the mice included:

• reduced testes size
• very low sperm counts
• atrophied spleens
• intestinal damage
• brain shrinkage
• inability to grow new brain cells

DePinho explained:

"We wanted to know: If you could flip the telomerase switch on and restore telomeres in animals with entrenched age-related disease, what would happen? Would it slow down aging, stabilize it, or even reverse it?"

The researchers found a way to switch on the telomerase gene which had been dormant in the mice, known as TERT. The TERT gene within the mouse was engineered to encode a fusion protein of TERT and the estrogen receptor.

The fusion protein only responded to a special form of estrogen - i.e. only this special form of estrogen could activate the fusion protein. So, the researchers could choose when to activate the telomeres, simply by giving the mice an estrogen-like drug.

A time-release pellet containing the estrogen drug was placed under the skin of some of the mice, while another type of pellet without the drug was given to the other mice.

Four weeks later the researchers noticed some impressive signs of rejuvenation among the mice which had received the estrogen-like drug. The treated mice had higher levels of telomerase and longer ones too. They noticed that the treated mice's cells were starting to grow again, there was a reversal of tissue degeneration, their spleens, testes and brain had started to increase in size.

DePinho wrote:

"It was akin to a Ponce de Leon effect." (a Spanish explorer who sought the mythical Fountain of Youth) "When we flipped the telomerase switched on and looked a month later, the brains had largely returned to normal."

The myelin sheaths which protect nerve cells began to regenerate - they had become very thin. A wide range of nerve cell types were being produced. The telomerase increase reactivated the brain stem cells so that new neurons started being produced.

The scientists wanted to determine whether all this improvement was also occurring in the mice's functional performance. They gave the mice functional tests, including placing certain smells mice link to danger in specific parts of their habitat to see whether they would avoid them. The prematurely aged mice would have walked straight into them. The mice that received the estrogen-like drug did avoid those areas.

DePinho added:

"One of the most amazing changes was in the animals' testes, which were essentially barren as aging caused the death and elimination of sperm cells," recounted DePinho. "When we restored telomerase, the testes produced new sperm cells, and the animals' fecundity was improved - their mates gave birth to larger litters."

The treated mice also lived longer than the others in the experiment, but no longer than a normal, healthy mouse.

The researchers concluded:

"This unprecedented reversal of age-related decline in the central nervous system and other organs vital to adult mammalian health justifies exploration of telomere rejuvenation strategies for age-associated diseases."