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Cloned Animals May Age Prematurely, Scientists Say

Genetics: Study suggests that process may transmit key biological 'markers' for aging from parent to offspring.


In a discovery that could chill efforts to clone humans, human organs and animals, the team that first cloned the sheep Dolly has found that at least some of the wear and tear of aging is transmitted from the parent to the clone during the process.

That could mean that the clone will not live as long as its parent, that it could have reproductive difficulties and that it could become susceptible to heart disease, cancer and other diseases of aging at a younger age than its parents, the team from Scotland's Roslin Institute and PPL Therapeutics reports in today's Nature.

The study involves telomeres, biological markers on DNA thought to tick down the time remaining until the organism is fated to die.

A newborn normally gets a fresh set of telomeres that permit a normal life span, but the clones receive shortened telomeres more like those of the genetic parent, the Roslin team reports.

The shortened telomeres could foreshadow a shortened life span and increased disease susceptibility, but the three cloned sheep at Roslin have not been alive long enough to determine if this theoretical possibility will be borne out in the real world.

"The first question I had as soon as I heard about Dolly was what do the telomeres look like, and here they are," said biologist Michael Rose of UC Irvine. "This validates the whole concept" that telomeres are shorter in older cells, he added. "What is not clear is the relationship between shortening and aging."

Biologists have assumed that shortening of telomeres is one of the factors that control the rate of aging and, in cells grown in the laboratory, that is certainly the case, he said. But in whole organisms, telomere shortening may simply be a marker for aging rather than a cause.

"But it is important that we now have experimental confirmation of what we suspected," added geneticist Leonard Hayflick of UC San Francisco, one of the pioneers in studying cellular aging.

Hayflick was the first to demonstrate that all cells have a built-in mechanism for aging. When cells are grown in the laboratory, they will reproduce only a limited number of times before becoming dormant and refusing to replicate further. The discovery of telomeres provided a molecular mechanism for this process.

Telomeres are long fragments of DNA that sit on the end of each cell's chromosomes like the tip of a shoelace. Chromosomes are packets of DNA that contain the blueprint for reproducing an organism, and researchers now believe that telomeres keep the DNA stable, just as the tip keeps a shoelace from fraying.

In cells, at least, the telomere represents a kind of bookkeeping device that controls aging. Each time a cell replicates, a fragment of the telomere is broken off and lost. When the whole telomere is gone, the chromosome breaks down, leaving the cell vulnerable to disease and death.

Microbes have an enzyme, called telomerase, that replaces the lost fragment so that the cells can live forever. Cancer cells have a similar enzyme, as do reproductive cells that produce sperm and eggs. But the rest of the cells in the body do not, leaving them susceptible to the vagaries of aging.

The biotech industry has shown great interest in telomerase because administering it to humans might extend life span, while telomerase blockers might prove an effective treatment for cancer. In fact, Geron Corp., one of the leaders in telomerase research, recently purchased PPL Therapeutics in the obvious hope of blending telomerase and cloning technologies.

Dolly was cloned in 1996 by Roslin researchers who took DNA from a mammary cell of a 6-year-old Dorset Finn sheep, inserted it into an unfertilized egg and induced it to grow into an adult sheep--the first time such a feat had been achieved with a mammal.

Questions immediately arose--although they were more philosophic than practical--about Dolly's true age. Because she was created with DNA that was already 6 years old, Dolly, whose birth age is now 3, could conceivably now be considered to be 9 years old.

The new results suggest that this may be a fair way of looking at it.

"When the [cloning] news first came out, somebody said that Dolly was a sheep in lamb's clothing," said molecular biologist Jerry Shay of the University of Texas Southwestern Medical Center. "I think that's an appropriate quote now."

Paul G. Shiels and his colleagues at Roslin and PPL Therapeutics took DNA from Dolly and two other sheep produced by cloning from lamb embryos, measured telomere length and compared it to telomere length in sheep of the same age who were born conventionally. All three of the clones are healthy, and Dolly has given birth to two healthy lambs.

They found that Dolly's telomeres were about 20% shorter than those of uncloned sheep of the same age. Those from the two other clones were only slightly shorter, reflecting the fact that they were cloned from embryos.

The researchers have not looked at telomere length in Dolly's offspring because she was mated with a normal sheep, which would affect the findings. But they are eager to see what the length will be when two cloned sheep are mated.

Sheep normally have a life span of 12 to 14 years. Unfortunately, no one has studied the length of telomeres in animals near death, so the significance of the finding is not clear.

"Dolly has shorter telomeres than age-matched controls," said Alan Colman, research director at PPL Therapeutics. "People have said that telomere loss is a cause of aging. We can equally say that it is a marker of aging, a consequence of aging. Or Dolly might have shorter telomeres and it has nothing to do with aging. We'll probably never know from observations of one animal."

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