Is a Clone Born at Age Zero?

In the overlap between research into aging and research into regeneration there is some interest in what exactly it is that happens between fertilization and later development of a zygote that enables old reproductive cells to produce young children. Some form of reset takes place, a clearing out of damage. This is also seen in induced pluripotency, whereby ordinary somatic cells are reprogrammed into a state very similar to that of embryonic stem cells. It is an open question as to whether any part of this natural rejuvenation mechanism can be safely harnessed and turned into a therapy, though it is worth noting that induction of induced pluripotency in the tissues of adult mice has been tried recently. Animal cloning is another line of research that might help to shed light on what happens in early development, a topic that was covered in some depth last year. Do clones age normally, and are they born with a similar level of molecular damage as their natural peers? Why, if so?

In 1997, Dolly the sheep was introduced to the world. The implications of cloning animals in our society were self-evident from the start. Our advancing ability to reprogram adult, already-specialized cells and start them over as something new may one day be the key to creating cells and organs that match the immune system of each individual patient in need of replacements. But what somehow got lost was the fact that a clone was born - at day zero - created from the cell of another animal that was 6 years old. Researchers have spent the past 20 years trying to untangle the mysteries of how clones age. How old, biologically, are these animals born from other adult animals' cells?

When Dolly was cloned, she was created using a cell from a 6-year-old sheep. And she died at age 6-and-a-half, a premature death for a breed that lives an average of nine years or more. People assumed that an offspring cloned from an adult was starting at an age disadvantage. Rather than truly being a "newborn," it seemed like a clone's internal age would be more advanced than the length of its own life would suggest. Thus the notion that clones' biological ages and their chronological ones were out of sync, and that "cloned animals will die young."

Some of us were convinced that if the cloning procedure was done properly, the biological clock should be reset - a newborn clone would truly start at age zero. We worked very hard to prove our point. We were not convinced by a single DNA analysis done in Dolly showing slightly shorter telomeres - the repetitive DNA sequences at the end of chromosomes that "count" how many times a cell divides. We presented strong scientific evidence showing that cloned cows had all the same molecular signs of aging as a nonclone, predicting a normal lifespan. Others showed the same in cloned mice. But we couldn't ignore reports from colleagues interpreting biological signs in cloned animals that they attributed to incomplete resetting of the biological clock. So the jury was out.

Aging studies are very hard to do because there are only two data points that really count: date of birth and date of death. If you want to know the lifespan of an individual you have to wait until its natural death. By 2012 that was in fact being accomplished: there were several cloned Dollies, all much older than Dolly at the time she had died, and they looked terrific. This work was finally published last year. "For those clones that survive beyond the perinatal period, the emerging consensus, supported by the current data, is that they are healthy and seem to age normally."

The new Dollies are now telling us that if we take a cell from an animal of any age, and we introduce its nucleus into a nonfertilized mature egg, we can have an individual born with its lifespan fully restored. They confirmed that all signs of biological and chronological age matched between cloned and noncloned sheep. There seems to be a natural built-in mechanism in the eggs that can rejuvenate a cell. We don't know what it is yet, but it is there. Our group as well as others are hard at work, and as soon as someone finds it, the most astonishing legacy of Dolly will be realized.


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