Prolongevity Update 

March 11, 2004

Advanced Cell Technology's Eight Cloned Calves 
    In April, 2000, II was excited when I read about Advanced Cell Technology's cloning of eight calves. What excited me about it was that they had enucleated eight bovine ova and then implanted in them eight nuclei from a very old cow. The resulting calves were brand, spanking new, as newborn calves are wont to be, with telomeres that were a little longer the average for newborn calves. But the nuclei implanted in those egg cells would have been old and damaged.
How Can Brand New Offspring Be Created from Old Organisms?
    That led me to wonder (for the first time), how can babies be born young? The germ cells that spawned them would have been somewhat aged and somewhat damaged. In an extreme case, using in vitro fertilization, a 60-year-old woman and an 80-year-old man could produce a baby whose age at birth might be 70... the average of the two parent's ages. And yet, that doesn't happen. Their issue would be as new and soft-skinned as any other baby. Granted, the risk of birth defects would be higher, but it wouldn't be catastrophically higher. Clearly, if any age-inflicted damage were able to accumulate, long before 1,000,000 generations had passed, the accumulated damage would have rendered the offspring non-viable. Some process of rejuvenation must be taking place to allow generation after generation of plants and animals to be created without accumulating any age-related defects.
The Preservation of Species
    My initial argument, in the spring of 2000, was that rectification of the genome would have to be complete or there would be "genetic drift" over the evolutionary history of a species, and 100,000,000 years later, the species (of, e. g., roaches or ants) would no longer exist. But later, I realized that "species" is a human-assigned term that means simply that different organisms are sufficiently similar that they can interbreed. A species consists of a group of individuals each of which is genetically unique. The composition of a species changes minutely each time a new  individual organism is created. Furthermore, "nature" doesn't act as a species-preserver. Unless you believe in intelligent design, "nature" doesn't exist, and "species"--groups of biologically similar organisms-- change over time in response to ever-changing environmental conditions. It now seems likely to me that no modern ants could interbreed with Cretaceous ants. 
    But this question is independent of whether or not aging accumulates in species. Obviously, it doesn't. Seedlings from the oldest of trees are just as pristine as seedlings from a first-blooming sapling. 
One Concept for Sidestepping Rejuvenation
    Another way in which aging might be sidestepped would revolve around the fact that women's egg cells are formed before birth (or so it has been thought: Breakthrough Turns Fertility Wisdom On End - ABC). The idea was that, perhaps, women's egg cells were protected from aging by lying dormant until they were ready to be used. Still, the male sperm that fertilized them, although created afresh for the occasion, come from tissue that ages with the prospective father. Furthermore, even though the aging of ova might be very slight, there would be some aging, especially between the time the ovum was created and the time that the developing fetus created new ova. Even though that might be only a few months, those months would add up unless there were some way to periodically annul their effects. But that's now been tossed into a cocked hat with this latest discovery that mice, and probably, women create new egg cells throughout their fertile years..
If Rejuvenation of a Fertilized Zygote Occurs, How Might It Happen?
    Since I'm only guessing that rejuvenation of a fertilized zygote does in fact happen, thinking about how it might take place becomes idle speculation based upon wishful thinking, but here goes.
    If fertilization of an oöcyte triggers rejuvenation of the fertilized cell, I would imagine that it would happen fast, before the cell has time to divide. It would include clean-up of the genome of the zygote, and the recycling or expulsion of previously-"indigestible" sludge in the cell (such as advanced glycation end products and lipofuscins) or the retention of these contaminants in one end of the zygote so that one of the two cells produced after division could be a cleaned-up daughter cell. (Another possibility could be the dilution of contaminants by splitting them equally between the two cells that are created in mitosis. But if that were the case, this dilution of contaminants should occur when differentiated somatic cells... viz., skin cells... divide in the body, and apparently, that doesn't happen.)
    What I hope is that a master gene triggers other genes in a choreographed genetic dance that leads to a veritable boil within the zygote. unprocessable sludge is either broken down or ejected from the cell. Improperly folded proteins (if any) are also recycled or eliminated. Of course, it would be easier to evict sludge from an isolated cell than it would from a cell that's part of an organism. Still, every cell has access to the bloodstream. There ought to be a way to expel foreign material from cells that would be carried away by the bloodstream. (You wonder how this is handled in animals that exhibit negligible senescence, like the Rough-eye Rockfish.)
    And somehow, the genome is completely cleaned up. This process wouldn't take longer than a few minutes, and might be over in seconds. Only then would the cell be cleared for division. And if this happens in undifferentiated cells, my hope is that it could also be triggered in differentiated cells. This might be followed by cell division in mitotic cells. In post-mitotic cells such as neurons and myocytes, it would rejuvenate the cells, and might of might not lead on to cellular division. (If cellular division were a necessary consequence, then this rejuvenation process couldn't be tolerated in post-mitotic tissue.) Such a process might be carried out piecemeal, applied to small patches of skin and internal tissue a piece at a time. Of course, tests would be carried out using tissue cultures first, and then yeast, roundworms, fruit flies and mice. With humans, it might be tried first on a very small patch of skin, so that application could be topical and very localized rather than systemic. 
    The key would lie in identifying and triggering the hypothetical gene that sets off this cleanup cascade.
What This Wouldn't Do
    Even in principle, there would be many limitations to such a rejuvenation mechanism. In his book, "Beyond the 120-Year Diet", Dr. Roy Walford mentions (on page 54) the gamma-crystalline protein in the eye, which is supplied during ontogeny and never replaced. Rejuvenating individual cells probably wouldn't replace that. Bony growths such as bunions might or might not disappear. Teeth would have to be replaced, either with implants or be re-growing teeth from "seeds" (something which is showing promise, but isn't here yet). Tissues that have cross-linked and become leathery might not be subject to replacement by suddenly-rejuvenated cells. Missing hair follicles might not regrow. Some of these developments occur during gestation, and might not automatically take place even if all one's cells were rejuvenated.

(To Be Continued)