Telomerase; Late-Life Selection; Pleiotropy vs. Mutation Accumulation


Longevity Index

Some Questions About the Antagonistic Plieotropy Model of Aging
    A human being has about 10,000,000,000,000 cells, while a fruit fly has only about 100,000. In other words, a human being has about 100,000,000 times as many cells that can potentially become malignant as a fruit fly. So fruit flies can laugh at cancer. So why don't fruit flies produce telomerase in all 100,000 of their cells? (And for all I know, perhaps they do.) And if they do, why do fruit flies grow old? 
    A similar situation exists with respect to mice. All other things being equal, mice should have about 1/500th the chance of developing cancer that we do. Why shouldn't wild mice have long telomeres, or generate telomerase as needed? With 1/500th the chance of presenting with cancer that we have, mice shouldn't have to worry terribly much about cancer. (Of course, mice in the wild wouldn't live long enough to grow old. Still, they could afford to be pretty cavalier about telomerase.)
    Looking at the other end of the spectrum, blue whales can weigh up to 150 tons, and would have at least 1,000 times as many cells as we do, and therefore, 1,000 times as many cells to potentially become malignant. Furthermore, bowhead cells can allegedly reach 200 years of age, and in any case, their life spans are at least comparable to humans. It seems reasonable to suppose that Nature has afforded whales 1,000 times the cancer protection that she has to humans. Since nature has already played her telomerase trump card with humans and gotten only 1/1,000th of the cancer protection that whales need, this cancer protection in whales has to take the form of something more effective than lack of telomerase. And as I've mentioned previously, whales must replenish red blood cells, their immune systems must pour out new white cells, and their testes must be refreshed even if they don't need to replace skin. Some of their tissues probably have to be telomerase-enabled just like ours.
    This suggests to me that telomerase may play a crucial tradeoff role in human cancer, but may be irrelevant with very small life forms like fruit flies, and not terribly relevant with small animals like mice, voles, etc. At the other end of the scale, other, far more powerful agents than a lack of telomerase must ward off cancer in large animals such as elephants and whales. 
    This also suggests to me that the largest whales might be promising candidates to examine  for 1,000-fold-better cancer defense mechanisms.

Problems with Late-in-Life Influences Upon Evolutionary Selection
    The authors of Reserve-capacity hypothesis (Weinstein & Ciszek 2002 have written about this about the question of whether natural selection operates throughout the lifespan or only to optimize reproduction:,
"Though the force of natural selection declines from the onset of reproduction, selection remains strong throughout the normal reproductive life-span, even as the effects of senescence are becoming increasingly evident. Further, adaptive variation among adult vertebrate forms leaves no doubt that selection retains substantial power during the process of senescence. Logical appeals to 'unselected' effects should be restricted to stages of life that were rarely if ever reached in the species' ancestral environment."
    Steve Coy has responded, based upon my summary in
Telomerase and Cancer, Take 3.:

You wrote:
"The authors observe that some (optimistic) gerontologists think that nature has selected for the reproductive phase of life, but that selection is inoperative once the individual gets past the reproductive years. leaving us free "to pursue a technological solution to fill in where selection leaves off". But the authors' thesis is that nature has optimally selected senescence as the lesser of two evils, selecting in the senescent phase of life as well as in the reproductive phase, tuning animals to minimum chances of cancer early on at the expense of senescence and exponentially rising cancer rates in the post-reproductive years.

Do they really suggest that evolutionary selection is somehow active "in the senescent phase of life as well as in the reproductive phase"?  What's the supposed mechanism?  Evolution "cares about" post-reproductive adults (for females at least this is well-defined) only to the extent that they can act to increase the chances of survival for their children and grandchildren.  This includes having the kids, raising them, and perhaps babysitting the grandkids, but at some point, when resources are tight (i.e. essentially all of prehistory) the best thing the post-reproductive adults can do *to maximize their kids' chance of survival* is simply to stop competing with them for those resources - or maybe be a step or two slower when the sabertooth make its charge.  It's true that natural selection will "optimize" these tradeoffs in a sense, but natural selection always applies the same "figure of merit", genetic survival.  If we wish to optimize a different figure of merit, e.g. the time integral of some measure of "quality of life", the optimum "tuning" will generally be different, possibly very different.

And of course, if we can find some other way to selectively kill off cancer cells, that changes the equations dramatically.

After thinking this morning about what I wrote last night, I've changed my mind. Last night, I said:

    "Steve, my guess would be that the authors would say that among humans, who have the ability to recognize parents/offspring and to maintain family ties throughout life (I think of Indian or Polynesian tribes), it might have been common that children's father would have died in the hunt or their mother would have perished in childbirth or of an infection, and the grandparent(s) would have had to rear the children. So the presence or absence of parents or grandparents might  have exerted a significant influence on the survival chances of their offspring. I'm guessing that the authors' argument is that although selection is primarily geared to early reproduction, there would have been secondary or tertiary survival value to having your parents or even your grandparents around to take care of you. This would have exerted some selection pressure to encourage late-life survival, although it would have been slight compared to the importance of good health during the reproductive years. 
    This is my guess at their drift.
    Of course, you're essentially saying the same thing, except that resources may have been too tight in Stone Age tribes for Mother Nature to afford the luxury of parents and grandparents, particularly once the children have come of age.
    It would seem to me that another counterargument might be that the reason tribes evolved might be because mortality was high in Stone Age tribes. The tribe would have provided for widows and orphans. In that case, the survival of parents and grandparents wouldn't have been so important in determining the survival of the offspring before and during their reproductive years. 
    It's interesting to me that we've had the opportunity to intermingle, during the centuries before the 21st, with Stone Age tribes, and socially, they differ more from each other than they do from us. Mother-in-law jokes go over big in Stone Age tribes, just as they do in fashionable salons. I've been told that among the Cherokees, elderly women were represented equally with elderly men on the tribal council. And parent/child love and family gatherings are probably written into our genes."

    But re-thinking this in the cold light of day, it seems to me that in what I wrote last night, I was chasing the wrong rabbit. Human grandparents can trace relationships through their grandchildren, but what about animals? In particular, what about oviparous animals such as amphibians? Generally, the parents have no inkling which tadpoles are their progeny. In any case, there would be so many of them, and they would be so instructed by instinct that it's hard to see how the existence of living parents or grandparents could boost their survival value. They'd be lucky if their parents didn't mindlessly eat them.
    So I agree with you. I don't see how long-lived predecessors could be anything but a drag on the young fry who are coming along.

    A paper, Study Backs Theory That Accumulating Mutations Of "Quiet" Genes Foster Aging, that hit the newswires today supports a different model of senescence (mutation accumulation or MA) than the antagonistic pleiotropy (AP) model described in the Weinstein & Ciszek paper above. The mutation accumulation model would allow for the rectification of certain genes, such as the defective gene for Huntington's Chorea or the defective genes for some cancers that strike late in life, without, presumably, producing harmful side effects. .The authors of the paper have studied "dominance variance" kinds of genetic effects that are predicted to increase with age only if the mutation accumulation (MA) theory is operating. They don't rule out antagonistic pleiotropy (AP). Both mechanisms could be in operation  If so, it will be important to distinguish those genes that are beneficial early in life but harmful in later life from those genes that offer no advantages early in life and are harmful later in life.
    Personally, I could imagine that other genes that are lethal early in life, like cystic fibrosis and muscular dystrophy, are going to be popular candidates for either abortion of the zygote or modification of the genome to correct these deadly mutations. (Of course, you wonder why these fatal alleles haven't already been expunged from the human gene pool.)
    Down's Syndrome might be another likely candidate
    I could imagine that in vitro fertilization is going to become the norm, so that zygotes can be screened for defects. Does nature have a reason for retaining the Huntington's Chorea phenotype? There will be a lot of debate over variety versus unacceptable harm, and the long-term implications for human evolution.