Antagonistic Pleiotropy:Dropping the Other Shoe

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It's time to drop the other shoe.
    The paper, Reserve-capacity hypothesis (Weinstein & Ciszek 2002), Model of Aging, discusses many topics, and among them is the observation that nature has evened up cancer probabilities among different tissues. The chances of breast or ovarian cancer are somewhere nearly comparable to the chances of getting cancer of the brain or of the colon. But the presence or absence of telomerase is an either/or condition. If our defense against cancer is a lack of telomerase, what other tuning can evolution perform? How can one tissue be protected more or less than another? And if, on the other hand, nature can adjust cancer susceptibilities independently of telomerase, then it indicates that the presence or absence of telomerase isn't the only, or necessarily even the principal, influence that determines vulnerability to cancer.
    The authors point out that some high-turnover human tissues, such as skin and bone marrow, possess telomerase and replenish their telomeres. The authors point out that bone marrow neoplasms such as leukemia and lymphoma strike children as frequently as adults. But that raises the question with me: why don't these cancers rise with adulthood like other cancers?  Also, skin expresses telomerase just like bone marrow. Why don't children get skin cancer? And why are skin cancers rare, mild, and late in life? The authors argue that the skin is protected from mutagens, and that it may exfoliate aberrant cells. But skin damage is primarily photolytic, so the skin is vulnerable to its principal mutagen: sunlight. Melanoma can crop up anywhere, but do squamous cell and basal cell carcinomas ever develop in skin that's been protected from light? (Cancer incidence rates for such sheltered skin is probably well-known.) Do polar bears get skin cancer? They're protected from the sun with thick fur, and the sun isn't that bright near the poles. Also, do mutagens circulate in the blood?
    With respect to the exfoliation of wayward cells, in spite of exfoliation, skin develops keratoses and cancers that don't slough off... just like other, telomerase-deficient  tissue.
    Breast tissue and brain tissue are protected from mutagens just like the dermis.. Why don't they express telomerase? The stomach, the small intestine, and the colon are all exposed to mutagens, and yet, the small intestine, alone among the three, rarely gets cancer.  
    But it would seem to me that the fundamental question is that of how important a role telomerase plays in comparison with other biochemical agencies in warding off cancers. Telomerase sounds to me as though its more-or-less an either/or condition, whereas such DNA-repair enzymes and other cancer defense mechanisms could vary continuously in effect. And considering the thousand-fold greater protection bestowed upon the whale, the role assumed by these supplementary defenses would appear to far outweigh that played by telomerase.
    It seems to me that we started with the thesis that humans lack telomerase in order to protect us against cancer during our reproductive years. But it turns out that those cells that express telomerase are no more vulnerable to cancer than our other cells, and maybe less so. So it can be done. Also, elephants and whales must have telomerase-equipped tissues, and yet, their likelihood of developing cancer can't be (in proportion to body size) greater than ours. Otherwise, they wouldn't be alive.
    The authors observe that when the body replaces cells that have senesced, it must generate a patchwork quilt of cells that must function less effectively than the original tissue. 
    It also seems to me to be the case that nature must possess other, more effective cancer defenses than the absence of telomerase.
    It's my suspicion that our lack of telomerase must not be primarily a cancer defense mechanism..
    We're really getting into the etiology of cancer here rather then simply antagonistic pleiotropy.
    
    I realize that the authors of this paper couldn't possibly do more in a professional journal article than sketch out the concepts that they're presenting. After that, they have to depend upon direct interpersonal discussions or upon in-depth papers to address all the questions and objections that could be raised. I suspect they would welcome, in a friendly spirit, constructive feedback of the issues they've addressed, and my own questions must eventually be directed toward such an inquiry.

 



(1)  Nature has evened up cancer probabilities among different tissues. The chances of breast or ovarian cancer are somewhere nearly comparable to the chances of getting cancer of the brain or of the colon. But the presence or absence of telomerase is an either/or condition. If our defense against cancer is a lack of telomerase, what tuning can evolution perform? And if, on the other hand, nature can adjust cancer susceptibilities independently of telomerase, then it indicates that telomerase isn't the only influence that determines vulnerability to cancer.