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Planet of the Geezers

by John G. Cramer

Alternate View Column AV-88
Keywords: telomere telomerase human aging cell division Hayflick limit chromosome reproduction immortality
Published in the February-1998 issue of Analog Science Fiction & Fact Magazine;
This column was written and submitted 07/30/97 and is copyrighted ©1997 by John G. Cramer.
All rights reserved. No part may be reproduced in any form without
the explicit permission of the author.
 

 

     As the aging Baby Boom generation nears retirement age in the next two decades, there is already a rising concern about how the retirement of this demographic tidal wave can be funded. But on the horizon there looms another development, not yet widely recognized, which threatens a far greater impact -- a cure for human aging may be almost at hand.

    The "biological clock" that Nature uses to implement aging in humans and animals, to determine when an organism has reached the end of its natural life-span and must die of old age, has probably been discovered. And it seems to be a clock that a clever repair man can tinker with, rebuild, or reset. With the understanding of this mechanism, it now seems very possible that a cure for aging, possibly even reversal of human aging, may become a standard medical treatment in the coming decade.

    The presence of the aging clock was discovered 35 years ago by Leonard Hayflick, then a young cell biologist working in Philadelphia. At the time, the biological dogma was that normal cells can reproduce by cell division indefinitely. However, Hayflick discovered that fibroblast cell cultures from human skin, which he was growing in his laboratory, showed a definite limit to the number of times they could divide. Further, he found that tissue from embryos could divide more times than tissue from young human adults, which in turn could divide more times than tissue from older humans. This limiting condition became known as the Hayflick Limit. Later it was discovered the limit has some exceptions: cancer cells and the cells in the male associated with sperm production seem to be exempt from the Hayflick Limit and can continue to divide indefinitely.

    The biological mechanism behind the Hayflick Limit was, until 1990, a mystery. It was clear that there was a biological clock ticking along within each cell, and that when that clock ran down, the cell ceased to divide and soon died. It was also clear that cancer cells were somehow resetting or ignoring this clock. But it was not clear what the clock was, or how it worked.

    A clue to the action of the aging clock was provided by the Hutchinson-Gilford (HG) syndrome, a remarkable childhood pathology first described in 1886. It was found that a few children (about one in 8,000,000) show signs of greatly accelerated aging. The HG child begins to show early aging symptoms in the first year of life and typically dies of what looks like advanced old age by the age of 13. Symptoms include gray hair, balding, "old" skin, facial changes characteristic of the elderly, senility, cataracts, heart disease, and strokes. The HG syndrome appeared to be a case where the aging clock was somehow ticking too fast, but its origins were mysterious.

    Then in 1990 with the work of Cal Harley (McMaster University) and Bruce Fuchter and Carol Greider (Cold Springs Harbor Laboratory), the telomere was discovered and the clock identified. A telomere is special DNA structure with the repeating nucleic acid sequence TTAGGGTTAGGGTTAGGG. It is found on the ends of chromosomes in the nucleus of a cell, rather like the plastic tips on the ends of a shoestring. It is thought to provide a "docking zone" or starting sequence for the enzymes that perform chromosome duplication when a cell divides, and also to provide an inert region that prevents one chromosome end from sticking to another.

    Young cells, it was found, have long telomeres containing perhaps 1,600 repetitions of the TTAGGG sequence. But each time a cell divides, the telomere region is incompletely reproduced and become shorter. Finally the telomere is used up, the duplication enzyme cannot dock, the cell can divide no further, and some of the chromosome ends may begin to stick together, disrupting its DNA function. When this happens to enough cells, the organism ages and dies.

    There is considerable controversy at present on the question of whether cells are governed by one aging mechanism or many, whether the telomere mechanism is the unique aging clock or is only one of several that combine to form the very complex and poorly understood aging process. But a growing segment of the molecular biology community is becoming convinced that the telomere may be the key to reversing human aging. A piece of evidence in support of this position is the 1992 observation that the telomere lengths at birth for children afflicted with the Hutchinson- Gilford syndrome are much shorter than those of normal children, and indeed are shorter than those of even very old normal adults.

    In any case, the telomere is a count-down clock which limits the number of times a cell can divide by becoming progressively shorter with each cell division. As mentioned above, some cells like cancer and male reproductive cells seem to be exempt from this mechanism. Detailed investigation has revealed the reason: the nuclei of these cells contain an enzyme called telomerase, part protein amino acid sequence and part RNA nucleic acid sequence, which acts to rebuild the telomeres on the chromosome ends as fast as they are shortened by cell division. Cells with nuclei containing sufficient telomerase are, in effect, immortal.

    Where does the telomerase in cancer cells come from? The DNA of every cell contains an nucleic acid structure for producing telomerase, but it is normally "switched off" and inactive. In cancer cells, however, telomerase production is switched on, flooding the nucleus with telomerase and permitting the cell to divide without limit. The telomerase enzyme, however, is rather fragile and cannot travel from cell to cell through the bloodstream. Thus, each cell must produce its own telomerase locally. Even if we could synthesize telomerase (we cannot at present), it could not be distributed to cells through injection.

    The understanding of the telomere clock as it functions in normal and abnormal cells raises several potential applications that are now being actively pursued:

(1)  detecting the presence of telomerase or telomerase fragments in body fluids would provide an early warning of cancer;

(2)  a drug that could suppress the production or supply of telomerase in cancer cells would strip them of their "immortality" and thus represent a general cure for cancer;

(3)  a drug that could, for a controlled period, switch on the production of telomerase in normal cells would, at some level, reverse the aging process; and

(4)  a modified form of telomerase might be synthesized and administered directly, particularly if a form could be found that was not broken down in the bloodstream.

    The Geron Corporation (Menlo Park, CA) specializes in the biopharmaceutical aspects of telomeres and telomerase. They have succeeded in cloning the RNA component of telomerase, and they offer a product for detecting telomerase. This has been applied successfully to the early detection of bladder cancer, as indicated by the presence of telomerase in urine. Similar attempts to use telomerase in blood as an indicator of cancer have been less successful because of the fragility of the enzyme in the bloodstream, but the detection technique has many other uses.

    There is presently a broad-based effort to find a drug that suppresses the production of telomerase in cells (particularly cancer cells). One such drug, involving a reverse-sense transcription of the RNA component of telomerase has already been produced by Geron in 1994 and found to be effective in suppressing the growth of cultures of ovarian cancer cells in the laboratory. Research on similar suppression of cancer in animals is now in progress.

    But it is hoped that there may be cheaper and less fragile drugs for suppressing telomerase in cancer cells. Many of the large drug companies have assembled "drug libraries", large collections of chemicals and drugs derived from plants and animals all over the world, for which no pharmaceutical use is presently known. Groups are now going through the extensive drug libraries of several large pharmaceutical firms, using the telomerase detection technique to search for a drug that will suppress the production of telomerase in cultures of cancer cells. For example, a drug may be added to a cancer cell culture while the telomerase level is monitored. A drop in that level would signal a possible new telomerase inhibitor, perhaps a general cure for cancer. A parallel effort, using much the same approach, is to use a culture of normal cells and search for a drug that would produce an increase in the telomerase level, thereby perhaps signaling a new drug that might reverse aging by rebuilding telomeres on command.

    A different approach to age reversal, as mentioned above, would be to synthesize and administer a modified form of telomerase directly. The modification is necessary because normal telomerase is broken down in the blood stream. The present roadblock to this approach is that we do not have a complete molecular map of the structure of telomerase. Its RNA component has been sequenced by Geron and others, but its protein component remains a mystery. Therefore, the origin of its structural fragility is not understood, so it is not possible to design a more robust substitute (or even to know if such a substitute is possible).


    OK, this is a science fiction magazine, so let's assume that telomerase is indeed the key to age reversal and consider some of the SF implications of this discovery.

    First, cosmetics: humans of the female gender spend an amazing amount of money on products that are alleged to "de-age" the texture of the skin, while males invest in remedies that promise to restore their thinning hair. The hair and skin are fortunately on the surface of the body, accessible without using the bloodstream. So suppose we mix some oily penetrant like lanolin or DMSO with synthesized normal fragile telomerase and sell it as a cosmetic to rejuvenate the skin and/or as a hair restorer? Since telomerase is a natural enzyme (like melatonin, currently available at your local health-food store), I don't think this could be regulated or suppressed by the FDA. (And it wouldn't even have to work!)

    Or suppose that in a few years an age-reversing treatment comes along. The course of treatment would probably be a good dose of telomerase inhibitor, maintained for long enough to make sure the patient had no undetected developing cancers, followed by a dose of telomerase enhancer that would cause the rebuilding of all of the body's telomeres. At a stroke the human lifespan might be increased to a few centuries.

    What are the implications of that? What would it do the population of the planet, the birth rate, the enthusiasm of some cultures for war, the retirement and Social Security systems, life insurance, the stock market (where a lot of retirement money is invested), the flow in our society of young people into the workforce and old people out? Would Earth become The Planet of the Geezers, ruled by the American Association of Retired Persons?

    Many SF writers, notably Robert Heinlein, Damon Knight, Frederik Pohl, Poul Anderson, and Bruce Sterling, have considered some of the implications of extended lifespans or cures for human aging, but I believe there are rich possibilities for new SF in this area to prepare us for the changes to come. Analog writers take note!


Caveat: The author of this column is a physicist with only a superficial appreciation of the subtleties of molecular biology. My information comes mainly from Michael Fossel's book referenced below, and my perspective is perhaps distorted by my lack of experience in this fascinating but complex field.


Reference:

Telomeres and Telomerace:
 Reversing Human Aging, Michael Fossel, PhD, MD, (Morrow, 1996).

SF Novels by John Cramer:  my two hard SF novels, Twistor and Einstein's Bridge, are newly released as eBooks by Book View Cafe and are available at : http://bookviewcafe.com/bookstore/?s=Cramer .

AV Columns Online: Electronic reprints of about 177 "The Alternate View" columns by John G. Cramer, previously published in Analog , are available online at: http://www.npl.washington.edu/av.


 
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