X-Message-Number: 22990 Date: Tue, 02 Dec 2003 09:38:25 -0500 From: Keith Henson <> Subject: Methuselah Mouse suggestion The mouse genome has been sequenced, the rat's is in process. There is a rodent, the naked mole rat, that is known to live 20 years. "Maximum longevity in this species is as yet unknown, since animals that have been in captivity for as long as 20 years are still currently living. This life span is unprecedented among small rodents." http://www-personal.umich.edu/~cberger/syllabusfolder/animaldiversity/Heterocephalus_glaber.html Sequencing naked mole rats and comparting to mice and rats would give you an idea of what *isn't* important as well as what might be. Little cut 'n paste might well result in some really long lived mice. You heard it here first. :-) Keith Henson PS Recently in online chat the subjects of this 1977 letter to Science came up. I had not thought about it for a long time. Science didn't publish the letter. Dr. Hayflick wrote me asking for a copy of the bamboo article. (I still have his letter.) After I wrote it, someone pointed me to another source where someone had proposed very close to the same rational for cell limits. Still, given what we can do with reading genes nowadays, there is a PhD thesis out there for the person who identifies the counter mechanisms for bamboo or the 13/17 year cicada. I came reasonably close to describing the way telomers function, something that was not well understood until the early 1990s. Figured I would put it up for your amusement. ****************** [Address and telephone long out of date!] ANALOG PRECISION INC 1620 N. Park Tucson, AZ 85119 Tel: 602-622-1344 Aug. 2, 1977 Letter Editor Science American Association for the Advancement of Science 151.5 Massachusetts Ave., NW Washington D. C. 20005 HENSON'S Hypothesis--"Cellular aging may be a defense against cancer" Two puzzling features of cellular in normal and cancerous cells have been known for more then a decade (1) . These are, 1. a limit on the number of times normal cells will divide in culture before "senescing" (i.e., they quit dividing), and 2. the observation that cancerous cells or cells transformed by viruses or chemical agents are not subject to this limit. To my limited knowledge neither a generally accepted mechanism nor a satisfactory evolutionary reason has been proposed for cellular aging. One theory, that of molecular clocks and programmed aging readily accounts for both phenomena but evolutionary objections have been raised to this theory. (2). Briefly stated the molecular clock theory proposes that cells have a counter (perhaps built into the chromosomes) which is decremented one count division. In this way, a cell "knows" how many divisions have occurred since the sperm/egg fusion or some other event. Programmed aging refers to the concert that cells would be inhibited from further division or killed when the count reaches zero. One of many possible physical methods by which this could be accomplished would be through the action of enzyme which cleaves a DNA base pair from the end of a chromosome at each division until the coding for a critical sequence was destroyed . (Some way to restore or reset this hypothetical "chromosomal counter would also be required, otherwise each generation would he shorter than the proceeding one!) Molecular clocks per se almost certainly exist, there seems to be no other way to explain the accuracy of the reproductive cycles of certain bamboo species, one of which, Phyllostarchy bambusoides waits 120 years between flowerings and then flowers world wide (3). The obvious difficulty with which a molecular clock explanation for cellular aging is that a complex method to cause an organism's death, long after the usual end of the reproductive period, seems unlikely to evolve unless is serves some other purpose. I believe a good case can be made for cellular senecesence (and possibly aging itself) being a side effect of one of the defences organisms have against cancer. (page 2) There are evidently a number of checks that inhibit cells from becoming cancerous and evidence exists that several mutations are required to transform cells into cancerous types. (4). A limit on the number of normally permitted divisions may be one of these mechanisms. If so, a cell could lost contact inhibition and begin to grow in a cancerous fashion, but unless it had also lost the division inhibit codon or was continuously resetting the counter, growth would stop when the remaining permitted divisions were used up. Microscopic invasive growths which might represent this class of limited cancers are reported to be 100 times more common than unlimited cancers (5). The advantages in an evolutionary sense of this line of defense from cancerous cells might outweigh the obvious disadvantages of cellular aging. H. Keith Henson BSEE (University of Arizona) 1620 N. Park Ave. Tucson, AZ 85719 1. Hayflick, L. "The Limited In Vitro Lifetime of Human Diploid Cell Strain," Expl. Cell Res. 37: 614-663 (1965). 2. Orgel, L. E., "Aging of Clones of Mammalian Cells," Nature, Lond. 243, 441-445 (1973). 3. Jazen, D. H. "Why Bamboo Waits So Long To Flower," Ann. Rev. Ecol. Syst. 1976 7:347-91. 4. Emmelot, P. and Scherer, E. "Multi-Hit Kinetics of Tumor Formation, with Special Reference to Experimental Liver and Human Lung Carcinogenesis and Some General Conclusions," Cancer Res. 37, 1702-1708, (June 1977). Carnes, J. "The Cancer Problem," Sci. Amer. Vol 233, Nov. 1975. cc to referenced authors. 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