Debate_on_telomerase

Graham Pawelec olxpa01 at mailserv.zdv.uni-tuebingen.de
Wed Feb 2 15:51:12 EST 1994


Concerning the recent debate on telomerase, may I summarize (so that experts
can correct me!) and ask a couple of questions?

The TELOMERE HYPOTHESIS of cellular ageing proposes that loss of telomeric 
DNA, and gradual shortening of telomeres, results, after a certain number of
cell divisions, in the inability of cells to divide again(1). Loss of telo-
meric DNA has been demonstrated in blood cells in vivo, and has been shown 
to occur more rapidly in premature ageing syndromes, eg. Hutchinson-Gilford
progeria(2) or trisomy-21(3). These investigators also examined lymphocytes
from normal donors cultured for 10  - 30 PD, and estimated a telomere DNA 
loss rate of 120 bp/cell doubling, comparable to that seen in other somatic
cells. Moreover, telomere lengths from lymphocytes of centenarians were si-
milar to those of senescent cells in culture, which suggests that telomere 
shortening may indeed by of relevance to normal immunosenescence(3). More-
over, telomere length in sperm DNA did NOT decrease with increasing age of 
the donor, suggesting that a mechanism for maintaining telomere length may 
be active in germ cells but not somatic cells(2,4). Such a factor, telome-
rase, an enzyme responsible for maintaining telomere length in unicellular 
eukaryotes, has been found in immortalized human cell lines and tumour 
cells, but not in normal somatic cells. Telomerase may be an obligate but 
late event in transformation, because transformed cells and tumour tissues
generally have critically short telomeres(5). 

However, it seems to me that the telomerase hypothesis is difficult to re-
concile with the dominance of the senescent state over the proliferative 
state in heterokaryons. A possible way out of this dilemma was suggested by
Shay et al(6) who pointed out that this could be explained by postulating 
dominant telomerase repressors in normal cells, which are lost in immortal 
cells. This hypothesis has not yet been experimentally tested - or could 
somebody tell me whether it has been in the meantime?. I also think that 
arguing against telomere shortening as a general mechanism of ageing is the
finding that, whereas senescence and immunosenescence are well-recognized
occurrences even in short-lived species such as mouse, telomere lengths are
NOT decreased during murine ageing, and neither are sperm telomeres longer 
than somatic tissue telomeres7. Isn't it unlikely that phenotypically simi-
lar ageing processes in human and mouse would involve telomere shortening 
in the former but not the latter?

References

  1. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of 
     human fibroblasts. Nature 1990;345:458-60.

  2. Allsopp RC, Vaziri H, Patterson C, et al. Telomere Length Predicts 
     Replicative Capacity of Human Fibroblasts. 
     Proc Natl Acad Sci USA 1992;89:10114-8.

  3. Vaziri H, Schachter F, Uchida I, et al. Loss of Telomeric DNA During 
     Aging of Normal and Trisomy-21 Human Lymphocytes. 
     Am J Hum Genet 1993;52(4):661-7.

  4. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC.
     Telomere reduction in human colorectal carcinoma and with ageing. 
     Nature 1990;346:866-8.

  5. Harley CB. Telomere Loss - Mitotic Clock or Genetic Time Bomb. 
     Mutat Res 1991;256:271-82.

  6. Shay JW, Wright WE, Werbin H. Loss of Telomeric DNA During Aging May 
     Predispose Cells to Cancer (Review). Int J Oncol 1993;3(4):559-63.

  7. Kipling D, Cooke HJ. Hypervariable ultra-long telomeres in mice. 
     Nature 1990;347:400-2.
   
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      #                                                          #
      #                      Graham Pawelec,                     #
      #          Second Department of Internal Medicine,         #
      #          University of Tuebingen Medical School,         #
      #               D-72076 Tuebingen, Germany;                #
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      #          Coordinator, European Union Concerted           #
      #           Action on the Molecular Biology of             #
      #              Immunosenescence, EUCAMBIS.                 #
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