Telomere shortening in vivo

Magnus Lynch mdl24 at cam.ac.uk
Mon Mar 13 21:14:38 EST 2000


Hello, I have been looking at telomere shortening in vivo and I have
written the following summary of what I have found out. If anybody can
spot any errors, misunderstandings or points that I have missed I would
be very grateful.

Magnus



There is strong evidence that in dividing cells such as human peripheral
blood lymphocytes & colon mucosa [Hastie, 1990], skin epidermal cells
[Lindsey, 1991], haematopoetic stem cells [Vaziri, 1993] and
granulocytes & naïve T cells [Rufer, 1999] telomere shortening occurs as
a function of age in vivo. Conversely, in non dividing cells such as
muscle [Oexle, 1997] and nervous tissue (brain) [Allsopp, 1995] no
telomere shortening is observed. 

For rarely dividing cell types such as fibroblasts, the situation is
more complicated. One study [Allsopp, 1992] found a small but
significant correlation between donor age and telomere length in
fibroblasts. In contrast, a later study [Mondello, 1999] found no
correlation between donor age and mean telomere length in fibroblasts. A
further study [Cristofalo, 1998] which used a large number of carefully
controlled samples, found no relation between donor age and
proliferative potential - as TRF length correlates extremely well with
replicative lifespan in vitro [Allsopp, 1992] it seems reasonable to
infer that there was also no correlation between donor age and mean TRF
length.

Both the Mondello and Cristofalo datasets have large variations between
individuals of the same age and it may be that these variations obscure
the correlation between telomere length / proliferative potential and
age, however the Cristofalo study also compares the proliferative
potential of several sets of cell lines derived from the same
individuals at different ages and again finds no correlation between
proliferative potential and age.

The method used by Mondello and many of the other studies to determine
telomere length is that of the terminal restriction fragment (TRF)
length which essentially determines a distribution of telomere lengths
across all cells in the sample and all chromosomes in the cells. It is
thought that not all fibroblasts divide continuously, rather subsets are
induced to proliferate in response to demand in their vicinity such as
injury [Alberts et al, 1994 p1179] thus it would be expected that the
number of divisions executed by different individual fibroblasts should
vary. If a minority of telomeres within individual cells or on
individual chromosomes decreased in length then the tail of the TRF
distribution would move to lower values, however the position of the
mean would not be significantly altered. This possibility cannot, thus
be excluded on the evidence of these studies. 

It may be that in vitro culture selects for cell lines with better
proliferative potential. This could explain the large differences in
replicative potential found in the Cristofalo study for the same
individuals at different ages. In addition it has been demonstrated [von
Zglinicki, 1998] that when cells are held at confluence for a period of
time then subsequently allowed to divide telomere shortening may be
transiently much greater per population doubling than normal due to
oxidative damage accumulated by the DNA during the period of confluence.
Many of the studies discussed including those of Allsopp, Cristofalo and
Mondello examine DNA from cells which have been passaged in culture for
a number of divisions rather than from biopsy material. It may be that
these decreases in telomere length are only present in these cultured
cells and are not actually present in cells which have been at
confluence in vivo.

References:

·	Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC.
Telomere reduction in human colorectal carcinoma and with ageing.
Nature. 1990 Aug 30;346(6287):866-8.
·	Lindsey J, McGill NI, Lindsey LA, Green DK, Cooke HJ.  In vivo loss of
telomeric repeats with age in humans. Mutat Res. 1991 Jan;256(1):45-8.
·	Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R, Cohen D,
Harley CB.  Loss of telomeric DNA during aging of normal and trisomy 21
human lymphocytes. Am J Hum Genet. 1993 Apr;52(4):661-7.
·	Rufer N, Brummendorf TH, Kolvraa S, Bischoff C, Christensen K,
Wadsworth L, Schulzer M, Lansdorp PM.  Telomere fluorescence
measurements in granulocytes and T lymphocyte subsets point to a high
turnover of hematopoietic stem cells and memory T cells in early
childhood. J Exp Med. 1999 Jul 19;190(2):157-67.
·	Oexle K, Zwirner A, Freudenberg K, Kohlschutter A, Speer A.
Examination of telomere lengths in muscle tissue casts doubt on
replicative aging as cause of progression in Duchenne muscular
dystrophy. Pediatr Res. 1997 Aug;42(2):226-31.
·	Allsopp RC, Chang E, Kashefi-Aazam M, Rogaev EI, Piatyszek MA, Shay
JW, Harley CB. Telomere shortening is associated with cell division in
vitro and in vivo. Exp Cell Res. 1995 Sep;220(1):194-200.
·	Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher
AB, Greider CW, Harley CB. Telomere length predicts replicative capacity
of human fibroblasts. Proc Natl Acad Sci U S A. 1992 Nov
1;89(21):10114-8.
·	Mondello C, Petropoulou C, Monti D, Gonos ES, Franceschi C, Nuzzo F.
Telomere length in fibroblasts and blood cells from healthy
centenarians. Exp Cell Res. 1999 Apr 10;248(1):234-42. 
·	Cristofalo VJ, Allen RG, Pignolo RJ, Martin BG, Beck JC. Relationship
between donor age and the replicative lifespan of human cells in
culture: a reevaluation. Proc Natl Acad Sci U S A. 1998 Sep
1;95(18):10614-9.
·	von Zglinicki T. Telomeres: influencing the rate of aging. Ann N Y
Acad Sci. 1998 Nov 20;854:318-27. Review.





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