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Molecular Mechanisms of Aging: Telomerase and Cellular Aging
Michael Sidiropoulos, M.Sc. (OT7)
Numerous mechanisms have been proposed to explain the
process of aging, including the prominent ‘telomerase theory’
and the ‘mitochondrial theory’. Two recent papers, both published in 1998, highlight the significance of the telomerase theory in the everlasting debate over the aging cell.
The articles, by Bodnar et al.1 and Vaziri and Benchimol,2 both
demonstrate that human cell senescence can be reversed by
transfection with a gene for the catalytic component of telomerase. These startling articles suggest that the “Hayflick limit”
can be extended, and propose numerous prospects for clinical
medicine.3
A 1998 review article by Fossel3 provides a good review of the
telomerase theory of aging, and provides prospective expectations and limitations of the theory in clinical applications. This
article presents the relevant facts and findings from Fossel’s
paper, and presents a simple description of the ‘telomerase theory’ of cellular aging and its potential clinical applications.
The Hayflick Limit
Normal somatic cells have limited replicative potential, dubbed
the Hayflick limit, which has been demonstrated in young skin
fibroblasts to be approximately 50 divisions.4 This replicative
potential is reached gradually, with progressive slowing of the
rate of divisions as well as manifestations of identifiable and
predictable morphological changes characteristic of “senescent
cells.”5 These senescent cells also express definable patterns of
changes in gene expression that accompany the replicative
block, termed “senescence-associated gene expression.”3,6-8
Telomeres, Telomerases and DNA Shortening
Eukaryotic chromosomes possess special structures, known as
telomeres, at their ends. One strand of each telomere is composed of tandem repeats of short, guanine-rich regions. The Grich telomere strand is made by an enzyme called telomerase.
Telomerase is a reverse transcriptase comprised of a short RNA
sequence that serves as the template for telomere synthesis and
includes a specific catalytic protein component. This mechanism ensures that chromosome ends can be rebuilt, and therefore do not suffer shortening with each round of cell division.9
However, during the eukaryotic process of DNA replication,
which is semi-conservative, DNA polymerase primers overlay
and cover a portion of the terminal chromosome.
Consequently, a portion of the telomere is not replicated and
therefore shortens with each cell division. Telomeres are known
to be shorter in senescent cells than in younger cells.10,11
Therefore, telomere shortening may be the “clock” that leads
to the shift toward senescent-associated gene expression and
ultimately cell senescence and the Hayflick limit.3
The Hayflick limit is a barrier to infinite replication, and has
very few known exceptions.4 These exceptions include cancer
cells and the germ cell lineage.12,13 Certain stem cell lines, such
as gastrointestinal crypt cells, liver cells, and hematopoietic stem
cells, also demonstrate replicative senescence, but do so with a
much extended cellular lifespan and a greater number of cell
divisions in comparison with other somatic cell types.14
Surprisingly, this extension corresponds with a transient expression of telomerase, which allows these cells to slow the rate at
which their telomere bases disappear.15,16 Telomerase expression
also occurs in the germ cell line and primordial stem cells. Since
these cells are not limited by replicative senescence, they have
a potential clinical application in the growth of tissues and
organs.3
The Cellular “Clock”
The articles by Bodnar et al.1 and Vaziri and Benchimol,2 have
both shed some light on what acts as the cellular “clock” that
times replicative senescence. Bodnar et al. have shown that the
telomere is the clock of replicative senescence and that it can
be reset.1 Vaziri and Benchimol,2 as well as others,17 have independently confirmed the work. As previously mentioned,
telomerases act by adding DNA bases to telomeres. This is
done through the use of a short RNA template that is present
in cells normally, and a catalytic protein component that is not
found in normal aging somatic cells. Bodnar et al. transfected a
gene for this catalytic component into cells and displayed that
this resulted in extended telomeres.1 The extended telomeres in
turn extended the replicative life span of the cells, giving them
a pattern of gene expression identical to young cells, and showing 40% more population doublings.3
The study by Bodnar et al.1 effectively demonstrated that telom-
volume 83, number 1, December 2005
17
eres are the timepieces of replicative aging. It is now known
that not only do telomeres shorten with cell aging, but also that
re-lengthening the telomere appears to reset gene expression,
cell morphology, and the replicative life span. However, questions remain about the role of cell senescence in the aging of
an entire organism, and whether our knowledge of cellular
senescence can be of potential therapeutic use in the treatment
of underlying age-related diseases. Possibilities for treatment
include alternatives to cancer therapy and effective prevention
and treatment of immune senescence, atherosclerosis, dermatologic aging, macular degeneration, and Alzheimer’s disease.3
References
1. Bodnar AG, Ouellette M, Folkis M, Holt SE, Chiu CP, Morin GB, et al.
Extension of life-span by introduction of telomerase into normal human cells.
Science. 1998 Jan 16;279(5349):334-5.
2. Vaziri H, Benchimol S. Reconstitution of telomerase activity in normal human
cells leads to elongation of telomeres and extended replicattive life span. Curr
Biol. 1998 Feb 26;8(5):279-82.
3. Fossel M. Telomerase and the aging cell: implications for human health. JAMA.
1998 Jun 3;279(21):1732-5.
4. Hayflick L, Moorehead PS. The Limited in vitro lifetime of human diploid cell
strains. Exp Aging Res. 1961;25:585-621.
5. Hayflick L. The cell biology of human aging. Sci Am. 1980;242:58-66.
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University of Toronto Medical Journal
6. Wright WE, Pereira-Smith OM, Shay JW. Reversible cellular senescence: implications for immortalization of normal diploid fibroblasts. Mol Cell Biol. 1989
July;9(7):3088-92.
7. Campisi J. The Biology of replicative senescence. Eur J Cancer. 1997
Apr;33:703-9.
8. Faraghar RGA, Shall S. Gerontology and drug development: the challenge of
the senescent cell. Drug Discovery Today. 1997 Feb;2(2):64-71.
9. Weaver RF. Molecular Biology. 1st ed. Boston: McGraw-Hill; 1999. p. 689-92.
10. Harley CB, Futcher AB, Greider CW. Telomeres shorten during aging of
human fibroblasts. Nature. 1990 May 31;345:458-60.
11. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire
RC. Telomere reduction in human colorectal carcinoma and with aging. Nature.
1990 Aug 30;346(6287):866-8.
12. Counter CM, Hirte HW, Bacchetti S, Harley CB. Telomerase activity in human
ovarian carcinoma. Proc Natl Acad Sci. 1994;91:2900-4.
13. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL. Specific
association of human telomerase activity with immortal cells and cancer. Science.
1994 Dec 23;266(5193):2011-5.
14. Chiu C-P, Dragowska W, Kim NW, Vaziri H, Yui J, Thomas TE, et al.
Differential expression of telomerase activity in hematopoietic progenitors from
adult human bone marrow. Stem Cells. 1996 Mar;14(2):239-48.
15. Counter CM, Gupta J, Harley CB, Leber B, Bacchetti S. Telomerase activity in
normal leukocytes and in hematologic malignancies. Blood. 1995 May
1;85(9):2315-20.
16. Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyama E, Piatyszek MA, et al.
Activation of telomerase in human lymphocytes and hematopoietic progenitor
cells. J Immunol. 1995 Oct 15;155(8):3711-5.
17. Counter CC, Meyerson M, Eaton EN, Ellisen LW, Caddle SD, Haber DA, et
al. Telomerase activity is restored in human cells by ectopic expression of
hTERT (hEST2), the catalytic subunit of telomerase. Oncogene. 1998 Mar
5;16(9):1217-22.