Telomeric Theory - Discussion
excelife at earthlink.net
Thu Oct 29 05:08:22 EST 1998
The predictability of results is the sign of a good theory. The telomeric
theory of aging has been able to explain many of the research findings on
aging or to show how they were irrelevant to this theory. This section will
expound on some of the major hypotheses derived from the telomeric theory and
suggest ways in which these can be tested.
The main hypothesis of the telomeric theory, as mentioned at the beginning of
this article, is that this telomeric limitation on the replicative ability of
dividing cell lines is the primary cause of aging and age related diseases.
The evidence needed to support this hypothesis is, of course, based on the
process by which telomeric elongation could achieve an extended life span.
The initial hypothesis of the telomeric theory, that maintaining telomeric
length would increase the replicative capacity of replicating cells, has been
pretty well established. That telomeric length is correlated with life span
in many higher organisms, that critically shortened telomeres are associated
with and probably causative of senescence and that many cells in elderly
humans have substantially shortened telomeres are also supported by the
These and other findings suggest some additional hypothesises of how
telomeric shortening could be a cause of aging in humans. Since systems
failures, including heart disease, tumor genesis, immunological failures and
endocrine system failures, are the primary, non-traumatic, causes of death in
developed countries, the telomeric theory should predict how telomeric length
is involved in these processes.
One major hypothesis, referenced earlier, is that early telomeric shortening
in stressed human vascular tissues can lead to artheriosclerosis and plaque
formation in veins and arteries.(1) The suggested mechanism of this process
is the entry of some of the cells in this system into the senescent phase of
development.(2) Apoptosis and increased collagenase production by senescent
cells would reduce available cellular mass in both the endothelial lining(3)
and the surrounding smooth muscle cells.(4) The telomeric theory predicts
that the introduction of h-TRT, the catalytic subunit of telomerase, into
these cells prior to their encountering critical shortening of the telomeres
would avoid senescence in the cells and and the related plaque formations.
Additionally, the telomeric theory suggests that where plaque formation
resulting from cellular loss has already occurred, a combination of h-TRT and
human growth factor FGF-I, (basic fibroblast growth factor)(5), may be
effective in restoring the lost cellular mass. This has the potential of
eliminating existing plaque formations.
Another major hypothesis of the telomeric theory is that telomeric
maintenance or elongation is the primary component of the immortalization of
cancer cells in humans.(6) Also that the enzyme telomerase plays a key role,
in the majority of cancers, in maintaining this telomeric length.(7) This
leads to the hypothesis that the de-activation of telomerase, in cancers in
which it is present, will limit the replicative capacity of those cells.(8)
Absent telomerase activity these cancerous cells should experience telomeric
shortening and shortly either senesce or enter crisis. Even if contact
inhibition should interfere with cellular replication and the associated
telomeric shortening the cancerous tissue will still have limited replicative
capacity and the tumor will not be able to grow significantly.
Immunosenescence provides another hypothesis related to the telomeric theory.
Here it is suggested that T-cell functioning is impaired by the accumulation
of senescent T-cells.(9) Although T-cells have active telomerase, its
activation is purported to be related to cd28, (a cell surface molecule).
Cd28s' decline with age(10) is thought to be associated with excess cellular
replication.(11) The decline of telomerase functioning resulting from this
reduction of cd28 allows the T-cells telomeres to reach critically shortened
length and the T-cells enter senescence.(12)
The telomeric theory hypothesizes that either the restoration of cd28
activity or the introduction of h-TRT will restore the functioning of
telomerase in these cells and avoid their entrance into senescence.
The decline of the endocrine systems with age is also thought to be related
to telomeric shortening in these cells.(13) The initiation of apoptosis and
the resulting cellular loss associated with senescence and the accumulation
of dysfunctional senescent cells are thought to be causative of declines in
the endocrine systems.(14)
It is hypothesized that the introduction of h-TRT into these cells, prior to
senescence, will allow these systems to maintain functional capacity well
beyond their normal period of decline.
Finally, assuming these age related diseases can be overcome, there still
remains the ultimate roadblock of life span being limited by "aging" itself.
The telomeric theory proposes that a major portion of this limiting factor is
related to the loss of replicative ability in the replicating cells in
humans.(15) The theory predicts that restoration of this replicative
capacity through telomeric maintenance and/or elongation will actually extend
the human life span. Additional interventions to restore cellular loss and
limited functioning in non-replicating cells will likely be necessary to
extend the human life span even further.
The telomeric theory of aging predicts that telomeric "therapy" alone will
get us beyond the 120 year limit on life span that we know today and with a
youthful and healthy constitution.
1) Chang E, Harley CB, Proc Natl Acad Sci U S A 1995 Nov
21;92(24):11190-11194, Telomere length and replicative aging in human
2) Bennett MR, Macdonald K, Chan SW, Boyle JJ, Weissberg PL, Circ Res 1998
Apr 6;82(6):704-712, Cooperative interactions between RB and p53 regulate
cell proliferation, cell senescence, and apoptosis in human vascular smooth
muscle cells from
3) Kumazaki T, Kobayashi M, Mitsui Y, Exp Cell Res 1993 Apr;205(2):396-402,
Enhanced expression of fibronectin during in vivo cellular aging of human
vascular endothelial cells and skin fibroblasts.
4) Tracy RE, Virchows Arch 1997 Feb;430(2):155-162, Declining density of
intimal smooth muscle cells as a precondition for atheronecrosis in the
5) Schumacher B, Pecher P, von Specht BU, Stegmann T
, Circulation 1998 Feb 24;97(7):645-650, Induction of neoangiogenesis in
ischemic myocardium by human growth factors: first clinical results of a new
treatment of coronary heart disease.
6) Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR, EMBO J 1995 Sep
1;14(17):4240-8, Telomere elongation in immortal human cells without
7) Andersen TI, Tidsskr Nor Laegeforen 1998 May 20;118(13):2043-6, Telomeres,
telomerase and development of cancer.
8) Shay JW, J Cell Physiol 1997 Nov;173(2):266-70, Telomerase in human
development and cancer.
9) Effros RB, Boucher N, Porter V, Zhu X, Spaulding C, Walford RL,
M, Cohen D, Schachter F , Exp Gerontol 1994 Nov-Dec;29(6):601-9, Decline in
CD28+ T cells in centenarians and in long-term T cell cultures:
a possible cause for both in vivo and in vitro immunosenescence.
10) Weyand CM, Brandes JC, Schmidt D, Fulbright JW, Goronzy JJ, Mech Ageing
Dev 1998 May15;102(2-3):131-147, Functional properties of CD4+ CD28- T cells
in the aging immune system.
11) Boucher N, Dufeu-Duchesne T, Vicaut E, Farge D, Effros RB, Schachter F,
Exp Gerontol 1998 May;33(3):267-82, CD28 expression in T cell aging and human
12) Effros RB, Am J Hum Genet 1998 May;62(5):1003-7, Replicative senescence
in the immune system: impact of the Hayflick limit on T-cell function in the
13) Aviv A, Aviv H, Hum Genet 1998 Jul;103(1):2-4, Telomeres, hidden
mosaicism, loss of heterozygosity, and complex genetic
14) Jacobsson G, Pelto-Huikko M, Meister B, Mech Ageing Dev 1998 Mar
16;101(1-2):33-41, Decreased mRNA levels for exocytotic proteins in the
pituitary of aged rats.
15) Allsopp RC, Chang E, Kashefi-Aazam M, Rogaev EI, Piatyszek MA, Shay JW,
Harley CB, Exp Cell Res 1995 Sep;220(1):194-200, Telomere shortening is
associated with cell division in vitro and in vivo.
(Next: Research Proposals)
Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.
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