Telomeric Theory - Discussion

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VI. DISCUSSION


A.  Hypothesises 


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 
research.

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.

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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 
vascular tissues.

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
atherosclerotic plaques.

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 
coronary artery.

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 
detectable telomerase
activity.

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, 
Kronenberg
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 
longevity.

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 
elderly

13) Aviv A, Aviv H, Hum Genet 1998 Jul;103(1):2-4, Telomeres, hidden 
mosaicism, loss of heterozygosity, and complex genetic
traits.

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.

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Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.
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