VI. Discussion
B. Research Proposals
The goal of the research into the telomeric theory of aging is to develop a
therapy, or a means of intervention that can have the effect of lengthening
the human life span. Avoidance and/or mitigation of age related diseases is
one of the steps to achieving that goal.
The research proposals below address some of the questions that need to be
answered to reach that goal.
1) Is telomeric shortening related to orgasmic aging?
While attempts to prove that the relationship between telomeric length and
life span of an organism are more than just a correlation may be premature.
An experiment to just see what occurs with universal telomeric lengthening,
in an organism, could provide us with some insight into the processes
involved.
This could possibly be achieved by lengthening the telomeres in the embryo of
a mammal through either re-combinant DNA techniques(103) or the introduction
of appropriate oglionucleotides.(104) Other processes that help determine
telomeric length(105) may hinder this approach but the verification that this
control does, indeed, exist would move the research forward.
If telomeric length is "regulated" during development then other procedures
would have to be utilized to achieve universal telomeric lengthening. One
such procedure would be the introduction of h-TRT, the catalytic protein
subunit of the enzyme telomerase(32), into existing cells. Vectors to
transfect cells with h-TRT are available including artificial human
chromosomes(16).
There are several less technically challenging methods of obtaining evidence
of telomeric lengths relation to orgasmic aging. A systematic study of
telomeric length across long and short lived species is a possibility. An
analysis of telomeric length between calorie restricted and non-calorie
restricted mice would also be of benefit. The role of telomerase and other
telomeric elongating processes in survival of species could be investigated
using the gene "knock-out" techniques.(53) And analysis of telomeric length
in those systems that caused death(106) in an organism could provide evidence
of this relationship.
2) Can telomeric lengthening restore lost functioning at the cellular level?
Approaches to this question are on more reliable ground and could lead to
practical applications.
Critically shortened telomeric length, is suggested to lead to the
un-silencing of the p-53 gene and entrance of the cell into senescence.(17)
It has already been demonstrated that lengthening of the telomeres prior to
reaching this point can lead to an increased replicative capacity for the
cell line and the avoidance of senescence.(30) Whether telomeric
lengthening, in cells already in senescence, can affect this process needs to
be explored.
The introduction of h-TRT into senescent cells and the resulting elongation
of the telomeres would provide some insightful results. Perhaps the p-53
gene would be re-silenced and the downstream proteins may be decreased
resulting in the resumption of normal cellular functioning. Or, more likely,
the telomeric lengthening would restore replicative capacity and avoid
entrance into crisis stage. But, at the same time the "abnormal" genetic
expression observed in senescent cells may not be capable of being silenced.
This could provide some useful information on the genesis of cancerous cell
lines.
The analysis of genetic expression in cells through high throughput
screening, DNA arrays and differential display analysis could provide some
useful information.(107) Comparison of telomeric length to the
transcriptional expression of specific genes may show a correlation. The use
of these procedures to observe cells transfected with h-TRT or processes to
artificially shorten the telomeres(108) may provide evidence of telomeric
control of these same genes.
3) Can entire cellular or organ systems be positively affected by telomeric
lengthening?
This is the most exciting line of research suggested by the telomeric theory.
The results of this research could have a positive impact on longevity.
Experiments to determine if this is a feasible approach need to be conducted.
One such experiment could be the introduction of h-TRT into one lobe of the
mouse pituitary glands to compare its aging and functioning over time with
the lobe not treated with h-TRT.(102) If the treated lobe can maintain
functioning beyond that of the untreated lobe then we will know we are on the
right track. Similar studies on other replicating cellular systems in a
variety of organisms would add to our knowledge.
Human studies on the effects of h-TRT on the aging of the cardio-vascular
system(1+) would seem to have the most practical applications. If it can be
demonstrated that telomeric lengthening in these cells can have an effect on
delaying or even reversing degradations in this system, it would be a major
advance.
4) Are there other applications of the telomeric theory to medical
procedures?
Research into the combination of growth factors with telomerase to produce
sufficient cellular mass for bone marrow transplantation are currently being
conducted.(45+) This same approach may be beneficial for other organ systems
either in-vitro or in-vivo. If sufficient cellular mass, retaining the
necessary replicative capacity, can be developed from a patient's own cells
then both the problems with supply and rejection could be overcome for a wide
range of transplants.
These are just a few of the questions and research proposals that are raised
by the telomeric theory of aging. Other questions that need to be addressed
will arise as the research progresses. More importantly, some of the answers
to these questions could have a profound effect on our knowledge of the
causes and "cures" for aging.
-----------------------------------------------------------------------------
1) Chang E, Harley CB, Proc Natl Acad Sci U S A 1995 Nov 21;92(24):11190-4,
Telomere length and replicative aging in human vascular tissues.
16) Grimes B, Cooke H, Hum Mol Genet 1998 Oct;7(10):1635-1640, Engineering
mammalian chromosomes.
17) Vaziri H, Biochemistry (Mosc) 1997 Nov;62(11):1306-1310, Critical
telomere shortening regulated by the ataxia-telangiectasia gene acts as a DNA
damage signal leading to activation of p53 protein and limited life-span of
human diploid fibroblasts. A review.
30) Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB,
Shay JW, Lichtsteiner S, Wright WE, Science 1998 Jan16;279(5349):349-352,
Extension of life-span by introduction of telomerase into normal human cells.
32) Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE, Bodnar AG,
Lichtsteiner S, Kim NW, Trager JB, Taylor RD, Carlos R, Andrews WH, Wright
WE, Shay JW, Harley CB, Morin GB, Nat Genet 1997Dec;17(4):498-502,
Reconstitution of human telomerase with the template RNA component hTR and
the catalytic protein subunit hTRT.
45) Yui J, Chiu CP, Lansdorp PM, Blood 1998 May 1;91(9):3255-3262, Telomerase
activity in candidate stem cells from fetal liver and adult bone marrow.
53) Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider
CW, Cell 1997 Oct 3;91(1):25-34, Telomere shortening and tumor formation by
mouse cells lacking telomerase RNA.
102) 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.
103) Westerman KA, Leboulch P, Proc Natl Acad Sci U S A 1996 Aug
20;93(17):8971-6, Reversible immortalization of mammalian cells mediated by
retroviral transfer and site-specific recombination.
104) Kowald A, J Mol Biol 1997 Nov 7;273(4):814-25, Possible mechanisms for
the regulation of telomere length.
105) Jones CJ, Soley A, Skinner JW, Gupta J, Haughton MF, Wyllie FS,
Schlumberger M, Bacchetti S, Wynford-Thomas D, Exp Cell Res 1998 May
1;240(2):333-9, Dissociation of telomere dynamics from telomerase activity in
human thyroid cancer cells.
106) Takeda T, Nippon Eiseigaku Zasshi 1996 Jul;51(2):569-578,
Senescence-accelerated mouse (SAM): with special reference to
age-associated pathologies and their modulation.
107) Goyns MH, Charlton MA, Dunford JE, Lavery WL, Merry BJ, Salehi M, Simoes
DC, Mech Ageing Dev 1998 Mar 16;101(1-2):73-90, Differential display analysis
of gene expression indicates that age-related changes are restricted to a
small cohort of genes.
108) LaBranche H, Dupuis S, Ben-David Y, Bani MR, Wellinger RJ, Chabot B, Nat
Genet 1998 Jun;19(2):199-202, Telomere elongation by hnRNP A1 and a
derivative that interacts with telomeric repeats and telomerase.
