Obstacles to The Telomeric Theory of Aging

Excelife excelife at earthlink.net
Wed Sep 16 04:24:32 EST 1998


IV. CRITICISMS, NEGATIVE FINDINGS & OBSTACLES


C. Obstacles


Besides the theoretical problems of non-replicating cellular systems and 
telomeres relationship to age-related genetic expression, there are a number 
of more mundane obstacles to the research.

The first is in identifying what we're talking about.  Determining the length 
of telomeres at the ends of the chromosomes and finding where telomerase is 
active are no easy matters.  Fortunately recent research has provided tests 
such as  fluorescence in situ hybridisation (FISH) for analyzing telomeres 
and a non-isotopic telomeric repeat amplification protocol (TRAP) for 
determining telomerase activity in bones have been developed.  Additionally 
Lawrence Berkeley Labs Life Sciences Div. has produced a "kit" for 
identifying senescent cells in-vivo.  More powerful methods may be required 
for future research but here the research is on the right track.

More troublesome are the procedural methods and protocols that may be 
required to implement therapies based on the telomeric theory of aging.

Assuming, for arguments sake, that the introduction of hTR or hTRT into a 
cell could restore its youthful viability, what vectors are available to 
deliver it to the desired cells?

Some recent research into mammalian artificial chromosomes has shown how 
alpha-satellite DNA can seed centromeres in human cells suggesting that they 
have the potential to be developed as gene delivery vectors.  This gets us 
across the cell wall and into the cell itself but whether it can be 
generalized to do this, in the manner and quantity required, remains to be 
seen.  This and other research into vectors suggest that delivery may not be 
a major problem.

Once in the cells in vivo, however we may run into some other problems.  None 
of these problems have yet been encountered but given Murphy's Law...

Some of these problems could be that the cellular maintenance system, 
possibly including genetic control of telomeric length, (similar to that 
shown in mice), could interfere with the process.  The lengthening of the 
telomeres might be seen by the cells maintenance system as a defect and the 
cell might initiate apoptosis.  The change in telomeric length might have a 
negative impact on age related genetic expression causing either 
in-appropriate proteins to be produced or necessary proteins not to be 
produced.  These are just a few potential problems but they help point out 
some of the complexities that may be encountered.

Additionally, it appears that replacing telomeric length in and of itself 
does not cause a cell to replicate.  This may be beneficial for worries about 
cancer but if the purpose of the "therapy" is to replace lost cellular mass 
then some additional step may be required.  And once the cell does divide it 
still needs to be integrated into it's proper environment.

Many of these problems are related to and controlled by "normal" genetic 
expression.  If telomeric length is shown to be a factor in determining this 
genetic expression, as is suggested by their role in transcriptional 
silencing in the yeast, Saccharomyces cerevisiae, then some of these problems 
may solve themselves.

There will, almost undoubtedly, be some problems and obstacles in our search 
for longevity through the research into the telomeric theory of aging but 
none that appear insurmountable and given the goal, well worth the effort to 
overcome.


(Next: Related Research)



Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.
http://home.earthlink.net/~excelife/index.html






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