Major Criticisms of The Telomeric Theory

Excelife excelife at earthlink.net
Fri Sep 11 19:10:17 EST 1998


 
IV. CRITICISMS, NEGATIVE FINDINGS & OBSTACLES
 

B. Major Criticisms

The major criticisms of the telomeric theory of aging fall into two 
categories.  The first is that there are some cells and organisms that age 
and die despite having significant remaining telomeric length on their 
chromosomes.  The second is that there is is insufficient evidence to show 
that telomeres have anything to with aging let alone longevity.

Some organisms, particularly in the lower phylums have evolved some unique 
ways of surviving.  The goal of this evolution is to pass intact genes on to 
their progeny.  The key here is "intact".  In most organisms these genes are 
organized into chromosomes held together at the ends of each chromosome by 
structures called telomeres.  The exact structure of these telomeres can vary 
between species as we can see with Drosophila melanogaster but their function 
remains the same, primarily to maintain the stability of the chromosomes.

So for survival of their species every organism has developed a process to 
conserve telomeric length on their chromosomes.  Most unicellular species 
like Budding yeast (S. cerevisea), and most mammals, (in their germ cells), 
utilize the enzyme telomerase to maintain their telomeres.  This enzyme adds 
telomeres to the ends of the chromosome but if the cell in which it is active 
replicates too fast the telomeres can be shortened faster than telomerase can 
replace them and the cell may eventually enter senescence, (see I. Theory E. 
Telomeres and Senescence).  Other organisms like the mosquito (Anopheles
gambiae), utilize DNA recombination to maintain telomeric length and as we 
have already seen in the mouse (Mus musculus), genes in the DNA can have an 
effect on determining telomeric length.

But what does this have to do with aging and the criticisms of the telomeric 
theory?  Well, each of these processes determines how the organism "ages".

For most unicellular organisms, utilizing telomeres to maintain telomeric 
length, their telomeres are fully maintained during mitotic division and 
theses organisms are essentially immortal.

Budding yeast (S. cerevisea), are an exception to this in that they go 
through assymetric mitotic division.  The mother cell of the yeast then age 
much in the same manner as most other eukaryote cells. Austriaco NR Jr, at 
The Massachusetts Institute of Technology has demonstrated how the telomeres 
in the mother cell regulate the silencing machinery of the genes to control  
aging in these cells.

Some multi-cellular organisms have developed a very effective way to maintain 
telomeric length without utilizing telomerase.  The adult cells of the worm 
(C. Elegans), and the fly (Drosophila melanogaster), and many other similar 
organisms avoid telomeric shortening by not dividing at all.  While the 
telomeric control of the transcriptional silencing machinery shown in S. 
cerevisea may also be functioning here, aging in these organisms is not a 
function of mitotic shortening of the telomeres.

Similarly the non-reproducing cells in humans, including nerve and muscle 
cells are post mitotic and do not age as a result of telomeric shortening. 
The viability of these cells could possibly be prolonged if other mitotic 
cellular system, like the circulatory and immune systems, are maintained by 
telomeric lengthening but this needs to be demonstrated.  The telomeres may 
also be involved in gene regulation over age in these cells and this 
regulation may be involved their aging but other interventions will most 
likely be required to maintain these cells, (see Related Research).

So if worms and flys age and die without losing telomeric length and the post 
mitotic cells in humans don't have shortened telomeres just how can telomeric 
shortening be a cause, let alone the controlling factor, of aging in humans?

Some research has shown that extending telomeric length by introducing 
h-TERT, the catalytic protein subunit of the enzyme telomerase can cause 
human replicating cells to survive well beyond their expected Hayflick limit, 
in a phenotypically youthful state.  But this may be a fluke and not 
applicable to aging.

Other research has shown that the loss of telomeres can result in the loss of 
cellular mass in organ systems of the body but this could be an aberration 
and not applicable to aging.

Still other research has shown telomeric length to be a controlling factor in 
the senescence of cells in the human body but this too may not be related to 
aging.

Cells cannot survive without maintaining telomeric length but they can't 
survive without cell walls either so this may not relate to aging.

Maintaining or adding telomeric length allows replicating cell lines to 
become immortal but that could lead to cancer and probably has no relation to 
aging.

And the fact that telomeric length may be involved in age related genetic 
expression probably has little to do with organismic aging.

So maybe I do agree with the critics, that telomeric loss over age is 
unrelated to aging.

But then I could be wrong! 


(Next: Obstacles to the research)  



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





 






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