IUBio

Telomeric Theory - Those Damn Mice

Excelife excelife at earthlink.net
Sun Sep 6 23:54:03 EST 1998


IV. CRITICISMS, NEGATIVE FINDINGS & OBSTACLES

 
A) THOSE DAMN MICE AND THEIR LONG TELOMERES


The mouse species Mus musculus has given the telomeric theory its biggest 
headache to date.  The length of their telomeres had been measured as being 
substantially longer than those found on the chromosomes in human cells yet 
their life span is only a tenth that of humans.  Just how could telomeres be 
linked to aging with discrepancies like this?

And then Dr C. Greider did an excellent series of experiments where the gene 
coding for the enzyme telomerase was "knocked out" and the mice not only 
survived for up to six generations but showed no observable changes in the 
life span of the different generations.  If telomerase wasn't available to 
restore telomeric length but the mice still survived then perhaps telomeres 
aren't involved in aging.

A very typical argument against the telomeric theory of aging would go 
something like this response recently posted in the newsgroups; "Note that 
the telomerase knock-out mice had normal life spans for *six* *generations* 
of steadily decreasing telomere length.  The only apparent effect was that 
the sixth generation was sterile.", "...the important point is that the life 
span was no different from that of the mouse strain that the knock-out line 
originated from." 

Well, I'm happy to report that these legitimate questions have been 
substantially answered in favor of the telomeric theory of aging!

As to why Dr. Greider's mice, with the gene that codes for the enzyme 
telomerase deleted, could survive for six generations with no difference in 
life span, is easily resolved.  The critics, like above, just assumed that 
all the telomeres in the mice were not being maintained in the absence of 
telomerase.

Recent studies have shown that this is not the case!  Some gene(s) on distal 
chromosome 2 of Mus musculus, Mus spretus, and presumably other mice, 
regulate telomeric length in these mice.  These Gene(s) are unrelated to 
telomerase and their products and actions await determination of exactly 
which gene(s) are involved.  By determining telomeric length in somatic 
cells, in the absence of telomerase, little difference would be expected in 
the functioning and life span of these cells, nor the life span of the mice 
themselves across the generations.

Those cells that normally require telomerase, like the germ cells, in Dr. 
Greider's knock out mice, are affected by the absence of the gene coding for 
telomerase.  After around six generations the telomeres in the germ cells are 
too short to support additional replications and the mice are sterile.  But 
the cells not requiring telomerase had their telomeres replenished during 
embryonic development of each generation by the genes described above.  

The answer to the first question, why the mice and their cells die with such 
long telomeres, was also amazingly simple.  It seems that some mice 
chromosomes have significantly shorter telomeres than the other chromosomes. 
Their length is such that they could cause a cell to enter senescence after 
approx. 10 population doublings, which is exactly what is observed in the 
studies of the mice.  Yeast studies have shown that the loss of a single 
telomere can result in cell-cycle arrest and chromosome loss.  Further test 
to determine which genes are on these mouse chromosomes, their functions in 
the cell and their relation to senescence and cellular death do have to be 
conducted but this does appear to be the answer to this question.

With the issues involving Dr. Greider's knock out mice substantially resolved 
there are no other major research studies that argue against the telomeric 
theory of aging being a valid hypothesis.

There are, however, many other questions and problems yet to be resolved.


(Next: The Major Criticisms)




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





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