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
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
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.