Telomerase deficient mice

Thomas Mahoney excelife at
Sat Mar 27 03:23:13 EST 1999

In article <36fb3ea4.708820210 at>, ufotruth at 

>I have a few questions, these might have already been answered before,
>but I think they are important and need answers if we are going to
>discuss telomerase knock-in and knock-out mice.
>1) Has *anyone* been able to "immortalize" a mouse cell by the
>insertion of a telomerase gene which would cause the cell to produce

Yes, the replicative cells of mice respond in the same manner as human cells 
when the catalytic component for telomerase is introduced.  They continue 
normal growth and don't enter senescence so long at the mTRT is active.

>2) If they have not been able to "immortalize" a mouse cell (other
>than a reproductive cell) by the insertion of a telomerase gene, then
>what was the obstacle that caused the cell to continue aging and
>growing older?

There is no block to the immortalization of mouse replicative cells that I 
know about.

Replicating mouse cells enter a senescent or slow growth stage at around ten 
population doublings.  (This may be related to a single chromosome with short 
telomeres, but this needs to be demonstrated.) If the cells continue to grow 
past this point, in vivo, they then grow into a tumor which is a leading 
cause of death in mice.

If telomeric lengthening could avoid this "uncontrolled" growth and the cells 
continued to express a phenotypically youthful state, as is suggested by the 
research, then the cells so treated would, likely, continue to function 
properly regardless of the age of the mice.

Whether this would affect life-span is an open question since the cells in 
the muscles and nerves etc.. would, probably, continue to age at a normal 

>From what I understand, it has been proven that as mice age, various
>cells of their body lose replicative potential. If this loss is from
>telomere shortening, then it seems that a telomerase "knock-in" mouse
>might either have a longer life-span, or at least be in better health
>in old age than a mouse that did not have telomerase activated.

The latter statement about health and avoidance of some age related diseases 
is suggested by the research cited.  Life-span effects were also suggested 
but only for latter generation mice.

My analysis, not universally accepted, is that the chromosome with the 
shortest telomeres is restored by some process, (possibly the genes on 
chromosome 3), in the first 4 or 5 generations of mice but disrupted by the 
severely shortened telomeres in the germ line by the 5th or 6th generation.

The chromosomes with the longer telomeres are maintained to at least the same 
length throughout the generations but become progressively shorter, resulting 
in the detrimental effects noted in the paper.

 >But if the aging of mouse cells are NOT caused by telomere shortening,
>and by something else, then probably a telomerase knock-in mouse would
>grow old and age just like a normal mouse, because its cells would
>keep on growing older, even though they had telomerase activated and
>elongated telomeres.

If the effects of embryonic telomeric lengthening could be restricted to 
replicating cellular systems, don't disrupt embryogenesis, don't cause 
disruptions in the endocrine system balances, don't disrupt the functioning 
of stem and satellite cells, don't interfere with nerve function and 
regulation and don't disrupt any other vital bodily systems then I would 
expect to see an improvement in longevity.

I suspect that a far more "targeted" use of telomeric elongation therapy 
would have a far better chance of achieving an extended life-span than a 
general application approach.

Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.

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