Telomeric Theory of Aging

Excelife excelife at
Thu Aug 20 04:29:38 EST 1998

In article <35db700f.25165798 at>, ufotruth at 
>Can you give any more information about this unrelated genetic
>component that also regulates telomere length in these mice?

Proc Natl Acad Sci U S A 1998 Jul 21;95(15):8648-8653

Telomere length regulation in mice is linked to a novel chromosome locus.

Zhu L, Hathcock KS, Hande P, Lansdorp PM, Seldin MF, Hodes RJ

Rowe Program in Genetics, Departments of Biological Chemistry and Medicine
University of California, Davis, Davis, CA 95616.

[Record supplied by publisher]

Little is known about the mechanisms that regulate species-specific
telomere length, particularly in mammalian species. The genetic regulation
of telomere length was therefore investigated by using two inter-fertile
species of mice, which differ in their telomere length. Mus musculus
(telomere length >25 kb) and Mus spretus (telomere length 5-15 kb) were
used to generate F1 crosses and reciprocal backcrosses, which were then
analyzed for regulation of telomere length. This analysis indicated that a
dominant and trans-acting mechanism exists capable of extensive elongation
of telomeres in somatic cells after fusion of parental germline cells with
discrepant telomere lengths. A genome wide screen of interspecific crosses,
using M. spretus as the recurrent parent, identified a 5-centimorgan region
on distal chromosome 2 that predominantly controls the observed
species-specific telomere length regulation. This locus is distinct from
candidate genes encoding known telomere-binding proteins or telomerase
components. These results demonstrate that an unidentified gene(s) mapped
to distal chromosome 2 regulates telomere length in the mouse.

>>Many other mammals more closely compare to the human model of telomeric 
>>shortening leading to cellular senescence and presumed aging of the 
>>Our knowledge of how to intervene in age related expression of specific 
>>is extremely limited so methods to re-activate the telomerase gene are not 
>>currently available.  
>But could we probably insert the telomerase gene to make the cells of
>an organism immortal just like organizations such as GERON have done
>with individual cells? GERON has made cells immortal without
>re-activating the telomerase genes already in the cells. Could we do
>the same with a whole organism?

Yes, the procedure used by Geron et al., (Nat Genet 1997 Dec;17(4):498-502 
"Reconstitution of human telomerase with the template RNA component hTR and 
the catalytic protein subunit hTRT"), could be delivered to most if not all 
cells in the body and alternatively, various vectors could be used to target 
specific cellular systems.  This is a logical step and I would be very 
surprised if this type of experimentation is not currently being conducted.

I would also not be surprised if this research were to run into some 
problems.  Some of which could be that the cellular maintenance system, 
possibly including genetic control of telomeric length, (similar to that 
shown in mice above), could interfere with the process or that the 
lengthening of the telomeres might be seen as a defect and the cells might 
initiate apoptosis, or, as Dr liu mentioned in another post, the change in 
telomeric length could 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.

We may be able to overcome these obstacles as they come up and I think this 
line of research will, eventually, achieve the desired result of extending 
the human life span.  And as you mentioned we just don't know until we do the 

>This is all very interesting. Thanks for the information. I just wish
>I had a doctorates degree in molecular biology so I could understand
>more of it. :-)

Either you've been doing your homework or you're a big fan of Socrates;-)  I 
suspect the latter but will respond to the former!

>Let me ask you a few questions. My mind is buzzing with them. If you
>could answer the following questions i would really appreciate it.  
>Can you tell us more about how mice age? 
>Do they NOT run out of telomeres before they grow old and die? 
>Or do mice "grow old" and die even though they have long telomeres?
>If mice DO "grow old" and die without their cells growing old
>individually or becoming senescent then what in the heck is making
>their dividing cells die?

The closest I could come to answering these questions was in the 
Senescence-accelerated mouse (SAM) described in Nippon Eiseigaku Zasshi 1996 
Jul;51(2):569-578.  These mice were tested for age related pathologies and 
accelerated senescence was common to all strains of these mice.  To my 
knowledge they have not been tested for telomeric length and no reference was 
made as to whether this "senescence" is that associated with telomeric loss 
or instead referred to the "slow growth" stage some mice cells go through at 
around 10 population doublings while still retaining substantial telomeric 

This strain of mice would be good candidates for experimentation in that the 
test for telomeric length at senescence would be easily accomplished and 
since the specific pathologies that kill the mice have been elucidated the 
cells in the system causing death could be individually tested for telomeric 
length post mortem.

>>Possibly, but no definitive study has been done to determine whether 
>>telomeric shortening is a causative factor in the death of mice.  The long 
>>telomeres of of mus musculus, the telomerase knock-out mice studied by Dr. 
>>C.Greider and the fact that mouse cells do not experience telomeric related 
>>senescence do suggest a different progression of cellular development 
>So what are you saying?

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