Telomeric Theory - Related Research - Genes & Aging

Excelife excelife at earthlink.net
Sun Oct 4 03:11:59 EST 1998


In article <3616e38e.261345775 at nntp.ix.netcom.com>, ufotruth at ix.netcom.com 
says...

>>The second most dramatic changes in genetic expression occurs at the time 
>>the cell enters senescence.  These have been discussed before and I won't 
>>bother with the details here.
>
>If the above is true then I am absolutely thrilled. Because the cells
>GERON immortalized did NOT grow old in anyway or become senescent at
>all! They stayed in a YOUNG and RAPIDLY DIVIDING state! So apparently
>by insertion of the telomerase gene,(protein subunit hTRT), you can keep 
>cells from having this dramatic age related genetic expression from 
>occurring.


This, along with the increased cellular replicative capacity, are the primary 
hypothesises of how telomeric lengthening may have a dramatic effect on human 
life span.


>>The changes that occur, over time, in the genes expressed or not expressed 
>>is what your question is about.  These changes have been noted in "older 
>>cells" in most studies I was able to find.  These would, for the most part, 
>>coincide with cells in the (latter) stages of approx 32 population 
>>doublings.  
>
>Now, I am not questioning your information but in the book I read by
>Leonard Hayflick his magic number was not 32 but 50.


I changed the above from "last" to "latter".  Senescence is induced at around 
the 32 population doubling figure but if senescence is by-passed, the cell 
can continue replicating up to the 50th population doubling, as shown by 
Hayflick. Another way of showing this is that at senescence the telomeres can 
still have 8-10 kbp remaining of their telomeric repeats but are in the 3-4 
kbp range or absent altogether when the cell enters crisis stage.

The studies mentioned above were in "older" cells, most likely senescent, but 
not yet at crisis. 



>But regardless at least we have now confirmed that cells DO INDEED age
>BEFORE they become senescent and by INSERTING the telomerase gene, (protein 
>subunit hTRT), in cells you can STOP cells from aging as they divide. 
>Actually, you can even keep them in a YOUNG and YOUTHFUL state!


No, the research has not "confirmed" this as yet.  There is a paucity of data 
one way or the other relating to late stage aging changes in dividing cells  
absent entrance into senescence.  Your conclusion, however, is accurate, as 
mentioned above, this is one of the goals of the telomeric theory of aging!



>It would be interesting if you could take some cells from the
>pituitary of a human being, let some of them age, and immortalize the
>rest of them with the telomerase gene (to keep them in a youthful
>state) and see if the telomerase positive cells produced the proper
>and needed amount of proteins verses the older cells.


This is one of the larger questions that needs to be addressed in the 
research into telomeric lengthening. The proper and appropriate expression of 
the numerous bio-chemicals, including hormones and enzymes etc.., is 
necessary for normal bodily maintenance. Exactly how telomeric lengthening 
affects or doesn't affect these processes will have a significant impact on 
the feasibility of developing therapies based on the telomeric theory of 
aging.
   

>Or even better, just immortalize an old cell and see if the level of
>these proteins increases.


The effects may vary depending on whether you are just maintaining telomeric 
length or actually lengthening the telomeres.  Time and research will tell.



>>Still, studies may show different genetic expression between young and old 
>>cells in the absence of the senescent state. (Although my brief Medline 
>>search couldn't come up with any, that is more a lack of knowing where to 
>>look rather than a lack of studies.)  This seems to be particularly true of 
>>some of the enzymes and hormones.  The production of various hormones are 
>>up regulated on an age dependant basis and the sudden onset of menopause 
>>suggest there is also an age related down regulation.
>
>Well, we know for a fact that as cells divide their dividing slows
>down and they age. We also know for a fact that cells immortalized by
>GERON stayed young and did not age in anyway. So if age related
>genetic expression causes cells to grow old then we now know for a
>fact that telomere elongation through insertion of the telomerase
>gene can PREVENT the age related genetic expression that causes cells
>to age.


That doesn't address the question.  There could very easily be some other 
portion of the genes that determines the timing of expression or 
non-expression of these various hormones and other bio-chemicals.  

It is possible that telomeric length may be determinant of this genetic 
expression through the mechanism of transcriptional silencing. Additionally, 
the decline in hormonal and other bio-chemical production may just be the 
result of cells entering senescence or being lost to apoptosis.  If these 
possibilities are, indeed, the case then telomeric lengthening may have some 
positive implications. 


 
>>The main reasons there is a lack of evidence for senescent cellular 
>>accumulation in the elderly is 1) it hasn't been looked for and 2) that up 
>>until recently it was extremely difficult to distinguish between senescent 
>>and non-senescent cells.  It was in 1995 that Dimri GP, et.al. in (Proc 
>>Natl Acad Sci U S A 1995 Sep 26;92(20):9363-7, "A biomarker that identifies 
>>senescent human cells in culture and in aging skin in vivo.), that they 
>>found a means of identifying senescent cells, and determined that there was 
>>"evidence that senescent cells may exist and accumulate with age in vivo."
>
>That is very interesting. It seems to me that further testing should
>be done to see if there is an accumulation of senescent cells with age
>in vivo. If the method of testing was not TOO expensive then perhaps
>it could be a project Lifeline Labs could undertake?


I agree that this type of research should be conducted.  This, however, 
raises the question of prioritizing the research within the telomeric theory. 
Is it more important to fund this type of research or to study how telomeric 
lengthening may avoid senescence in endothelial cells in the veins?  I will 
be going into this in more detail in the discussion section, of my posts, on 
the telomeric theory of aging.


>>Transcriptional silencing of genes, ie;blocking a gene from being 
>>expressed, and conversely un-silencing of genes is the mechanism by which 
>>genes are differentially expressed. This is true for different types of 
>>cells, in individual cells and in cell lines over age.  The telomeres have 
>>been shown to be involved in some portions of these processes.  It is yet 
>>to be determined if they are a major or a bit player and the research is 
>>continuing.
>
>It seems to me, and I might be wrong, that the answer is very clear.
>
>Normal cells lose their telomeres and age as they divide and then
>eventually become senescent. 
>
>Immortalized cells, whose telomeres have been elongated with the
>telomerase gene, stay YOUNG, don't become senescent, and do not age.
>
>It seems to me the answer is clear.
>
>Isn't it great!


I hope it is as simple as that!  But, as I mentioned above, and in several 
other posts, there are likely to be some problems encountered along the way.

It is probable that telomeric lengthening can avoid the senescent stage of 
development, in replicating cells, and all the problems associated with that 
stage but what other effects it may have in a functioning organism are yet to 
be determined.

I do believe that the research into the telomeric theory of aging can 
overcome any of the potential obstacles and given the goal, longevity, I also 
think it is well worth an extensive and co-ordinated effort!




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



  

 





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