In article <35EF706B.5366 at netcom.ca>, tmatth at netcom.ca says...
>>>>>> The cite for this study is Am J. Hum.Gen. 62-5 May 98;(1003-1007). A
>> better study addressing your question would be Effros RB, Pawlee G,
>> Immunology Today, 1997, 18;(450-454) where she researches the Hayflick
>> limit and immune exhaustion.
>>>> Tom, I'll try to get my copy scanned and send it to you.
>>No need. Aubrey sent me a note telling me that the AJHG reference full
>text was available online FREE!
>It is at:
>>I just read it. It is a great article. And now I have to agree that
>there is *very* strong evidence that replicative senescence is a major
>factor in the reduced immunocompetence of many elderly people. Based on
>the wealth of detail in the article, I have several thoughts about how
>one might aleviate this problem. BTW, T-cells senesce even though they
>*do* express telomerase -- they just don't seem to know how to use it
Yes, the T cells appear to replicate at a faster rate than the telomerase can
replace the lost telomeres. Because telomerase is present they don't lose as
much telomeric length as normal repicating cells but the telomeres none the
less shorten with each replication.
Just conjecturing but it seems if the infection is fought off prior to
critical telomeric shortening then the T cells would most likely resume their
normal rate of replication and the telomerase would be able to restore
But if the infection were severe then some of the T cells would reach
critical telomeric length and enter senesence, thus producing fewer cells to
fight this or subsequent infections. Add to this Dr. Effros results that
these senescent T cells don't initiate apoptosis and possibly prevent their
replacement with more functional T cells and we have a good theory for
>> Her subsequent work has gone on to describe how replicative senescence can
>> cause immune exhaustion and that "the proportion of replicative senescent
>> T cells within individual subjects may serve as a measure of'immunological
>> age'." It's exciting work that I'll be following closely.
>>Yes, I will too. Immune decline has always been a major concern of mine
>and I do everything that I can to keep my immune system in peak shape.
>As a result, I am never sick. Now I must examine carefully what I am
>doing to make sure that it is not causing any overstimulation and
>overproliferation of T-cells, thereby trading off current and continued
>competence for earlier immunological exhaustion.
I don't think you have to be overly worried on this count. Telomerase
apparently maintains the replicative capacity of the T cells under most
normal conditions and the wide variance in immunological functioning in the
elderly seems to support this. It appears that the decline is only apparent
when the individual has encountered some severe infection that stressed the T
cells beyond their replicative capacity as described by Dr. Effros. And, of
course, by aging itself, (see below).
>My reading of the Effros paper was that even though T-cells make
>telomerase, it did not seem to do any good since there hayflick limit
>was only 25-40 doublings anyway.
The problem here isn't with telomerase itself but the expression of the cd 28
molecule. I don't know if the gene expressing cd 28 has been identified but
its expression is apparently necessary for telomerase activation. We're back
to the question of what mechanism controls age related expression of genes.
Cd 28 is not expressed in senescent cells. But did senescence, (as a result
of critical telomeric shortening), stop the expression of the gene or did the
cessation of the expression of the gene cause the telomeric shortening
leading to senescence? Chicken or egg?
>Also, the article pointed out that the
>accumulation of senescent memory cell which are also resisted to
>apoptosis is a major problem since if they would only die off, they
>could be replaced by new younger ones (generated from stem cells as I
>understand it). My question to this is why won't either donations of
>blood or development of a method to process the blood of the aged and
>remove the senescent cells help to solve this problem?
Excellent questions! But aren't you being a bit presumptuous:-) Imagine
moving from theory through basic research to designing specific therapies!
Just what's come over you Tom? Are you trying to live forever;-).
But seriously, these strategies are well worth checking out. I would also
include the introduction of hTERT, the catalytic protein subunit of
telomerase, into these senescent T cells. This would activate telomerase
production outside genetic control and possibly restore the replicative
capability of the cells. Alternatively, if the gene coding for cd 28 could
be re-activated in these senescent T cells then they could possibly produce
their own telomerase.
>> Someone else who has a poor diet, high blood pressure and is overweight
>> may stress the cardio-vascular system to a greater degree than the
>> immunological system. Whichever, (replicative), cellular system is
>> stressed the most and has has a high cellular turnover will experience
>> telomeric shortening and an increased proportion of senescent cells to a
>> greater degree than other less stressed systems. This is a likely cause of
>> some age-related diseases.
>>The kind of system-differential aging is, of course, the norm, but it
>does not imply that cell senescence is involved in any other system.
But it is a good starting point. If therapies can be designed to restore
replicative capacity in senescent cells or to avoid senescence altogether
then we might be able to intervene in some of the major causes of death in
the U.S. like heart disease and immunological failure, (not to mention the
work being done on cancer).
>> It fully conforms to the telomeric theory of aging that suggests that if a
>> person were born with shortened telomeres their cells would senesce faster
>> and they would exhibit the signs of aging.
>>>> >Just as correlation is not cause, so too "fully conforming" is not proof
>> >or verification.
>>>> Every piece of the puzzle moves us a little closer to understanding aging.
>> If it didn't conform to the theory then we'd have something to worry >>
>>>> By the way, just how do the oxidative stress theories account for these
>>Tut, tut Tom! You can't win your arguments that way :)
I do apologize! I was being a bit facetious:-)
>To be very clear, oxidative stress need have no relevance to progeria
>and Werner's for it to still be a major cause of death in normal aging.
You are right. There is still the question of the aging of both individual
and non-replicating cells.
Theres still a long way to go but the research is on the right track!
Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.