In article <35EDE86E.10F2 at netcom.ca>, tmatth at netcom.ca says...
>> >To be precise, are you saying that Rita Effros has found that the
>> >*majority* of memory T-cells are now longer able to divide and produce
>> >more such T-cells? Do you have a reference for this?
>>>> The cite for this study is Am J. Hum.Gen. 62-5 May 98;(1003-1007). A
>> study addressing your question would be Effros RB, Pawlee G, Immunology
>> Today, 1997, 18;(450-454) where she researches the Hayflick limit and
>>Unfortunately, the first has no abstract on medline and the second is so
>brief that it is useless. I will have to consult the articles themselves
>sometime to see precisely what they found.
Tom, I'll try to get my copy scanned and send it to you.
>> Yes the "memory" T-cells showed senescent characteristics including the
>> inability to replicate and the short telomeres associated with senescence.
>>But as the following recent Effros abstract shows, you have gone too far
>if you imply that it is *proven* that the lowered immumity of the aged
>is *caused* by T-cell senescence. (CAPS mine, for emphasis)
You are correct that this is just a logical hypothesis based on the evidence
so far described in the research. It will be several more years until tests
to verify the validity of this "causal" relationship can be completed.
>Dev Comp Immunol 1997 Nov;21(6):471-478
>Loss of CD28 expression on T lymphocytes: a marker of replicative
>Department of Pathology and Laboratory Medicine, UCLA School of Medicine
>>The CD28 molecule, a disulfide-linked homodimer expressed on peripheral
>T cells and thymocytes, mediates an essential costimulatory signal
>following engagement of the T cell receptor (TCR). Increased proportions
>of CD28- T cells have been observed during aging and in situations of
>chronic immune stimulation, but the origin and functional
>characteristics of these cells have been unclear. T cells which reach
>replicative senescence IN CULTURE after multiple rounds of cell division
>have shortened telomeres, respond poorly to stress stimuli, and no
>longer express CD28, suggesting that CD28- T cells observed in vivo MAY
>be the progeny of memory cells which have been repeatedly stimulated.
>This review describes the features of T cell replicative senescence,
>presents several possible mechanisms for the generation of senescent T
>cells in vivo, and proposes that REPLICATIVE SENESCENCE MAY EXPLAIN
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.
>> Specifically a cell surface molecule CD28 is not expressed in senescent
>> T-cells. One proposed function of CD28 is the induction of the enzyme
>> telomerase, (Weng et al. J. Exp. Med. 1996, 183:2472-2479). Lacking the
>> expression of telomerase the telomeres in these T-cells shortened and the
>> cells entered senescence.
>>>> The implications being that re-activating telomerase prior to critical
>> telomeric shortening can avoid senescence altogether and maintain
>> of the immune system.
>>Sorry, but I still see no clear evidence that cell senescence is
>responsible for the decline of the immune systems of normal aged,
There is very clear evidence supporting this causal relationship and no solid
arguments against it but as we agreed earlier, additional research needs to
be completed to "prove" the theory.
>although I do agree it seems reasonable that this is the case with AIDS
>patients or others with life-long overly stimulated immune systems
Your right on point here. The telomeric theory of aging argues that an
individuals developmental history is determinant of which cellular system of
the body will "age" fastest.
Someone whos' immunological system has been stressed to the the point of
telomerase being unable to maintain telomeric length in the T cells may
experience a decline or "aging" of their immunological system. 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.
>> >> Tahara H, et al, at Hiroshima University School of Medicine, Japan,
>> >> demonstrated that "a significant proportion of WRN, (Werner's
>> >> cell strains showed drastic shortening or lengthening of telomere
>> >> during cell passages compared with normal cell strains" This confirms
>> >> earlier studies that Werner's syndrome and the childhood aging disease
>> >> progeria result from errors in the system(s) that maintain telomeric >>
>>> >But it doesn't say anything about whether these diseases are related to
>> >normal aging.
>>> 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
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 about!
By the way, just how do the oxidative stress theories account for these
Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.