Current Research Into Telomeres III

Tom Matthews tmatth at netcom.ca
Wed Sep 2 19:53:02 EST 1998


Excelife wrote:
> 
> In article <35ECC85A.513B at netcom.ca>, tmatth at netcom.ca says...
> >
> >Excelife wrote:
> >
> >> Dr R. Effros at U.C.L.A. is researching the effects of telomeric >>
> shortening on the T-Cells in the immunological systems of the elderly.   >>
> Her observations include the dominance of senescent "memory" T-cells in >>
> aged individuals
> >
> >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 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.

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.
 
> >> which may "prevent renewal of the T-cell pool with more functional
> >>T-cells".  The implications being that the restoration of replicative
> >>capacity in those T-cells that are approaching senescence could have the
> >>effect of restoring functioning of some parts of the immunological system
> >>in the elderly.
> 
> >Or since now you say "are approaching senescence" do you mean that she
> >found that the T-cells had reduced replicative ability in older people?
> >(which would not necessarily be related to any telomere shortening).
> 
> 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)

Dev Comp Immunol 1997 Nov;21(6):471-478 
Loss of CD28 expression on T lymphocytes: a marker of replicative
senescence.
Effros RB
Department of Pathology and Laboratory Medicine, UCLA School of Medicine
90095-1732, USA. 

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
IMMUNE EXHAUSTION.  

> 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 functioning
> 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,
although I do agree it seems reasonable that this is the case with AIDS
patients or others with life-long overly stimulated immune systems
 
> >> Tahara H, et al, at Hiroshima University School of Medicine, Japan,
> >> demonstrated that "a significant proportion of WRN, (Werner's syndrome),
> >> cell strains showed drastic shortening or lengthening of telomere lengths
> >> 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 >>
> length.

> >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
or verification.

 
--Tom 
Tom Matthews
 
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