Telomerase & Aging

Don Ashley dashley at TENET.EDU
Sun Apr 14 22:18:07 EST 1996

Mike West founded Geron. 1987 <$100,000.  1996 >$70 million.

On Thu, 11 Apr 1996, Jean-Pierre Issa wrote:

> mwest at ("Mike West") wrote:
> >                      Subject:                              Time:  1:22 PM
> >  OFFICE MEMO         Telomerase & Aging                    Date:  4/10/96
> What office? :) If you don't mind me asking, do you work at Geron ? 
> >
> >In response to Dr. Issa's recent concerns about the telomere-aging connection
> >I offer the following thoughts:
> No need to be formal: This is Usenet. Call me Jean-Pierre.
> >Comment:  The striking thing about telomerase expression which is thought to
> >make cells immortal, is that it is NOT expressed by many cell types.  It is
> >clearly abundant in the reproductive cells which obviously allows them to make
> >the species immortal, and abnormally in malignant cells likewise conferring
> >replicative immortality to them, however, it is conspicuously absent in most
> >somatic cells and tissues.  It appears to be true that there is a low (<100X
> >less activity) of telomerase in candidate hematapoietic stem cells, but the
> >biology there is not clear and all the evidence suggests that telomeres are
> >being lost with age in vivo in these cells and when the candidate cells are
> >passaged in vitro as well.  So clearly the telomerase that is there is not
> >repairing telomere loss.  The only normal cells that are known to have stable
> >telomeres are the reproductive cells.  (Keratinocyte stem cells may also have
> >low levels, but again, they are not maintaining telomere length)
> I do not have the paper in front of me, but I thought that peripheral
> blood lymphocytes had about 10% of the telomerase activity seen in
> some tumors. Also, I heard that stem cells from several different
> organs have easily detectable telomerase activity. (Certainly, all
> these cells have abundant telomere RNA as recently shown by Greider et
> al. and others).
> Stem cells, to my knowledge, cannot be passaged in-vitro (the
> committed progeny quickly takes over the cultures). Thus, I am not
> sure that stem cells still lose telomere length with age (correct me
> if I am wrong...).
> Still, why do aging tissues lose telomere length if stem cells express
> telomerase ? Obviously, I don't know. Since 'committed' cells lose
> telomerase activity, subsequent generations derived from these cells
> will have shorter telomeres.Is it possible then that the loss of
> telomere length in aging tissues reflects a changing ratio of stem
> cells-early progenitors to late progenitors-differentiated cells ?
> have I confused everybody ?
> (snip)
> >Comment:  This isn't really true.  First, few would suggest that all of the
> >cells in a given tissue would need to reach critical telomere length and the
> >Hayflick limit for pathological consequences too occur.  In the immune system,
> >for example, perhaps only <10% of lymphocytes reaching senescence could impair
> >a robust response to a pathogen and lead to a fatal infection.  Similar logic
> >would apply to other tissues.
> Yes and no... see my other post in this thread.
> > In the case of the immune system, lymphocytes
> >are observed to reach the Hayflick limit at about 5-7 kbp terminal restriction
> >fragment length which is interpreted as a "critical length" where perhaps one
> >or more telomeres actually have lost repeats and trigger a cell cycle
> >checkpoint arrest.  If you look at the peripheral blood lymphocytes of aging
> >people, you see the TRF length drops to about 5 kbp (the Hayflick limit) in
> >centenarians (Am. J. Hum. Genetics 52: 661).  Similar results have been
> >reported for vascular intima, Hematapoietic stem cells (PNAS 91: 9857) etc.
> Please don't take my next remarks in a negative way: They are solely
> for discussion purposes - I do believe telomeres are important !
> Nevertheless, the length of telomeres in peripheral blood lymphocytes
> is not directly relevant to aging: These cells, for the most part, do
> not divide... It may be relevant to gene expression changes and/or
> genetic instability, but that remains to be demonstrated.
> As mentioned above, what is critical to in vivo senescence / loss of
> replicative ability is telomere length in stem cells. the PNAS paper
> you reference is great. Nonetheless, to my knowledge, most stem cell
> biologists believe that the 'true' stem cell is not necessarily the
> CD34+ CD38lo fraction they studied. Primitive hematopoietic cells yes,
> stem cells, probably not. Furthermore, as mentioned above, the 'stem
> cell' is thought to be an essentially dormant cell. In culture, it
> quickly is taken over by committed cells. Before you ask, I believe
> the 'true' stem cell is this very rare cell that is required for
> regenerating a lethally irradiated bone marrow, and that is (perhaps)
> immortal.
> the PNAS paper, however makes several important points relevant to
> this discussion: In the same individual, telomere length is greater in
> primitive hematopoietic cells than in differentiated cells. It is
> therefore probably even greater in the 'true' stem cell... See above
> for implications of this finding. Furthermore, in the paper, there
> seems to be very little difference in telomere length between the bone
> marrow of a 19 yr old, and the bone marrow of a 59 yr old... this begs
> the question: is telomere length simply a reflection of differentiated
> status rather than age ? (again, see above).
> (Snip)
> > But, to argue against the telomere
> >hypothesis for mammalian cells based on the fact that paramecia clonal
> >senescence in the absence of conjugation is probably a stretch, don't you
> >think?
> Absolutely.
> Still, as I understand it, the relation between telomere length and
> age is also confusing in rodents (am I wrong ?). Doesn't this trouble
> you ? Anyone knows of a telomere length / aging connection in
> primates?
> (Snip)
> >But I assure you, much research into telomere length and aging is
> >going on !
> >>Comment:  A lot, especially in the telomerase-cancer connection.
> More research is good ! But, let's not get started on the
> telomerase-cancer connection ! :)
> Thank you for a good discussion.
> Jean-Pierre Issa

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