mwest at geron.com ("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
