Subject: Time: 1:22 PM
OFFICE MEMO Telomerase & Aging Date: 4/10/96
In response to Dr. Issa's recent concerns about the telomere-aging connection
I offer the following thoughts:
His comments were:
There are many more good labs studying the telomere/aging connection
than you imply. Unfortunately, there are many holes in the
(fascinating) speculation that telomere loss 'causes' aging. Some that
come to mind:
1- Many normal cells (specially stem cells) express telomerase and
thus can repair/replace any significant telomere loss.
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)
2- Cells from elderly individuals have not yet reached a 'critical'
telomere shortening (which happens if you culture these cells to
senescence.
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. 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.
3- Dr. Blackburn (one of the telomere pioneers) has shown that in
Tetrahymena (I think, but I may be wrong), telomeres shorten until
middle-age, THEN they start elongating again! At the end of these
organisms' life span, their telomeres are nearly the same length as
when they are born. (PNAS, 1994).
Actually paramecia. Yes, maybe the senescence you see in paramecia is caused
by another mechanism (though some argue that Dr. Blackburn's data actually
support a role for telomere loss in this peculiar type of senescence). It is
certainly true that telomere loss appears to play no role in the limited
budding capacity of maternal yeast. 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?
Thus, the telomere loss - aging connection remains somewhat
speculative. It is possible that even a small degree of telomere
shortening causes significant changes in gene expression elsewhere in
the genome, thus linking it to aging, but I do not think this has been
firmly demonstrated yet.
Comment: I think everyone would agree that the hypothesis is still "young"
but the amazing thing to me is the breadth of data pouring in to support it
(such as the recent EMBO J paper showing a direct causal connection e.g. lengthening
telomeres increases the replicative lifespan of cells) and the predictive
power of the theory.
But I assure you, much research into telomere length and aging is
going on !
Comment: A lot, especially in the telomerase-cancer connection.
-MWest
Regards,
Jean-Pierre Issa, MD
Johns Hopkins Oncology Center
