Telomerase & Aging

Don Ashley dashley at TENET.EDU
Thu Apr 11 03:50:19 EST 1996

This is a request for a source and summary of the EMBO J paper cited 
below showing the relationship of telomere length to replicative lifespan 
of cells.

Thanks....Don Ashley, Houston

On 10 Apr 1996, Mike West wrote:

>                       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.

Please summarize and give source of the EMBO J paper.....Don

> 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

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