Reversing Human Aging
obogler at ucsd.edu
Mon Jul 29 10:47:54 EST 1996
> First: telomere shortening does not (even theoretically) "cause" aging.
> Rather it times the onset and progression of aging in cells, ultimately
> resulting in the myriad of disease that we collectively associate with
> (and sometimes define as) aging.
That's a the crux: what is a basic fact to you, is a huge assumption to me - namely that
cellular senescence causes ageing. Yes, there is a positive correlation with the number
of senescent cells that are found in people with increasing age, but that is not
evidence of causation.
> The "causes" of aging are the usual
> suspects: free radicals, spontaneous isomerization, and so forth, as well
> as the subsequent damage they cause. Telomere shortening alters gene
> expression ("SGE" or senescent gene expression) by limiting a cell's
> ability to maintain homeostasis and fulfill its normal physiologic role
> vis a vis other cells.
So now you have me confused - is ageing accumulated damage (nothing to do with
telomeres) or is it cellular senescence (you implicate telomeres)?
Or is it, conveniently both? Are you saying that senescent cells can no longer repair
themselves from stochastic damage because they are senescent, and that causes ageing? If
yes, I must remind you that many non-dividing cells do just fine for 100 years at times,
without division - eg. the neurons and muscles you mention in the next paragraph.
> Second: many normal cells do not divide (postnatally) and therefore do
> not show telomere shortening, senescent gene expression, or direct cell
> senescence. Typical cells in this category include neurons (but not the
> glia cells which make up 90% of the nervous system by cell numbers) ...
As I am glial biologist, I'll restrict my comments to this system. One has to
distinguish between post-mitotic cells (which can't divide under any circumstance - most
neurons) and non-dividing cells. Astrocytes and oligodendrocytes fall into this category
after birth, as they do not divide except in pathological situations. (I can quote
references if you like). Therefore, if they show age related damage as you state they do
so in a way that has nothing to do with telomere length. The telomere theory, which
proposes clonal senescence driven by the clock of telomere shortening, does demand a
steady turn over of cells.
> ... In both cases,
> non-aging cells are the "innocent bystanders" to the pathology of cells
> which do age. It is hard to believe how people STILL confuse cell
> division with aging pathology and try to cite neurons and muscle cells as
> evidence against the telomere theory of aging when their very lack of
> *direct* aging changes supports the theory.
Is that really true - are there no direct ageing changes in neurons at all? Are you
suggesting that all the changes are due to glial cells? As above, they aren't dividing
either, though, when compared to say fibroblasts, intestinal mucosa, blood cells etc.
> Third: we can *probably* find a therapeutic window between aging and
> cancer. The approach would be to first use a TI (telomerase inhibitor) to
> force senescence (and death) of cancer cells, THEN proceed to telomerase
> activation in remaining cells. If we reconstitute youthful immune
> function (aged lymphocytes have shorter telomeres), we may enable the
> immune system to more effectively recognize and more efficiently kill
> remaining early clonal populations of cancer cells whose telomeres were
> still sufficiently long to survive initial TI therapy. Theory...
Now you equate cellular senescence with death - I thought we were all clear that
senescence is not death (perhaps that's why death is in a bracket!).
That the TI therapy is selective for cancer cells is rendered unlikely by the likelihood
that immortal stem cells in the body (eg germ cells, intestinal crypt cells, blood cell
stem cells etc.) also use telomerase.
Then you suggest that switching on telomerase in other cells isn't going to rescue the
recently senescent cancer cells, but is also not going to make other cells immortal.
Your therapeutic window seems about as convincing as that currently employed in classic
> Fourth: is it too early to speculate? Not in my mind: clearly others
> disagree, stating that the book should be banned (seriously)
I would *never* say that
I must agree here.
My own feeling is that: 1) the general public is capable
> (on the average) of drawing its own conclusions,
As judged by the huge consuption of melatonin currently in vogue, or cigarettes, say?
You promise immortality and people will do anything.
and that 2) the social
> implications of altering the healthy human lifespan will be so profound
> that early discussion is imperative.
Discussion, yes. But the title of your book wasn't even graced by a question mark! The
promise of immortality just around the corner does not constitute discussion. Your title
even suggests that you can reverse ageing! Hmm, what could the motive have been?
> Fifth: telomere shortening does NOT merely correlate with cell aging, but
> is causal. This was true until three years ago and the data was published
> only this spring (March 15, 1996 in EMB0 by Jerry Shay, Woody Wright, et
> al) when we found that lengthening the telomere pushed back the Hayflick
> limit correspondingly. Causing telomere shortening the "cause" of
> cellular senescence is still sloppy: see point one above.
The article came out April 1st in EMBO (vol15, pp1734-1741), and is not as elegant a
demonstration of the effect as you imply. They lengthened telomeres in an *immortal*
cell line (large T) by using any of a number of sequence unrelated oligonucleotide
treatments that they can not explain - described as an "indirect mechanism. Then they
fused these cells with mortal cells and showed an increased Hayflick limit. It is
preliminary evidence that is rather weak - the assumptions are twofold: that the
oligonucleotide treatment acted *only* to alter the telomere length (unlikely - see vast
literature on unexplained oligo effects), and that in the fusions, the only thing that
mattered was the telomeres.
Furthermore the authors fail to explain how the long telomeres they introduce manage to
make the cells ignore the short telomeres of the cells original chromosomes! So far, the
theory has stated that if even one telomere falls below threshold that the cell stops
dividing. This paper is therefore *far* from conclusive proof that telomere length
regulates sensecence, let alone that it regulates ageing. The field awaits the forced
expression of the telomerase holoenzyme in normal cells.
I look forward to a continued discussion on this interesting area.
Oliver Bogler, Ph.D.
obogler at ucsd.edu
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