FWD>RE>FWD>RE>Premature Age

Mike West mwest at geron.com
Thu Apr 11 17:45:10 EST 1996


Mail*Link( SMTP               FWD>RE>FWD>RE>Premature Ageing


>Recently, U.T. Southwestern published in EMBO J evidence of causality,
>extending the telomereres of cells increased their replicative capacity as
you
>would predict.  

I have not yet seen this paper, although I have heard some of this
data before (is it out yet?, could you summarize it for us?).

They reported that extending the telomere length in mortal hybrids of normal
skin fibroblasts and the reversible immortal cell line IDH4 (the hybrid being
mortal and losing telomeres with cell division) increased the replicative
lifespan of the cells.  This is the only way yet thought of to test the
telomere hypothesis in regard to telomere loss causing cell senescence and the
results were positive.  The flip side of the coin, does inhibiting telomerase
in an immortal cell lead to telomere loss and a delayed cell death, has
already been demonstrated and published in human cells (Science 269:
1236-1241), and previously in tetrahymena and yeast.

This is very interesting but, as I am sure you know, there is still
some controversy over whether replicative senescence (the Hayflick
limit) truly reflects in-vivo aging.

>Yes, but I would suggest that there is growing evidence that senescent cells
are an increasing percentage of the cells in various tissues as a function of
age, and studies of the altered gene expression of senescent cells suggest
that these cells could have a dominant effect on age-related changes in
tissue, (e.g. the marked elevation of collagenase activity in senescent
fibroblasts could result in the observed age-related loss of dermal collagen
with age (Arch Dermatol. 130: 87-95).

The pictures I have seen suggest that less than 10% of aged skin cells
stain positive for beta-gal. I think this is fairly recent data, and I
have not seen the published papers on this subject. Nevertheless, much
of aging physiology is difficult to explain by  loss of function in a
minority of cells. For example, changes in cardiac contractility,
vascular reactivity, pulmonary compliance etc... appear fairly
extensive. In addition, many organs can tolerate loss of a
considerable fraction of cells without gross physiologic consequences
(think of a unilateral nephrectomy: 50% cell loss without much
immediate effects. 

I agree that the age-dependent loss of myocardial function probably reflects
muscle loss by vascular insufficiency or loss from other causes than cell
senescence since the myocardium is postmitotic in the adult and has no stem
cells.  I doubt that anyone would suggest that all pathology is directly
linked to cell senescence.  But one could argue that loss of myocardium
through ischemia is indirectly caused by atherosclerosis, which may in turn be
(in part) caused by the senescence of the endothelium.  This is actually an
interesting possibility since telomeres are observed to shorten with age in
the intima, and particularly in vessels where atherosclerosis is observed. 
Also, the role of endothelial injury in the early stages of athero is now well
accepted, and accelerated cell turnover of endothelial cells is seen in
association with the diseased regions.  In addition, changes in gene
expression of senescent endothelial cells (such as increased ICAM-1) have been
reported that are consistent with the cells playing a role in pathogenesis. 
In regard to other tissues, such as vascular compliance and changes in
pulmonary function, the alterations in gene expression with cell senescence
are frequently just the types of changes that could play a role in these
disorders.  For instance, in senile emphysema (and aneurysms), the culprit is
thought to be elastolytic proteases, and these are markedy increased in
senescent cells.


Well, yes and know: I agree that a senescent cell may be a 'sick'
cell. But many of the 'aging' diseases you mention are not simply a
reflection of advanced age. Take atherosclerosis, the #1 killer in
developed countries: Atherosclerosis is almost unheard of in non-human
mammals in the wild, yet they age and 'die of old age'. Similarly,
human tribes that have a drastically different diet (no NaCl, high
KCl, high melatonin -  just kidding) have a low incidence of
atherosclerosis, yet... they still die at an advanced age. As
mentioned in my previous post, some autopsies in older people do not
detect atherosclerosis or significant pathology. I believe, as you
probably do, that there is more to human aging than an accumulation of
diseases. I wish I knew, however, what this 'more' is !
BTW, what is AMD ?

Primates, such as rhesus are observed to age in a manner very analogous to
humans, e.g. athero, alzheimers, etc.  In regard to humans, in speaking with
pathologists, I'll give the example of Tom Norwood in Seattle, a card carrying
pathologist and gerontologist, he has represented to me that out of hundreds
of autopsies, he has bascially never seen an elderly person in the U.S. that
didn't have atherosclerosis somewhere in their vascular tree.  Yes, maybe
alterations in diet may impact the disease progression, but it is hard to
maintain that in the U.S. that has one of the best records for nutrition in
the world, that all of our citizens are abnormal in regard to an atherogenic
diet.  But the point was really to suggest that in framing these basic (almost
philosophical) questions about what is aging and what is disease, maybe it is
helpful in part to recognize that there are some age-related diseases that
occur in virtually everone with age, such as athero, AMD (Age-related macular
degeneration), osteoporosis, etc.  Maybe a focus on these diseases and their
etiology may provide valuable insight into the relationship between aging and
disease.
-MWest





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