mwest at geron.com ("Mike West") wrote:
(Snip)
About Telomeres and aging
> This is correlative evidence.
>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?).
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.
>>In regard to evidence that cell senescence is occuring in vivo, the evidence
>is seen in many ways. Cells cultured in primary cultures from old people's
>tissues contain many large nondividing cells that have many markers of cell
>senescence (morphological, gene tag markers, enzyme markers such as beta gal,
>and lastly telomere length) For instance in the case of skin, dermal
>fibroblasts from aged donors turn blue in X-gal as do cells at the Hayflick
>limit and telomere length has been shown to shorten in the skin with age.
>When the beta-gal assay was performed on skin sections in situ, blue cells
>were shown to be present only in donors over the age of 30 or so, and only a
>percentage (probably less that 50%) were seen to show senescent markers even
>in very old donors. But this is what many would expect, that is, that cell
>senescence in a minority of cells can have a dominant effect on tissue
>metabolism.
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.
>Personally, I like to say that no one dies of old age, but rather, we die
>because of disease. But that isn't to say that disease and aging aren't
>sometimes the same thing. If we defined age-related pathology not as the many
>pathologies that simply increase in frequency with age, but as pathologies
>that virtually everone sees manifestations of in advanced age (such as
>atherosclerosis, AMD, osteoporosis, etc, then maybe, these pathologies are
>actually the manifestation of aging in that given tissue (i.e. sometimes a
>senescent cell may be a "sick" cell.
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 ?
