Mike,
You make many excellent points. I agree that the age-related emergence
of an 'abnormal' population of cells that secretes proteases etc...
could be a major factor in in-vivo aging. I was not aware, however,
that cells that which reached replicative senescence could display
such gain of function - I always thought of these cells as essentially
quiescent. I stand corrected (and educated...). You have to admit,
though, that data is lacking to link telomere shortening with such
gene 'activation'.
I also do not believe that the issue of telomere shortening in any
stem cell (lung, colon, hematopoietic...) has been resolved. This is
obviously the subject of further research rather than further
discussion...
Finally, I would like to hear your thoughts on the implications of
telomerase activity in mouse cells: Mice still senesce in-vivo and
die... I am not sure that the cancer incidence in non-inbred mice is
much higher than that seen in humans... Doesn't this argue against the
telomere loss/aging connection and the telomerase/cancer connection ?
Jean-Pierre Issa
mwest at geron.com ("Mike West") wrote:
>>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.
>(Forwarded from another thread).
>Mouse cells are known to immortalize at a relatively high frequency, and
>telomerase is detectable in adult mouse tissues such as liver and kidney,
>therefore, telomerase may not be as tightly regulated in mice as in humans,
>consistent with the ability of humans to live far longer without cancer, so
>you might not expect to see the replicative senescence in mice, and related
>age-related pathology, that you see in humans.
