Identify Author?

Tom Matthews tmatth at netcom.ca
Sun Aug 30 21:06:55 EST 1998


Excelife wrote:
> 
> I downloaded the following paper from the net and when I got around to
> reading it I couldn't identify its source.  Does any one know who wrote it,
> its cite or its URL?
> 
> It's an excellent article and I would like to credit its creator.

Yes, it is an excellent article. I learn or confirmed a lot by reading
it. It is also full of exciting new hypotheses. However, like so many
that I read on telomeres, it makes some unproven assumptions to push its
point of view. Here are some comments on a few selected parts:

> (The loss of generalized growth factors and subsequent appearance of
> senescent cells resulting in the outward manifestation of aging and
> increased risk of cancer)

Yes, such accumulization of scenescent cells would certainly cause some
"aging" decline if anyone lived long enough for that to take place. But
I have not yet seen any good evidence that this relates to "the outward
manifestation of aging and increased risk of cancer" that we currently
see in those of advanced chronological age. 

> Why is this important to the study of aging? Cell Function As an individual
> ages the number of cells stopped by P53, with short telomeres in G1 (called
> "senescent cells") is found to increase in most replicative tissue.

How many cells of which tissues of a healthy 100 year old are senescent?
Is the number significant for the functionality of those tissues? Are
there in fact any senescent cells at all in such a person?
How about the same questions for a very un-healthy, near death 100 year
old?

> Senescent cells often develop their own phenotype which is different
> than that of earlier passages. Senescent cells adhere less rigorously to
> their differentiated phenotype then do dividing or quiescent cells. As the
> percentage of these senescent cells increase, it can be predicted that the
> functionality of the tissue they are part will deteriorate or at least
> change. 

Is this not also true for aged cells with are not technically senescent?
And thus this well known effect of aging is quite independent of
telomere shortening and scenescence.

> Many age associated changes in tissue structure can be attributed
> to this phenomena of cellular senescence.

And to many, many other effects of cell aging, as well, I understand.
 
>   Another characteristic of senescent cells is the increased rate of free
> radical production which is also a hallmark of old tissue. Whether the free
> radicals are the product of senescent cells or some other change that occurs
> during aging is not known. It is interesting to note that in cells undergoing
> apoptosis the rate of free radical production increases and the cells lose
> contact with their extra cellular environment. Could senescence be the result
> of failed or stalled apoptosis?

Here, at least, the author admits that "aging" and "old tissue" have
similar effects to senescent cells without the cells involved
necessarily being senescent.
 
> Function of Senescent cells
> 
>  The senescent phenotype has no obvious purpose in the organization of
> tissue.  The senescent phenotype is generally characteristic of the tissue
> type but less differentiated. For example; senescent fibroblasts produce
> different more embryonic isotypes of collagen than proliferating cells.
> Senescent cells also produce more free radicals than nonsenescent cells.
> This leads one to assume that senescence represents an aberrant condition
> which a cell is not intended to remain in for any length of time.
                     ^^^^^^^^^^^
Since "intension" is meaningless in this context, no such assumption
should be entertained.

> How do senescent cells build up?
> 
> Four possibilities:
> 
>      1. Stem cells produce daughters with shorter telomeres so that they
> reach senescence before they are sloughed off.(This assumes that stem
> cells are losing telomeric DNA)
>      2. Stem cells produce fewer daughters to proliferate so that each
> daughtes must divide more times to maintain the population in the
> tissue..thus cells are more prone to reach senescence before being removed.
>      3. Removal of old (more prone to senescence) cells is somehow
> impaired
>      4. Stem cells are removed or inactivated by some undiscovered
> means, perhaps autoimmune attack? (leading to condition #1)

It seems to me that this analysis only applies to those tissue which
have stem cells normally expressing telomerase. I thought the majority
of body cell types did not have any such progenitor cells remaing after
embryogenesis was complete.

> Relationship to aging
> 
> Is the rate of appearance of senescent cells constant with age so that
> we gradually build up a sizable population of senescent cells? I am
> conducting a literature search to determine if any research has been done on
> the subject.

This is key, IMO. I hope that the author provides us with his search
results.

> Is the rate of appearance subject to central control or is it
> the result of accumulation of random wear and tear damage?

Another key question.

> Since we know
> that the absolute number of senescent cells increases as
> we age

Do we? We know that the doubling potential of cells from chronologically
older individuals is lower, but do we know anything much at all about
their percentage of senescent cells?

> and we know that there are factors which influence stem cell
> proliferation, is there a correlation between the appearance of senescent
> cells and the amount of the various poetic factors. Is there a cofactor which
> could influence stem cell proliferation such as a generalized growth factor.
> Studies have revealed that the concentration of many circulating hormones
> which may affect cell proliferation, change as we age. Hormones like, growth
> hormone, many of the steroids, melatonin, cytokines, cortico-steroids and
> peptide hormones.

These are all excellent questions for those cells type which have stem
cells. Again I am confused at how this affect dividing cell types, in
general.

> In order to determine whether these factors have any
> effect on senescent cell appearance I propose to conduct several experiments
> which will determine:
> 
>      1 If telomerase is modulated to any extent by factors which are
> known to change over time in correlation to the appearance of senescent
> cells. Materials like melatonin, steroid hormones, GH ,IGF, hematopoietic
> factors and other growth related materials .
>      2. If the senescent phenotype can be induced by changes other than
> short telomeres. Changes in the availability of energy in the cell as
> modulated by hormones (thyroid for example.)
>      3. Test protein turnover and overall profile in senescent cells as
> compared to dividing cells.
>      4. Assay senescent cells for indications of an attempt to initiate
> apoptosis, like relocation of cytC from mitochondria, amount of bcl-2, DNA
> laddering and acridine orange staining.

Great experiments! We certainly need more money in anti-aging research.

To most of the rest which I have omitted, I only have one word: WOW!
Very exciting stuff!

--Tom 
Tom Matthews
 
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