Cells and Aging

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Sat Mar 6 11:19:04 EST 1999


Tom Mahoney wrote:

> Dr Vaziri has done some research at the Ontario Cancer Institute, that
> shows that shortened telomeres lead to dicentric chromosomes.  By
> definition that would include a disruption of the heterochromatin.  It
> is at this point that the p-16/p-53 senescence block is initiated.

It is news to me that all senescent-by-action-of-p-16/p-53 cells have
dicentric chromosomes.  If you have a specific reference, please provide it.

> I recommend the following research paper that will give a little insight
> into the process of muscle cell replication over age... Decary S, Mouly V,
> Hamida CB, Sautet A, Barbet JP, Butler-Browne GS, Hum Gene Ther 1997 Aug
> 10;8(12):1429-38

Have you seen the whole paper?  I haven't, but the abstract appears to say
that the shortening of telomeres occurs during youth (ie growth), which as
for dermal fibroblasts (cf our discussion of a few months ago) says nothing
about the rest of life.  Please clarify.

> Brittle bones can also fall under the purview of replicative senescence. 
> Kassem M, et al Osteoporos Int 7(6):514-524 provides a good example

The abstract says nothing about correlation with donor age.  Does the paper? 

> I am asking for references to research that shows a gradual decline in
> system functioning unrelated to cellular loss or senescence.

How unrelated?  For example, Decary et al above say that telomeres of
mature muscle don't shorten; clearly muscle declines.  Cristofalo et al
last year showed that fibroblast replicative capacity doesn't diminish
with age; but fibroblast wound-healing capacity slows.  These are both
papers that you brought to the group's attention yourself, so I presume
you somehow don't count them as showing a gradual decline in system
functioning unrelated to cellular loss or senescence.  Please clarify.

> cells do not turn 
> cancerous until after by-passing senescence and re-activating telomerase

What definition of "cancerous" are you using here?

> Throw in some stem and satellite cells and you have a pretty complex
> biological system.
> 
> That's one of the benefits of having a theory which can unify these various 
> processes into a an understandable framework.  By knowing that shortened 
> telomeres causes any particular cell to enter apoptosis or senescence then
> we can understand why [various things]

Tom, I think if you read your statement a few times you will see why so many
people on this group have difficulty with your style of reasoning.  The fact
that a wide-ranging theory can provide candidate mechanisms to exmplain a
lot of diverse phenomena is persuasive that the theory is correct only if
no other theory can do the same to a comparable extent.  Perhaps the thing
that grates most heavily is your persistent use of the word "logical" to
describe your reasoning, as if to imply that other, equally robust lines
of reasoning are illogical.  This is simply not the way science is done.

> Additionally the recent findings for both muscle and nerve cells suggests 
> that telomeric shortening is operational in those cells, (or at least
> their stem or precursor cells), as well.  The exact process by which this 
> shortening occurs has yet to be elucidated but the research continues.

Tom, look here.  You know perfectly well that there is a solid argument,
as well as plenty of direct evidence from papers that you yourself cite
(eg Decary et al above), that the telomere shortening of precursor cells
says nothing about the mature cells.  Why try to slide all these invalid
implications past us?  It wastes my time and others'.  I hope you will
not describe the above extrapolation as "logical".

> That this thinning is the result of telomeric induced apoptosis is not
> only logical but supported by Bennett et al when they point out "the
> relatively low level of cell proliferation and high level of apoptosis
> seen in VSMCs,(vascular smooth muscle cells), in human atherosclerotic
> plaques.

What mention do Bennett et al make of telomeres?  There are other causes
of apoptosis...

> Research results are not only necessary but they form our entire basis
> for understanding aging.  Fortunately the research supporting telomeric 
> shortening, as being a substantial cause of aging in humans, continues to 
> mount.  

Unfortunately, research results only show what they show.  Poor logic
applied to good research is no more use than good logic applied to poor
research.

Aubrey de Grey




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