Premature Ageing

Oliver Bogler obogler at ucsd.edu
Tue Apr 2 19:10:36 EST 1996


Guy Dunphy wrote:
>
> Oliver Bogler <obogler at ucsd.edu> wrote:
>
> >Guy Dunphy wrote:
>
> >> Anyone know if more recent work has examined the condition of the telomeres
> >> in Werner syndrome patients?
>
> Well?

I didn't answer because I don't know.

> >> Isn't it amazing the number of researchers who are looking into telomeres,
> >> 'just for the cancer connection'!
> >> What a bunch of funding whimps. Go on, admit it you guys, WE ALL WANT TO BE
> >> IMMORTAL.
(snip)
> >This is all very interesting, but you seem to unaware that there is no evidence of a
> >connection between telomere length/cellular ageing and organismal ageing. Organismal
> >ageing is better discussed in terms of mortality - no one dies of "old age".
>
> Oddly enough, that was what my grandfather died of.
>
> >There is always a "pathology", and that has nothing to do with telomere length.
>
> Now who' s making unproven assertions?

OK - so why don't you define the condition that immeadiately precedes death by old age.
Please remember that kidney failure, pneumonia or other opportunistic infections 
permitted by a failing immune system, strokes, heart attacks etc. are all defined 
pathologies that are different from old age.
I suggest that those deaths that are attributed to old age are just not carefully defined
in other terms. The underlying point is that telomere shortening does not lead to an
inevitable death or pathology. People with very short telomeres, and fibroblast clones 
that can only undergo very few divisions, can still live for many years (eg. George 
Burns). In contrast other people with longer telomeres, and more vibrant fibroblast 
clones, can die of pathologies otherwise associated with old age (Sergei Gringkov, about 
30 year old Russian gold medalist in pairs skating who died of heart disease at the end 
of last year).

> >Of course, older
> >people have older cells that may be less good at doing their stuff, contributing to a
> >conditions that kills.
>
> Exactly. Even  where infectious disease was the cause of death, perhaps an
> immune system with a smaller proportion of 'tellomere challenged' cells would
> have mounted an effective defense. So how do we ever decide whether the root
> cause of a particular death was short tellomeres. Can't. All we can do is see if
> an experimental population with 'new, improved' tellomere restoration has longer
> average lifetimes than a control.

So far a pretty good correlation between cancer and telomerase activity has been
established. Those who believe that telomeres are key to cell ageing and on the other 
side of the coin cancer, would surely argue that your experiments would lead to increased 
cancer risk. No evidence that telomere length determines the effectiveness of a cell, say 
of the immune system, exists

> >Also, the fossil record would look at people with no basic health care or sanitation, that
> >were predated actively. Hardly a fair comparison.
>
> My point was, that all other things (predation, lifestyle, etc) remaining equal,
> there may have been a relatively sudden change in average human lifespan.
> I wondered if any one could examine a human bone fossil and say: "Hey, this
> fellow was 200 years old when he died!"  How would we tell?
> Are there no instances of other species, where there are two distinct strains,
> differing only in their average lifespans? Which strain would win out in an
> evolutionary contest?

You can tell alot from the bones - for example the wear and tear on teeth. And you might
say that the longests telomere lengths in the worls won't help you survive if you don't
have teeth to eat with (I'm talking in the stone age etc).

> >In general, in the wild, animals never
> >reach their maximum possible age because they get eaten first!
>
> Probably true, animals always get eaten before 'maximum' age. But humans
> (even prehistoric ones) have social structures that tend to distort such purely
> ecological models.

I would include diseases in the environmental effects that lead to death before ageing 
can affect the organism in pre modern medical society. Therefore, modern sanitation 
followed by antibiotics are the two advances that significantly affected mortality. These 
advances are purely cultural, and so independant of biological evolution. They have, if 
you will, unmasked ageing and new age-related diseases such as heart attacks and cancer.

> >So I guess, most scientists who work on telomeres do so to learn more about tumors, than
> >for the sake of living forever. Also the connection between cellular ageing and telomere
> >length is so far only correlative: no direct evidence of causation has been provided.
>
> And the way to prove it, is to switch on the teleomere patch-up system in a cell
> line, and see what happens. You know that, right? Anyone trying to do it?

The problem is that telomerase, the enzyme that extends telomeres, is a multicomponent
complex, and until all the components are cloned, there is no way to do the experiment.
Experiments have shown that the amount of the one part (the RNA component) that is cloned 
is not a good indicator of telomerase activity.

snip.
 
> Certainly, I'm aware there is no direct proven link yet. But then, I'm not
> writing research papers, I'm just speculating. So I don't have to stick to
> discussion of proven facts.

That is your perogative. Of course, it will detract somewhat from the discussion, and
temper the enthusiasm of those responding to your posts.

snip
 
> And in this case, my speculation is that as the telomeres shorten (at differing
> rates) in the various populations of cells in the body,  and the statistical
> spread (of cells in each line that have exhausted their telomeres and begun to
> suffer loss of whatever genes were nearest the fraying ends

The "genes at the ends of chromosomes" theory is clearly wrong - they have simply no 
tbeen found. More likely, is that the frayed end of a chromosome signals the cell cycle 
machinery of the cell (which regulates cell division) to halt the process until the 
damaged DNA can be repaired. This is a fairly well established mechanism in other 
situations (eg chromosome breaks).

snip

> After all, there are _lots_ of variables. Telomere exhaustion will doubtless
> occur at different rates in different:-
>    - individuals  (hence the spread of rates of aging between people)

I feel compelled to repeat that there is no established link between telomere length and
life expectancy. Telomeres are not the holy grail of ageing research. Many cells in the
body are post-mitotic - they never divide after development is complete. They can live 
for very long times with no reference to their telomeres, without telomerase activity and
lengthening their telomeres would have no effect.
By weak analogy, the telomere might be more like the tire on a car. If you want to drive
somewhere, you need the tire. If you're parked for good, you don't need it. The tire does
not actually move the car, though you might be initally mislead into thinking it does -
after all that's where the car and the road meet.

>    - cell lines (so different organs and metabolic systems will 'age'
>      differently in any individual)
>    - individual chromosomes (and hence 'hit' different genes first - so the
>      mechanisms of failure will be many and varied.)
> In a given individual, with so many different modes of failure coming into play,
> all of them in statistical fashion among cell populations (rather than all or
> nothing effects), then its no wonder that aging looks like a general systemic
> decline in effectiveness.

Does it?
 
> Then again, I'd be surprised if other age related problems (such as mechanical
> and structural wear and alteration) don't show up in the first experimental
> subjects to have their 'telomere aging' fixed.
> For instance, there's also the mitochondria functionality problem.
>
> But I just have a gut feeling that telomere loss is the major cause of the
> 'cellular death' clock.  (Hope its not just wishful thinking.)

There is no cellular death clock - you may be thinking of cellular senescence. Senescent
cells are not dead - they accumulate with age, but can be viable for many years as old
people show.

> Incidentally, while I'm talking to someone who no doubt knows, are there
> any listservers that carry more detailed information about this topic?

Sorry - I don't know.

Thank you for an interesting discussion.

Best wishes,

Oliver




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