Caloric Restriction preserves replicative potential.....

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Mon Jan 18 08:51:50 EST 1999


William wrote:

> So do you mean that if you have lets say
> five generations of telomerase knock-out mice, that with each
> generation the telomere lengths of their organs, or lets just say
> their skin for an example, gets shorter and shorter? But at the same
> time their replicative capacity stays the same?

Yes (see Blasco et al, Cell 91:25).  Incidentally, Magnus: Blasco is
giving a talk in Pharmacology on the Downing Site tomorrow week (26th).
Don't miss it (4:30).

> I wonder if the cells of mice have *ever* been immortalized in
> in-vitro by a telomerase gene? If they have then that would show that
> their senescense and aging is not regulated by their telomere lengths.

I don't see what you mean.  Immortalisation certainly requres telomere
maintenance *eventually*, because some time or other the telomeres will
otherwise get too short and chromosomes will join together, etc.  What
I was pointing out is just that the senescence at about 10 doublings
which mouse cells exhibit may well be caused by something other than
telomere shortening, before telomere shortening proceeds enough to be
noticed.

> If we could discover what mechanism causes their cells to age and
> senesce then perhaps we could search for a similar mechanism in human
> cells, even though it may not be the primary one at work.

Yes.

Magnus Lynch wrote:

> As I understand it the normal mechanism of replicative senescence in
> vitro is ...

Spot on -- for human cells.

> absolute telomere length is irrelevant as the cellular proteins which
> detect telomere length can be set for an arbitrary minimum length

Possibly, but the longer the telomeres are, the more implausible it is
that the mechanism should be so accurate.

> Is it possible that the length of the telomeres is detected at the
> beginning of development by some as yet unidentified mechanism and
> then 'remembered' by the cell throughout the lifetime of the animal

I can't think of any direct evidence against that (though, of course,
its plausibility relies on thinking of a mechanism).  I think it might
be difficult to test: for example, it would predict that cells taken
from a telomerase knock-in mouse whose zygotic telomeres were a lot
longer than normal would NOT have an increased replicative capacity,
but unfortunately that is also the prediction of the theory that mouse
cells' replicative lifespan is determined by a telomere-independent
mechanism.

Jennifer Ann Petersen wrote:

> I would expect more similarities between our aging causes and mice
> then between us and some unrelated species. I assume thats one reason
> we see research using mice rather than some other species, like carp or
> something?

Sure.  Unfortunately, mice may, possibly, not be quite closely enough
related to humans to tell us all we need to know.  The difference in
how mouse vs human cells senesce and immortalise is a telling example. 

Aubrey de Grey




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