Is there a connection between Telomeres, Free Radicals, and the Aging Process?

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Sun Jul 26 12:42:58 EST 1998

Dear William,

Thanks for your very perceptive questions.  

> We know for a fact that by keeping telomeres enlongated that
> cells can be made immortal or at least reproduce many more times than
> the Hayflick Limit. But I have also read that free radicals also have
> an affect on aging ... certain worms that had been
> genetically engineered to produce fewer free radicals lived many times
> longer than their normal life span

This is all correct, and moreover the relationship between free radical
production and lifespan has been shown to apply between warm-blooded
species too, so it's not just that worms are weird.  Most of the best
studies have compared rats with pigeons: they are about the same size,
but rats live only about four years and pigeons about 35, and pigeons
make a lot fewer free radicals.

> So, it seems like both free radical production and telomeres have are
> involved in the aging process.

Not necessarily.  The behaviour of dividing cells in the lab is not a
reliable indicator of what happens in the body, because most cells in
the body either never divide (nerves and muscle fibres, for example)
or only divide very very rarely, typically in response to wounding (the
cells in the lower layers of the skin, for example).  It's possible that
some cells in the body divide often enough to get near their Hayflick
limit, but it cannot yet be said whether those cells cause us to age.

I'm re-ordering your questions: you'll see why.

> 4) Have there been any tests or experiments done to see whether the
> telomeres of cells treated with anti-oxidants, which would have fewer
> free radicals, shorten faster or slower than cells with a higher
> ammount of free radicals?

It has been shown that high free radical levels accelerate telomere
shortening.  A recent reference is: Oexle and Zwirner, Hum Mol Genet
1997 Jun;6(6):905-908.

> 2) Is it possible that free radicals in a cell could either inhibit
> the telomerase enzyme in cells or actually shorten the telomeres of
> chromosomes?

Yes.  One of the nasty things that free radicals do is to damage DNA.
In particular, they occasionally cause chromosomes to break in two.
Now: the cell has a very effective system for repairing chromosome
breaks, so in general this is not much of a problem.  But what that
system does is to join together, end to end, two molecules of DNA.
Now, two unbroken, intact chromosomes are also two molecules of DNA.
Therefore, the repair system must be very careful to join together
ends that look like breaks but not ends that look like bona fide ends,
or else we'd rapidly end up with one (circular) chromosome in each
cell, which is incompatible with further cell division.  It's thought
that this is a vital function of telomere sequences: they are seen as
"bona fide ends" by the breakage repair system and are left alone.

Now, suppose a chromosome break occurs really close to the end of the
chromosome -- so near, in fact, that it's actually within the telomere
sequences.  Then, because of the above, it will not be repaired.  So
the chromosome's telomere sequence will suddenly, permanently, be
shorter than before -- just as if it had been through some extra cell
divisions.  In this way, free radical damage can accelerate telomere
shortening and reduce cells' Hayflick limit.  But beware again: this
doesn't tell us anything about cells that aren't dividing.  Beware also
that this model for how free radicals accelerate telomere shortening,
though highly plausible, is not yet proven (as far as I know).

> 3) Could it be that in creatures with fewer free radicals that cells
> do not get damaged as often, so cells do not need to reproduce as many
> times during a certain period of time, so that the telomeres of the
> chromosomes are simply not used up as fast?

Probably not.  This could happen if cells die and their neighbours have
to divide to replace them, but there is no evidence that cell death is
anywhere near that extensive.

> 1) If limiting the number of free radicals (either through genetic
> engineering or with anti-oxidants) has allowed certain creatures to
> live longer and their cells to replicate more times than normal does
> this mean that the reduction of free radicals has somehow prevented
> their telomeres from shortening?

No.  The reduction of free radicals may have slowed the shortening of
telomeres (see above), but we don't know that that is the mechanism by
which the reduction of free radicals extended lifespan.  In fact there
is a good reason to think that it isn't: namely, that long-lived species
actually produce LOWER amounts of antioxidant enzymes!  That is, they
get their lower free radical damage by achieving lower free radical
production, rather than by better free radical mopping-up.  That in turn
tells us that parts of the cell which can be protected by antioxidant
enzymes ARE protected -- sufficiently -- in both short- and long-lived
species: the levels of enzymes are turned up on demand.  What it also
tells us is that there must be some other parts of the cell which are
NOT protected by antioxidant enzymes, and which can therefore only be
preserved by reducing the production of free radicals in the first place.
So, the question is: which places are likely to be unprotected?  Answer:
places very close to where free radicals are made, which free radicals
can therefore damage very quickly, before the enzymes can get at them.
Mostly this means mitochondria.  But in particular, it rather strongly
excludes anything in the nucleus, because the processes which make free
radicals (particularly aerobic respiration, but others too) happen only
in the cytoplasm, not in the nucleus.  Now, of course our chromosomes
(and hence our telomeres) are in the nucleus.  Hence, any shortening
that they undergo due to free radical damage should be retarded by high
levels of antioxidant enzymes.  Hence, since long-lived species don't
have high levels of antioxidant enzymes, telomere shortening due to
free radical damage can't be the main determinant of the rate of aging.

I must stress that the above is NOT watertight -- it is purely a short
summary of one argument.  There are plenty of holes in it: for example,
there may be free radical-producing processes in the nucleus that we
don't yet know about.  Nonetheless, I consider the above to be the
strongest argument available, at the moment, for the irrelevance to
aging of free radical-induced telomere shortening.

Aubrey de Grey

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