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

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Mon Jul 27 15:27:26 EST 1998

> I sure did wish that I had an education and could do some experiments

Don't worry ... at this rate, when you do get the chance to do some,
you'll do the right ones!  Also, some scientists (myself included)
make their contributions without doing experiments: they spend all
their time analysing other people's experiments and advancing the

> Do you think that a copy of that article
> would be at a local library or do you think I would need to go to a
> university library to find it?

Probably only at a university or a hospital.  But there are some good
articles in much more widely accessible magazines, such as Scientific
American.  There was an excellent article there about a year ago on
mitochondria and free radicals in aging, by Doug Wallace: it was in
the August 1997 issue, page 40-47.  You can find others by looking in
Medline (http://www3.ncbi.nlm.nih.gov/PubMed/index.html) and using
this search string:

sci am[jour] AND aging

Medline is a fantastic resource.  It contains the summaries from most
papers, so you can read quite a lot about what they discovered without
having to go to a university library.

> is there any evidence that the telomeres of pigeons
> also shorten slower than the telomeres of rats? 

I don't think so.  The evidence would be complicated though, because it
is well established that some short-lived species (such as mice) have
very long telomeres.  More on this below.

> it seems that cells
> reaching the Hayflick limit would be a factor in aging because if all
> of the cells in the human body that CAN divide just STOPPED dividing
> (or even a good number of them) that aging and death would be the
> result

Yes (if we replace CAN by MUST, which is fine).  The operative word,
though, is "would" -- see below.

> by taking cells
> from young verses old individuals that the cells from older people
> cannot reproduce nearly as many times as the cells from young
> individuals.

True.  The classic paper is Proc Natl Acad Sci USA 1992 Nov 1;89(21):
10114-10118.  The data were very "scattered" with regard to age though:
that is, people of similar ages had widely varying telomere lengths.
But there was much less scatter with regard to the relationship between
initial telomere length and replicative capacity: that is, two cultures
with the same initial telomere length (disregarding the age of the
donor) always had very similar replicative capacity.  Another paper,
Mutat Res 1991; 256:45-48, which looked at a more rapidly-dividing cell
type, got a better correlation of telomere length with age (though they
didn't measure subsequent replicative capacity).

> Now, I might be wrong, I will admit that, but it seems to
> me that because of this, telomere shortening MUST be at least ONE
> major factor in aging.

I'm afraid not.  What it tells us is that telomere shortening WOULD
be a factor in aging if cells actually reached replicative senescence
in the body, because they would be required to divide but would not
be able to do so.  But the only way that they could be a CAUSATIVE
factor in aging is if they actually reach, in the body, a state that
is harmful to us.  Telomere specialists have realised this for a long
time and have been looking for changes that occur in a cell's behaviour
when it has got, say, only half way to its Hayflick limit.  They have
found some interesting things: for example, fibroblasts that are quite
close to their Hayflick limit secrete a lot of collagenase, which is
an enzyme that breaks down extracellular protein.  But they have not
yet found anything that can clearly be seen to be toxic and is present
at significant levels in living animals.

Another thing we must bear in mind is that there is a positive benefit
for humans in not maintaining telomere length in dividing cells: namely,
that if they go cancerous then the tumour will not grow to a harmful
size because its telomeres will get too short and will arrest its growth.
Cancers can only get away if, in addition to cell cycle mutations and
others, they also have a mutation that turns on their telomerase (or
something equivalent).  Now, it initially seemed that no somatic cells
expressed telomerase in humans, but recently it was found that trace
levels are indeed present in several rather rapidly-dividing cell types;
the simplest explanation for this is that they need to divide more than
they could if they had zero telomere maintenance, so they turn on just
enough to get through our lifetime.  This makes it look rather like a
peripheral process, coping with a lifespan that is defined elsewhere.
Moreover, it also rather suggests that if such cells suddenly found
themselves being asked to survive a lot longer than now, they could
happily do so by turning on a little telomerase.  This is emphatically
only a suggestion though - it's hard to test.

> If high free radical activity accelerates telomere
> shortening is it "possible" that "normal" or "average" free radical
> activity might cause the normal rate of telomere shortening in cells?
> Do you think an experiment could be done to see if very low free
> radical activity could reduce the rate of telomere shortening?

It is fairly safe to say that if high free radical activity accelerates
telomere shortening then low free radical activity will reduce it.  Thus
we can fairly confidently say that there is a connection there.  But that
doesn't answer the question whether free radical damage is the main cause
of telomere shortening in the body (more important than straightforward
cell division).  Even less does it tell us whether telomere shortening
(by either or both mechanisms) drives aging.

> But this does tell us that the majority of cells that DO divide could
> have the telomeres shortened by free radicals.

And/or just by cell division.

> It would be really neat for someone to try and do an experiment to
> test this model. 

Neat, but not relevant to aging unless telomere shortening by radical
damage is a major causative agent in aging.

> If the reduction of free radicals did not cause the extended life span
> by either slowing the shortening of telomeres or by killing fewer
> cells so that the cells did not have to divide to repair damaged
> tissue as many times, then how did the free radicals extend the
> lifespan?

The most popular answer to this among specialists is "mainly because
less damage was done to mitochondria".  My answer, which is a bit more
specific and much more controversial, is "mainly because less damage was
done to mitochondrial DNA".  Mitochondrial DNA is circular, so it has
no telomeres, but it can still be damaged.  I won't elaborate in this
posting because that would make it rather long!  There is an enormous
literature on this theory ("the mitochondrial free radical theory of

> Also, there is another question that needs to be asked. Could it be
> that the telomeres of pigeons are naturally longer to begin with than
> the telomeres of rats? 

A fine question; I don't know.  But we do know that telomere length at
birth is a poor predictor of lifespan, because mice (which live a couple
of years) have much longer telomeres than humans.  Among primates, the
telomere length at birth IS quite a good predictor of lifespan; but that
tells us nothing if we accept the anti-cancer motivation I mentioned
above.  (Mice cannot use telomere length as an anti-cancer trick, since
a tumour the size of a marble (which is about what they get to with no
telomere maintenance) will kill a mouse anyway.  Primates can pull this
trick because we're big enough.)

Recently, experiments have been done with mutant mice which can't maintain
their telomeres in the germ line either, so each generation of those mice 
is born with shorter telomeres than their parents.  There appears to be
no effect on their rate of aging.  After six or seven generations several
other things start to go wrong, but lifespan isn't affected.  Main papers
are Cell 1997 Oct 3;91(1):25-34 and Nature 1998 Apr 9; 292(6676) 569-574.

> Whether
> the ammounts of free radicals are reduced by anti-oxidant enzymes or
> by just a lower production of free radicals then it seems both could
> "possibly" cause the telomeres to shorten at a slower rate.

You're absolutely right.  So, to go from "possibly" to "actually" we
need more information.  The fact that long-lived species have low free
radical production but LOW enzymatic antioxidants suggests that the
enzymatic antioxidants are "keeping pace" with other aspects of aging
over which they have no control -- just like telomerase in rapidly
dividing cells, above.  (In this case the cost of "unnecessary" over-
production is not cancer, it's just wasted energy in building unused

> But what if it is
> part of nature TO let the free radicals slowly reduce the telomere to
> cause cellular aging?

OK, this is a very different and also rather big subject.  This is not
asking "how" we age -- the mechanisms -- but "why" we age -- why a finite
lifespan has evolved and an indefinite one hasn't (or at least not among
warm-blooded animals.  Basically the current consensus is that aging (of
the sort that we experience) is not an active, programmed process but
rather a simple inadequacy of maintenance.  Unfortunately, it seems that
the answer to "why" doesn't answer the "how".  Consider telomeres: let's
suppose that telomere shortening really does drive aging.  Then the way
it does so is because telomerase is turned off as an anti-cancer trick.
But cancer could just as effectively be retarded by other tricks, such
as better DNA repair so that the cancer never begins.  The logic would
then be that the turning-off of telomerase is the simplest, cheapest
approach.  Analogous logic exists if mitochondrial damage drives aging,
for example.

> Can the free radicals that are made in the cytoplasm travel to the
> nucleous to do damage?

Sure.  (Actually "travel" is not quite what happens -- they tend to react
with something, but that reaction makes a new free radical, which reacts
with another, etc.)  The proportion that actually get to the nucleus is
therefore controlled by the amount of antioxidants that can destroy them
beforehand, and by the amount that are produced in the first place.

> Do you think that low levels of free radicals could cause a cell to
> keep on reproducing and dividing even if the telomeres have all been
> used up?

No, since human cells with no telomerase have never been persuaded to
do this in the lab.  Many things have been tried, and plenty of those
would have varied the levels of free radicals.

> Do you know whether the cells of these organisms, such as flys and
> worms, that have been genetically engineered to longer and produce
> fewer free radicals, replicate more times than normal?

No cells in adult flies or worms, except for those that form the eggs
and sperm, do any division at all.  This is a good reason to think that
telomere shortening due to cell division has nothing to do with aging
in those organisms -- a much stronger argument, for example, than any
that I've made above about humans.  (I didn't mention this before,
because I'm not a great fan of inter-phylum comparisons as ways to
learn about human aging -- I don't think mitochondria have much to do
with fly and worm aging either!  Free radical damage is probably very
important though, since flies and worms have a rather more primitive
antioxidant enzyme arsenal than us.)  Of course that doesn't exclude
the possibility that telomere shortening through free radical damage
is important in fly or worm aging.  Telomeres in flies are very weird
-- they aren't actually maintained by a telomerase -- but in worms it
is a question that would be interesting.  I couldn't find anything in
Medline to suggest that anyone has measured telomere length in young
and old worms; it's certainly not a difficult experiment. 

> Could you recomend any semi easiy to understand information that I can
> find on the net that would explain more about free radicals and how
> they might cause aging?)

I wrote a short piece last year for that purpose which you can find at:


I recommend Wallace's Sci. Am. article for something more detailed
but equally (perhaps more!) easy to understand.

> Do you think that there could be anyway to make these non-somatic
> cells reproduce? Because it would be absolutely horrible if telomerase
> therapy allowed peoples somatic cells to stay young forever but their
> non-somatic cells to keep on aging causing all kinds of problems.

I must correct a small terminological error of Thomas's here.  "Somatic"
does not mean "dividing".  Nerves etc are somatic cells just like blood
stem cells etc.  The only cells that are not somatic are those which
make eggs and sperm.  In other words, "somatic" means "not germ-line".

To answer your question though: it's not clear.  Muscle fibres don't
reproduce, but there is a special type of cell called a satellite cell
which is found in small numbers throughout our muscle, and they can and
do reproduce.  They do so in response to injury to the surrounding
muscle, and are crucial to its healing.  Nerves are a bit harder, but
even they may be replaceable -- there have been reports of progenitor
nerve cells in adult forebrain for example (Cereb Cortex 4: 576-589).
Other non-dividing cells (such as in the kidney) may also be hard.

Lou Pagnucco wrote:

> cells were cultured under high pressure of oxygen gas.  This 
> (presumably) greatly increased free radical production, and led to 
> a premature shortening of the cells' telomeres.

Yes, I should have mentioned that one before.  It is Exp Cell Res 1995; 220(1):186-193.

Aubrey de Grey

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