Cause of aging

Steven B. Harris sbharris at
Sun Aug 16 20:15:22 EST 1998

In <35D744FB.3E4718D4 at> James <james at> writes: 

  >>I have to diagree with Steve's interpretation here.  There is
nothing wrong with calling something the "free radical theory of
aging" just because SOME of our cells CAN deal with the free
radicals.  True, that does mean that in SOME cells the problem
could be interpreted as lack of a system/ability which other
cells have.  So?  In the cells in question the "Free Radical
Theory of Aging" is still a perfectly accurate name (and I would
submit that "in the cells in question" is all that we can worry
about, or assign a name to, because the causes of aging likely
vary from cell type to cell type).<<

   They may or they may not.  I would argue that if all cells
make free radicals and only some cells, tissues, and organisms
age, then the idea that free radicals "cause" aging in any kind
of final sense, is at the very least grossly incomplete, and at
worse, silly and wrong.  And no, it doesn't help to qualify it
and back down and claim you're only talking about some tissues
and some cells and some part of aging.  The name is out there,
and it's going to be influential.  Too influential (think of
Pearson and Shaw for illustration of this).

   Again, let me use a metaphorical analogy (forgive me).  It's
sort of a 60's activist analogy, and for that, especially forgive

   Imagine, if you will, a "theory of pothole numbers" (street
aging) which posits that potholes in a city's streets are the
result of wear and tear by traffic.  There may be some truth in
this, but such a wear and tear pothole theory is obviously at
least very incomplete, because it doesn't tell you a thing about
why some cities have potholes, and others of the same size and
with the same traffic load and weather, don't.  Or why pothole
frequency may differ with the streets of the same traffic load,
even in the same city.  So, the traffic wear theory is, by far,
not a complete theory of potholes.  It's just a start.  It might,
however, by itself engender a lot of speculation on how to reduce
potholes by re-directing traffic, mandating lighter vehicles,
legislating gasoline and travel restriction, tire re-design, and
so on and so on unpleasantness.  None of which may be much fun,
but with all this to go on as a theory, it's all we have.

   But we're smart, and knowledge progresses.  Now suppose we
study the problem a while more, and we discover that in cities
with no potholes, there is much more efficient repair system. 
Also, we notice that streets put down at different times by
different construction companies, which are picked by city
government representatives, have different wear and tear rates,
even with the same loads.  And finally, we notice that pothole
repair activity differs in richer sections of town vs. poorer
ones, even controlling for traffic.  Hmmm.

   Obviously, we now realize by doing comparisons, a good theory
of potholes will be more a theory of pothole repair, not traffic
load, since all cities have hard road wear, but some cities
hardly have any potholes.  Moreover, we even have some 
correlations of pothole repair activity with government activity,
and have begun to realize that any complete pothole theory which
explains the pothole difference from place to place, and city to
city, is going to be more political than mechanical.  Thus, at
this point, we really need to stop talking about "traffic wear"
theories of potholes, and start talking about "government-
efficiency" theories of potholes.  Even if we haven't quite
figured out which elements of government efficiency and politics
are responsible, at least we know this is the direction to do
further pure explanatory research in, and finally interventive
action in.  Continuing to talk about traffic wear theories in
most cases just **diverts our attention** from the underlying
causes (one would say the REAL causes) of "why" there are
potholes in some places and not others.  In that sense, 
wear-and-tear theories of potholes are rather counterproductive,
simply because a different kind of action is needed to make
cities free of potholes.

   We have come to this same place in aging.  We know all aerobic
cells make free radicals at a rapid rate, but we know some cells
don't age at all.  Any good and complete and comprehensive theory
of aging will thus be a theory of *failure of repair* of free-
radical *and other* damage, not simply a theory of free radical
damage.  Moreover, in aging we have a clue finally as to which
kinds of cells fail to repair themselves--- they are always 
non-dividing ones.  Thus, we have the important clue that the
failure to repair damage which causes aging (which is an 
accumulation of damage), is associated with failure of cells to
divide.  So we can put that in our theory also.  Though we still
know none of the biochemical mechanisms of this, we've at least
made progress in aging.  Much as we have made progress, with the
realization that the pothole problem was political, not physical,
even if we might not yet know anything about city government
inside infighting.

   >>If I am understanding you correctly, you would prefer that
it be called something like the "I'm not dividing and that is
causing problems Theory of Aging."<<

    It's specifically causing *repair* problems.  I'd prefer to
assert something like "Division-Inhibition Associated 
Repair-Attenuation Makes Aging."  Call it the DIARAMA hypothesis. 
You're welcome to come up with something snappier.  But whatever
you come up with, you need to recognize that--- until we have a
name for what is happening, which refers to something more
fundamental than the various damage things that go on in non-
dividing cells, and the proximate reasons for all of them-- we
won't recognize that the one thing they all share is that they
ALL cause change and damage which builds up over time, AND that
this change and damage in dividing cells is of a sort which
nature is quite *capable* of fixing, BUT DOESN'T.  And FURTHER,
that this failure ONLY happens in non-dividing, or differentiated
cells.  Thus, as with potholes, aging is a "political" problem of
repair resources, and repair system capability, not simply, and
stupidly, one of straight wear-and-tear of a sort which is with
us always, and which is perfectly fixable in dividing cells. 
When we realize this, we may begin to make more progress in
fixing aging in non-dividing cells.  Just as realizing more about
the underlying causes may help you rid your city of potholes.

   >>And that might be OK too.  But I tend to look at these
things from a "How can we solve the problem?" point of view.  So
instantly two options come to mind as a result of this 
discussion.  First, we can fix these cells by making them divide. 
Second, we can try to reduce/eliminate free radical damage.
  Certainly the second possibility is more likely to be 
physiologically relevant, since you can't very well tell all your
post-mitotic cell types to start dividing again (and expect to
live).  Free radicals are the RELEVANT concern, even though you
could make an argument that they are not necessarily the 
universal root of the problem.  So the name of the theory
is more accurate as it stands.<<

   First, the name is *not* more accurate, in any sense.  You
want the name of the theory of aging to reflect the root cause as
much as you can, whether you can fix it or not.  In the pothole
problem, your mayor and your election system and your road
construction and repair companies may all be totally corrupt and
in bed with each other, and be entrenched in ways where they
can't easily be voted out.  But that still doesn't excuse you
from deciding to call it your theory of potholes a "wear and
tear" theory, just because you can't do anything ABOUT City Hall
(This sounds vaguely like what Communist writers had to do in the
Stalin era).  That's defeatism.  The first step to solving any
problem is to identify it.  The second is to publically name it,
and draw attention to it.  Put enough pictures of the hizzoner
The Mayor near every pothole, and you may find that wear-and-tear
theories of street aging are suddenly not as relevant to your
solution as you thought.  Hey, you might NOT have to ration
driving at all!  You might not have to spend money for wider
tires and bypass roads.  It's all in how you think about things.

   Second, the very names of theories narrow your mind, and keep
you from thinking laterally and outside the box.  Aging is
accumulated damage, but there's nothing to say that free radicals
cause all of it.  All we know is that with cell division the body
is capable of repairing all of the damage AND the aging).  That's
what we need to keep in mind-- the critical fact.  And we need a
phrase to do it.

   Finally, the name of the hypothesis above (DIARAMA) merely
notes that failure of repair is ASSOCIATED with failure of cell
division.  It doesn't say that restoration of cell division will
be necessary for repair (though for all we know, that might turn
out to be the case, absent new intracellular repair mechanisms
not found in nature).  But by focusing on the fact that full
repair and de-aging is ASSOCIATED with cell division, we are
encouraged to see what it is about cell division that triggers
the extremely efficient age repair systems that we have in nature
already.  The ones that have kept life around in an oxygen
atmosphere for 2.5 billion years, or something like that.  When
we find out how this kind of thing works, we may be able to turn
it on, even in differentiated cells.  But we won't look for ways
to do this without a new paradigm to help us in our thinking. 
The "free radical theory of aging" is, I am afraid, not that
paradigm.  We need something new that reflects what we now
realize about the root causes of the process.  New understanding
DEMANDS new language.  I'm quite open to suggestions that will
help me with this.

                               Steve Harris, M.D.  


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