Free radical Damage as a contribution to cell ageing?

Sydney Shall bafa1 at
Mon Feb 15 06:06:32 EST 1993

Question? Do free radicals and superoxide species contribute to cell ageing?

It is necessary to divide up the discussion into two parts; 
one should, I think, first separate out non-dividing cells from 
normal proliferating cells. There is abundant evidence that in fact 
free radicals and superoxide species can and do damage living cells. 
There is also much data that shows that living cells are able to repair 
much of the damage that these agents cause.  The situation with 
non-dividing cells is unclear in my view; it is highly probable that 
free radicals and superoxide species do in fact contribute to damage 
and perhaps death of these cells eventually. However, even here one 
must take into account the state of the mitochondria. 
For the moment, I will leave this discussion in this unsatisfactoryu state,
for other contributions.

Now I can offer my views on the situation regarding proliferating cells
in in vitro culture.  In this case it is almost certain to me that
damage of any sort is not part of the mechanism, because it has become
clearly established that the cessation of growth is not due to celling killing,
but is due to a process whic I have long-ago call cellular mortalization; 
which is in contrast to the immortralization of cultures one sees when
the cells are derived from tumours, or when the normal cells had been
exposed to DNA viruses, radiation or mutagenic chemicals. What actually
happens during the "ageing" of normal cells in culture is that at each
generation a fraction of the new-born cells become mortalized, that
means reproductively sterile, but otherwise metabolically active.  In
very old-fashioned words, these cells become post-mitotic, or if you
prefer, terminally differentiated.  For the case of cells in culture,
both human and rodent this is a statement of experimental results, and
not an hypothesis.  Thus, we now know that duringm cellular senescence
in vitro the phenomenon is due to a progressive and continual increase
in the fraction of cells that cannot divide.  There is no significant
fraction of cell death in these cultures. This statement has been 
experimentally documented.  Therefore, in this specific case we cannot
look for an explanation for the limited lifespan in terms of damage 
to the cell and cell death.

There is a more subtle view which proposes that while cell death is
not involved, DNA damge is the cause of the cessation of proliferation.
This is then attributed to very specific DNA damage which inactivates
those specific genes which cause the limited life-span or which are
required to achieve cell proliferation. This more sophisticated theory
is more difficult to disprove, but is highly unlikely; the kinetics of
mortalization are totally different from what one would expect.  For
example, mortalization of the culture actually starts from the beginning of the 
culture and increases progressively; this is precisely contrary to what
the mutation theory (Which I have just deswcribed) would predict.

In summary then, it is clear that cell death is not part of the
phenomenon of cell ageing in in vitro culture.  Whether it plays a 
significant part in ageing in intact bodies is less clear, but I
would guess from the available evidence that this is highly likely.

Sydney SHALL.



Sydney SHALL,
Laboratory of Cell and Molecular Biology,
Biology Building,
University of Sussex,
East Sussex BN1 9QG,

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