I would like networkers opinions on an idea we have been discussing in
Australia. This is that transposable elements are the principal cause of
ageing.
If you consider all methods of mutation accumulation,most mutations that are
deleterious would be removed from a population by selection. Transposable
elements, particularly retro-transposons are different. They can replicate
within a cell, accumulating for some time without conferring any disadvantage.
However the exponential growth within the cell means that at some time the
rate of damage accumulation is sufficient to stop all cells in their tracks.
I suggest that the type of damage that is critical to cessation of growth is
ss DNa breaks. These would lead to aneuploidy and worse if replication
proceeded. The cell contains a set of guardians including p53 and p21 which
are responsible for preventing entry into S phase until the damage is
repaired. Senesecence is characterised by sufficient ss DNA breaks to slow and
ultimately stop cell cycling. The same reaction is responsible for the
alterations in protein synthesis.
Notice that this process would be independent of ploidy number.
Immortalisation: the first step- loss of functional guardian genes. This would
result in chromosomal instability and ultimately death for most cells. However
if a cell is able to lose sufficient of the active transposable elements when
it loses chromosomal pieces, it can continue to replicate and has progressed
through to a immortality
In non dividing cells. other modes of DNA damage may not be so readily
removed. At the same time many of the DNA alterations may not be so
deleterious. However TEs have to be able to replicate in non dividing cells as
described above, and because they can exponentially increase, may pose the
single biggest threat to non dividing cells as well. Steve McKechnie and I
have published a paper in Ann NY Acad Sci , 673, 83-91, 1993 in which we
indicate that TEs are important in the ageing of Drosophila. A paper follows
in which Inhibitors of reverse transcriptase, which would be expected to
inhibit replication of TEs, slows ageing. This is Driver and Vogrig, Ann NY
Acad Sci, in press.
TEs are faced with the survival logic of a parasite. To replicate they msut do
some damage, but if they replicate too much they will kill the host and die
with it. There is a double problem. Germ line mutations cannot be too high. In
addition most transposable elements are active in somatic tissue, in many
cases more so than in the germ line. As far as the somatic activity goes,
there will be no selection if the activity is sufficiently that the host would
be expected to die of something else first, such as predation or starvation.
Thus one would expect that in general ageing would not set in until after most
animals would die in the wild. A rapid change in environmental conditions such
as has happened with some human populations, would change this and ageing
could be a major factor in adult viability.
See also
Murrey, V (1990) Mut Res 237:59-63
Brown, AR, Tso POP and Cutler RG (1991). Arch Gerontol and Geriatrics 13:15-30
I would particularly like to hear from someone from the RG Cutler group.
Chris Driver
Deakin University
Australia
15-30
