Transposable elements cause ageing?

Chris Driver drierac at deakin.edu.au
Wed Jul 6 10:09:54 EST 1994


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    




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