Transposable elements cause ageing?
mpm at seqanal.mi.uky.edu
Fri Jul 8 09:40:02 EST 1994
Chris Driver (drierac at deakin.edu.au) wrote:
: I would like networkers opinions on an idea we have been discussing in
: Australia. This is that transposable elements are the principal cause of
: 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
As is often the case, I think it is important here to distinguish the
umbrella of "aging" from senesence. Clearly there are components of aging
which are completely independent of the genome. Loss of elasticity in
fibrous, acellular tissue and accumulation of calcium-phosphate precipitates
in the mitochondrial matrix come to mind. In this regard, I applaud you
for separately discussing senesence and non-dividing cells.
The immortalization problem is sticky. Although I don't have the references
handy, others have shown correlation of immortalization with oncogenes (e.g.,
v-myc) or loss of tumor suppressor genes. It is difficult to believe
intuitively that -- given the number of TE's you propose to be flopping
around in our genomes -- that all of the senesence-invoking ones could be
lost simultaneously often enough to generate immortalization at the rate
one sees it occur in cultured cells. The odds just seem against it.
I look forward to reading your Ann. NY Acad. Sci. paper(s).
Steven W. Barger, Ph.D.
Sanders-Brown Center on Aging
University of Kentucky
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