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> Third, lets assume that the free radicals lead to DNA mutations (which
> is one way cancer develops) or worse leads to DNA double strand breaks.
The idea that DSBs are worse than cancer is the only thing up to this point that is dubious -- see below.
> DNA double strand breaks are bad. There are 3 possible results:
There's a fourth -- cell senescence. It's long been suspected and is now firmly demonstrated that the reason why mouse cells in culture have a very small Hayflick limit is because they respond to double strand breaks by senescing. Human cells are better at repairing (or preventing) DSBs so they only senesce when they get short telomeres. In vivo, we don't yet know for sure what happens because the best histochemical assay for human senescent cells doesn't work well in mice. There is some evidence that some senescent cells in vivo in humans are caused by short telomeres but some may also be caused by DSBs.
> The above seems to explain much of aging and cancer, but now the
> problem gets worse. If (b) goes on for long enough you will gradually
> accumulate mutations in various (most probably different) genes in
> *ALL* cells. i.e. the genomic "program" that the cells require to
> operate properly is gradually corrupted in random ways.
This sounds very logical, but it breaks down when you plug in numbers to compare mutations that cause cancer with mutations that don't. The key point is that cancer can kill you starting from just one cell, in contrast to non-cancer mutations which have to accumulate in a large proportion of cells (just as Robert points out). The only things that can be set against this are (1) that there are more genes mutations in which can make the cell dysfunctional than genes mutations in which can contribute to its becoming a cancer, and (2) that it takes several mutations to make a full-blown cancer. But (1) isn't a particularly big number -- probably a good 1% of genes are involved in cell cycle control at one level or another -- and (2) is undermined both by the "mutator mutation" phenomenon (the first relevant mutation may be one that globally increases genomic instability) and also by the amplification phenomenon (an early mutation that releases cell cycle control will cause the cell to become at least a few thousand cells before anything like angiogenesis inhibition kicks in, and it only takes any one of them to acquire subsequent mutations).
These facts, added to the fact that there are lots of ways for the cell to lose cell cycle control, mean that evolution has been forced to make our DNA maintenance and repair machinery far better than it needs to be in respect of non-cancer-related genes, just in order to be good enough in respect of cancer-related genes to stop us dying of cancer very young. This is brilliant for life extension, because it means that "all" we need to do to make somatic nuclear mutations irrelevent to our health for far more than a currently normal lifespan is to cure cancer really well. See
http://www.gen.cam.ac.uk/sens/SENS3.htm
for a summary of how I think we need to proceed.
The above logic applies just as well to epimutations (chances to histone and DNA methylation, etc) as to sequence changes.
> if the mutations occur within genes rather than say regulatory regions
> now you will probably have a protein that will not fold properly. This
> will probably be detected and the protein will be degraded. But the
> lack of a sufficient quantity of these proteins will probably result in
> cellular signals to make more of them. But they or at least half of
> them will not fold properly either. Now both protein manufacture and
> many types of protein degradation require energy (ATP). So when the
> cells detect a decline in ATP (due to futile synthesis and degradation
> of proteins) they may attempt to increase energy production.
This doesn't really work. The extra demand on the cell consists of making and degrading the proteins expressed by just one gene, possibly at twice the normal level. That won't change the cell's overall bioenergetics.
> The net result is that you get an exponential decline in function (i.e.
> aging). So far I've only managed to imagine two solutions for this.
>
> 1. Develop better DNA repair processes that do not allow the genome to
> become corrupted.
This is a decidedly mediocre solution since it only slows things down, rather than eliminating existing damage.
> 2. Shift things to allow more apoptosis when DNA double strand breaks
> are detected but also increase the replacement rate by stem cells.
This is a much better solution. It also applies to senescent cells, in the scenario that they actually matter at the tissue level despite being very rare; Judy Campisi is working on trying to push senescent cells to be more apoptosis-prone.
Aubrey de Grey
[Posted by: Aubrey de Grey at April 4, 2004 4:35 AM]
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