There are two types of accumulating change that happen to our chromosomes as we age: mutations and epimutations. Mutations are changes to the DNA sequence, and epimutations are changes to the "decorations" of that DNA which control its propensity to be decoded into proteins. Luckily, we don't need to deal with these two phenomena separately, because we can obviate them both in the same way.

This is another of the areas of aging in which evolution has done the really hard work for us. We have an enormous amount of DNA, and the job of keeping it intact and functional is incredibly complicated. But evolution had to do it, so it has developed the necessary sophistication for us. We're particularly lucky in one way: evolution (since the emergence of vertebrates, anyway) has had one DNA maintenance problem that is far bigger than all the others, and that is to stop organisms from dying of cancer. Cancer can kill us even if one cell gets the wrong mutations (or epimutations), whereas any loss of function in any genes that have nothing to do with cancer are harmless unless and until they have happened to a lot of the cells in a given tissue. So, all those genes get a free ride -- they are already maintained far better than we need them to be in anything like a normal lifetime.

[Note: the above is a slight oversimplification, in that DNA damage and mutation may be a significant cause of two of the other problems that SENS seeks to repair, cell depletion and cell toxicity, because cells can either commit suicide or go into a "senescent" non-dividing state as a pre-emptive response to DNA damage that stops it developing into cancer. But these special cases need not concern us here because they are dealt with by their respective parts of the SENS scheme.]

This means that we don't actually need to fix chromosomal mutations at all in order to stop them from killing us: all we need to do is develop a really really good cure for cancer. The one that I favour (which was the topic of the third SENS roundtable, a roundtable meeting I convened in Cambridge in 2002) is called WILT, for Whole-body Interdiction of Lengthening of Telomeres. This is a very ambitious but potentially far more comprehensive and long-term approach to combating cancer than anything currently available or in development. It's based on the "end replication problem" that we've known about for over 30 years: the fact that, when a cell divides and its DNA is replicated, the very end of each chromosome loses a small amount of DNA. Human chromosomes are built in such a way that, if human cells divide more than about 50 times, they lose enough DNA to make their chromosome ends misbehave and join together. We have a special enzyme called "telomerase" that solves this problem in our gonads (which have to solve it somehow, so that children are not born with shorter chromosomes than their parents), and which is also active at low levels in some particularly frequently-dividing cell types such as blood stem cells. Nearly all cancers turn on telomerase in order to allow them to divide indefinitely; if they couldn't do that they they would never grow big enough to kill us. (Actually a small minority of cancers turn on a different system, called ALT, which stands for "alternative lengthening of telomeres".)

WILT proposes the total elimination of the genes for telomerase and ALT from all of our cells, or at least from all cells that can divide. People are looking hard at suppressing telomerase using drugs, but WILT improves on drug-mediated telomerase inhibition, because the cancer cell cannot mutate to resist this treatment -- it would have to create a whole enzyme, telomerase, out of thin air. The big problem, of course, is that not only would we need really good gene targeting to delete the telomerase genes in tissues that don't rely on stem cells, but also we would have to get really good at regularly replenishing the stem cells in the blood, gut, skin and any other tissues in which the stem cells divide a lot. The idea sounds crazy at first hearing, but it may well be possible, because initial technology already exists to repopulate these stem cells (though in the gut it's only been done in mice so far). The telomere reserve of neonatal stem cells suffices for about a decade, judging from the age of onset of dyskeratosis congenita, a disease associated with inadequate telomere maintenance. So, in theory, a decadal repopulation of all our stem cell populations with new ones whose telomeres had been restored in the laboratory, but which had no telomerase or ALT genes of their own, should maintain the relevant tissues indefinitely while preventing any cancer from reaching a life-threatening stage. Cells already in the body would need either to be killed off without killing the engineered cells (in the case of stem cells for rapidly renewing tissues like the blood) or or to have their telomerase and ALT genes deleted in situ (in the case of dividion-competent but normally quiescent cells like the liver or glia); both approaches are, again, already close to being technically feasible in mice.

Talks on this topic at IABG 10:
de Grey      Broccoli      Kmiec

Talks on this topic at SENS2:
de Grey      Marciniak      Goodwin      Blasco      Porteous      Margison      Stelzner