Two types of change accumulate in our chromosomes as we age: mutations and epimutations. Mutations are changes to the DNA sequence itself whereas 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 render them both harmless in the same way. For brevity, the term "mutations" is used below to refer to both types of changes.
This is an area of aging in which evolution has done the really hard work for us. We have an enormous amount of DNA – about 3 billion base pairs – and the job of keeping it intact and functional is incredibly complicated. But, through evolution, the necessary sophistication has developed. We're particularly lucky in one way: evolution (since the emergence of vertebrates, anyway) has faced 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, 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. Because the same maintenance machinery repairs and proofreads all genes – not just the ones that are more commonly involved in cancer – the fidelity of the entire code gets maintained at the very high standards that already keep us from getting cancer for many decades. So, even genes that don't usually contribute to cancer if mutated get a free ride; they are already maintained far better than we need them to be in anything like a normal lifetime. For rather esoteric reasons, this theory is called protagonistic pleiotropy (PP).
It's possible that non-cancerous mutations may still cause us some problems, such as mutations that kill cells in very small populations (where the loss of even a few cells can have a significant effect on function), or that cause cells to enter into a metabolic state that makes them toxic to their neighbours (so that damage to just a few isolated cells causes problems to normal, unmutated cells around them). However, these special cases need not concern us here because they are dealt with by other arms of the SENS platform: stem cell therapy and selective removal of toxic cells.
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. WILT (which was the topic of the third SENS Roundtable) is an acronym 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 is based on the one inescapable vulnerability that all cancer cells share in common: their absolute need to renew their telomeres, the long stretches of gibberish DNA that cap their chromosomes. Telomeres fulfil a role that is similar to that of the nibs on the tips of your shoelaces, keeping the DNA from becoming frayed and unravelled. Each time a cell reproduces, the telomeres become a little worn down, and when a cell runs out of telomeres it quickly self-destructs. Because cancer cells reproduce at a furious pace, they quickly reach the ends of their telomeric "ropes", and need to find a way to exploit the cell's natural machinery for renewing telomeres (telomerase and ALT) to restore normal telomere length, or their growth will come to an end. The thorough elimination of these genes from all of our dividing cells thus spells the doom of cancer.
Some scientists that have previously thought along these lines are trying to accomplish the same thing by developing drugs to inhibit these enzymes, but this approach suffers the vulnerability that cancers could evolve a whole host of minor changes that reduce such drugs' effectiveness. WILT, by contrast, removes the genes altogether, making it impossible for cancers to continue growing unless they manage to create a whole new telomerase or ALT enzyme out of thin air – a vanishingly unlikely possibility.
This is a bold idea, but it may well be possible not only to delete the gene, but to keep our bodies supplied with normal cells, because the technology already exists to repopulate the stem cells of the blood and (in mice) the gut, and the skin shouldn't be too tricky either. The telomere reserve of our stem cells is enough to keep normal cells going for about a decade, judging from the age of onset of dyskeratosis congenita, a disease associated with inadequate telomere maintenance. So, in theory, the replenishment of all our stem cell populations once a decade with new ones that have no telomerase or ALT genes of their own, but whose telomeres had been restored in the laboratory, should maintain the relevant tissues indefinitely while preventing any cancer from reaching a life-threatening stage.
To make this work, cells already in the body (and therefore equipped with the potential to have their native telomerase enzymes activated) would need either to be cleared out so that only engineered cells remain (in the case of stem cells for rapidly renewing tissues like the blood), or to have their telomerase and ALT genes deleted (in the case of cells from tissues that aren't routinely renewed, and that we therefore can't afford to simply remove and replace). Both approaches are, again, already close to being technically feasible in mice, with blood and gut tissues already replaceable and the skin and lungs not far behind (and under hot pursuit).
SENS Foundation is planning three projects in the OncoSENS strand.
The first project aims to characterise the enzyme responsible for ALT, which is still unknown. Recently, however, observations in two different organs have given good reason to consider a hitherto unsuspected gene. A relatively simple series of experiments could test this hypothesis.
The second project addresses a potential problem with the WILT strategy. It's possible that telomerase activity per se – independent of telomere length – may have roles in maintaining the health of the stem cells themselves, or of their rarely-dividing neighbours in the so-called "stem cell niche". We are arranging a project to address this question, in the blood of mice, with the world's leading professor in the area.
Finally, the theory that non-cancer-causing mutations are unlikely to be harmful in a normal lifetime – protagonistic pleiotropy – is not yet widely accepted. We are therefore seeking to initiate a rigorous study into the effects of such mutations.
Talks on this topic at IABG 10: de Grey, Broccoli, Kmiec
At SENS2: de Grey, Marciniak, Goodwin, Blasco, Porteus, Margison, Stelzner
