Aubrey de Grey of the SENS Research Foundation needs little introduction to the audience here. His efforts and those of his allies have gone a long way towards ensuring that we will benefit from the first generation of rejuvenation therapies to emerge over the years ahead. The interviewer here is focused on the science of SENS, the Strategies for Engineered Negligible Senescence, a recipe for the control of aging through periodic repair and reversal of its root causes. I encourage you to read the whole interview rather than just the snippets below; it is fairly long.
Feinerman: The past five years have been remarkable. Now every day I read new articles and news about age reversal. I believe we will remember 2016-2017 as the most important years. Do you share this feeling?
de Grey: Yes and no. Yes, in the sense that there are indeed more and more exciting breakthroughs being made in the lab - and of course I am very proud that SENS Research Foundation is responsible for some of them. But no, in the sense that there is still a terribly long way to go; we need to fix a lot of different things in order to get rid of ageing, and for some of them we are still at a very early stage in the research.
Feinerman: Your famous book "Ending Ageing" was published 10 years ago. Would you like to make a new version?
de Grey: I probably should, at some point, but it's not a priority, because the overall approach that we described in that book has stood the test of time: we have made plenty of progress, and we have not come across any unforeseen obstacles that made us change course with regard to any of the types of damage.
Feinerman: You look for bacteria who feed on dead animals to find enzymes capable of breaking glucosepane. How do you find useful bacteria?
de Grey: We are using a "metagenomic" strategy for identifying enzymes that can break glucosepane: we take standard E. coli bacteria, we break one or two of their genes so that they become unable to synthesise one or another chemical (in this case typically arginine or lysine) so that they need to take it up from their surroundings. Then we add random DNA from the environment, which could come from any bacteria, even unculturable ones, and add bits of it to the E. coli. Very occasionally the new DNA may encode an enzyme that breaks glucosepane, and if so, the bacteria will grow even without any arginine or lysine in the environment, if (but only if) we give them glucosepane instead and they break it to create arginine and lysine.
Feinerman: In your book you proposed Whole-body Interdiction of Lengthening of Telomeres (WILT) - the removal of telomerase in all cells in order to prevent cancer and reseeding stem cell populations regularly. Has there been any success in that?
de Grey: We are making progress there, yes; in particular we have shown that telomerase-negative stem cell reseeding works for the blood. However, no, the problem with non-integrating telomerase is that it will extend cancer telomeres just as much as normal cells' telomeres. I support that research, though, not least because there may be breakthroughs in combating cancer in other ways (especially with the immune system), in which case it would be much safer to stimulate telomerase systemically.
Feinerman: Now we have very precise CRISPR, and removing genes is easier than inserting ones because you can target the same cell more than once. When we solve delivery problems will we be able to apply WILT?
de Grey: Yes, certainly.
Feinerman: Why can't we remove telomerase locally in compromised tissue?
de Grey: It's being tried, but it is very difficult to make the removal selective.
Feinerman: There is growing evidence that epigenetic changes are highly organized and may be one of the causes of ageing. What do you think? Maybe should we consider epigenetic changes as another type of damage in SENS model, calling EpiSENS?
de Grey: We need to be much more precise with definitions in order to answer your question. Epigenetic changes can be classified into two main classes: shift and noise. Shift means changes that occur in a coordinated manner among all cells of a given type and tissue, whereas noise means changes that occur in some such cells but not others, increasing the variability of that type of cell. Shifts are caused by some sort of program (genetic changes to the cell's environment), so yes, they can potentially be reversed by restoring the environment and putting the program into reverse. Noise, on the other hand, is not reversible. And we have for several years worked on determining whether it happens enough to matter in a currently normal lifetime. We have not got to a definitive answer, but it's looking though no, epigenetic noise accumulates too slowly to matter, other than maybe for cancer (which, of course, we are addressing in other ways).
Feinerman: Should we use reprogramming factors to reverse the epigenetic program?
de Grey: Probably not. There may be some benefits in doing so, as a way to restore the numbers of certain types of stem cells, but we can always do that by other methods (especially by direct stem cell transplantation), so I don't think we will ever actually need to dedifferentiate cells in vivo.
Feinerman: What do you think of the idea of Whole-body Induced Cell Turnover (WICT)?
de Grey: The general idea of accelerating cell turnover is definitely a good one. It is a bit like the idea of replacing whole organs: if you replace the entire structure, you don't need to repair the damage that the structure contains. However, also like replacement of organs, it has potential downsides, because evolution has give us a particular rate of turnover of particular cells, and the function of each of our cell types is optimised for that. So it may end up being complicated, with many pros and cons.
Feinerman: Won't it be easier to print or grow new organs instead of rejuvenating the old ones?
de Grey: That's absolutely correct. I expect that in the early days of implementing SENS, some organs will be easier to replace than to repair. However, of course replacing an organ requires invasive surgery, so we will want to develop repair eventually.
Feinerman: What in your opinion will be the order of arrival of rejuvenating therapies?
de Grey: Well, a lot of the stem cell side of things is in clinical trials already, and removal of amyloid is there too in the case of Alzheimer's. Next on the list will probably be senescent cell ablation, which Unity Biotechnology are saying will be in the clinic next year, and removal of intracellular garbage for macular degeneration will also be, courtesy of our spinout Ichor Therapeutics. The other three are harder but they are all chugging along!
Feinerman: There are about twenty various types of amyloids, we can see some success in removing transthyretin and beta-amyloid. What is about others? Can we scale success in removing the above two on the others?
de Grey: I'm very confident that the removal of other amyloids can be achieved using more or less the same methods that have worked against those two. The next one on my list would be islet amyloid, which contributes to diabetes.
Feinerman: When I ask people to donate to SENS Research Foundation they often say that their a few bucks don't matter. What can you say to our readers to encourage them?
de Grey: One way to say it is to calculate how many dollars it would take to save a life by donating to SENS. I estimate that a budget of $50 million per year would let us go three times faster than now and would bring forward the defeat of ageing by about a decade. About 400 million people die of ageing in a decade, so that means donating to SENS has a bang-for-the-buck of roughly one life per dollar. No other cause comes anywhere near that.