Starting to Make SENS
Dr. Aubrey de Grey is a pioneering theoretical scientist in the field of human aging (biogerontology). He is well known in many scientific and Transhumanist circles, and has attracted many supporters and critics because of his claims that human aging can be eliminated as a cause of death in our lifetimes, pushing human lifespans into the hundreds of years. De Grey’s plan to defeat aging is called “Strategies for Engineered Negligible Senescence” (SENS), and is comprised of a wide array of cutting-edge medical therapies meant to reverse the damaging effects of the seven biochemical causes of aging. He recently published a book entitled Ending Aging, which discusses SENS in great depth. Useful background information on SENS can be found at SENS.org.
De Grey holds a B.A. in Computer Science from Cambridge University, and was awarded a Ph.D from the same institution for later work on the interplay between mitochondrial mutations, free radical production, and human aging.
David Germino for H+ magazine: Thank you for joining us, Dr. de Grey. To begin, your theory to end aging and to extend human lives for hundreds of years will certainly strike many readers as shocking. Surely, common criticisms to your ideas will include:
a. Indefinite lifespans would lead to overpopulation, and we would all either die from starvation, or if we lived, the quality of life would be terrible because it would be so crowded.
b. Living for hundreds of years would get really boring and wouldn’t be worth it.
c. Living for hundreds of years would be agony since your extra years granted by medical science would be spent as a sick, bedridden old person.
d. It is immoral and selfish to devote money to keeping a couple of elderly, rich Westerners alive past their normal human limits when there are millions of poor people in the Third World dying at young ages of diseases that we could more cheaply alleviate or cure.
e. Using science to extend one’s lifespan indefinitely is against God, and if you do it, you go to Hell.
f. People who want to cure aging are just afraid of death. Being afraid to die is cowardly, selfish and abnormal. When it is your time to go, you should do so like a brave person and to make room for everyone else.
What are your counterarguments to these points?
Aubrey de Grey:
a. We could choose to avoid these problems either by not using the anti-aging therapies or by having fewer kids, or by technological improvements to manage a higher population. Future generations have the right to make that choice for themselves, not to have the choice of not using the therapies imposed on them by our failure to develop the therapies.
b. Maybe some people would not know what to do with the extra time, but plenty of people would, and we should develop these therapies for them.
c. No – being frail is risky, so the only way we’ll ever extend life is by extending healthy, youthful life.
d. It’s not a zero-sum game: the political problems in saving African children are independent of the scientific problems of saving elderly Westerners. Besides, isn’t ageism supposed to be bad? And what could be more ageist than to say that the elderly don’t deserve life-saving therapies?
e. On the contrary, using science to alleviate the suffering of aging is mandated by God, and doesn’t stop Him from pushing you under a truck when he wants to call you to the next world.
f. The longevity benefits of these therapies are not the main purpose; they’re a side-benefit. The main purpose is to stop people from getting Alzheimer’s, or cancer, or heart disease, or diabetes. It just happens that the way we’ll do that will also make people unlikely to die peacefully in their sleep.
H+: You have repeatedly said that SENS will slow and then reverse the aging process by improving organ function and tissue quality, in turn allowing older people to biologically rejuvenate themselves. But what consequences do you imagine SENS would have for one’s external appearance? Could you “go back” to a youthful appearance of your choosing, would you be stuck looking like an octogenarian (albeit a very healthy one), or would you look really bizarre in some way?
AdG: SENS will rejuvenate the outside of the body just as thoroughly as the inside. Thus, indeed, you would revert to a youthful appearance of your choosing.
H+: SENS describes a whole battery of medical treatments that could theoretically defeat the aging process. These treatments range from relatively simple ones like injecting people with enzymes that can break down tough wastes inside of cells, to highly advanced ones like genetically altering trillions of somatic cells in full grown adults. Considering the differential technical challenges, what SENS therapies will most likely become available first, and which will be developed last?
AdG: Some of them are already pretty close: probably the closest is in fact not the enzyme therapy you mention, but the use of vaccines to eliminate extracellular aggregates (especially amyloid). But when we consider the others, actually I wouldn’t like to make the call, because the hardest ones are the ones that the SENS Foundation and I are prioritizing in terms of the early research. In other words, we’re hoping that they will start to catch up with the easier ones. I suspect that the challenge of genetically modifying a high proportion of cells by somatic gene therapy will have been largely solved before we complete the development of all the genes that we want to introduce.
H+: How long will it be until the various SENS treatments are available?
AdG: I think there’s a 50% chance of getting the first-generation SENS therapies working within 25-30 years. But that’s only an estimate, and it’s a highly speculative one: I think there’s at least a 10% chance that we will hit so many unforeseen problems that we won’t get there for 100 years. This is not something special about SENS, though: any technology that’s two or more years away could easily be 100 years away.
H+: In Chapter 14 of Ending Aging you remark:
“We will almost certainly take centuries to reach the level of control over aging that we have over the aging of vintage cars—totally comprehensive, indefinite maintenance of full function—but because longevity escape velocity is not very fast, we will probably achieve something functionally equivalent within only a few decades from now…”
Should this be taken to mean that you don’t believe medical science is improving at an exponential rate?
AdG: No – it’s just because the defeat of aging gets harder and harder as we push lifespans out further.
H+: Are you worried that a single company or government might obtain the secrets to longevity first and then use its monopoly on the science to hold the human race hostage forever (or even for just a long period of time)?
AdG: There’s no chance whatever of this scenario, because the defeat of aging will depend on the simultaneous application of a lot of different interventions, all of which will first have been developed in the laboratory rather than in humans.
H+: One plank of SENS is something you call “Whole body Interdiction of Lengthening of Telomeres” (WILT). The treatment involves the use of gene therapy to eliminate the ability of all somatic cells to lengthen their own telomeres, which should lead to the total defeat of cancer. Of course, this would also severely limit the number of times the cells could reproduce before dying, meaning organs and tissues composed of WILT-modified cells would “wear out” after only a few years, killing the person. Your solution is to periodically replenish WILT organs and tissues with implantations of healthy, young, genetically engineered stem cells, which would proliferate in place of their failing predecessors, keeping the organs and tissues going. But how come you don’t discuss the more obvious solution to the problem—organ replacement? Couldn’t we just grow entire new body parts in vitro and then implant them into aged people via surgery as the old ones wore out?
AdG: The problem with organ replacement for WILT is that the tissues that would be most affected by the loss of telomere elongation capacity are mostly not amenable to transplantation. It might in principle become possible to grow lungs outside the body, but it’s a long way away, and it’s probably even harder to grow intestines. And for the other two main examples, the skin and the bone marrow, transplantation of pre-fabricated tissue is basically inconceivable, whereas stem cell replenishment is quite foreseeable (and in the case of bone marrow is already relatively routine).
H+: Let’s say I am a very old man who is going to the doctor for his first WILT treatment. What exactly happens to me? Do they stick needles into my body to inject in new stem cells, or do I just take pills? Do I have to stay there for an extended period of time? Do I have to visit multiple times for each treatment? How do I feel during all this? Does my external appearance change during the procedure?
AdG: Stem cell treatments are mostly done with injections, but some of them (including ones for WILT) will be done from the outside, using technologies borrowed from cosmetic surgery for example. At first, these therapies will be quite experimental, so people will need to be monitored carefully for a while, but that will be a temporary phase. I don’t think the patient will feel unusual or experience any change of appearance.
There should be no perceptible “macro-changes” as a result of WILT—the idea is to stop cancers from getting large enough to be noticed at all.
H+: You and even your opponents agree that genetic mutations are a major cause of aging (though you disagree with them on important specifics). Your solution is WILT, but what do you think of the possibility that advanced nanomachines could be injected into aging people for the purposes of DNA repair, which would obviate the need for any new cell transfer?
AdG: I think we may indeed be able to use nanomedicine to repair the body in the future – in fact, we will probably be able to do many things that way that we can never do with straight biotechnology, and repairing mutations is one good example of that. But I don’t think we’ll be able to develop those nanomachines very soon, so I want to figure out how to keep us alive until then.
H+: The previous question brings up a second one. As people age, their nuclear DNA (nDNA) accumulates damage and mutations. If mutations occur to a few critical genes in a cell, the cell will become cancerous, which everyone—including you—agrees is very bad. But you diverge from other biogerontologists in your view of how harmful non-cancerous DNA mutations are. Many of your professional critics believe that accumulation of large amounts of damage is a major contributor to aging and death among people who currently live to normal ages. You, on the other hand, dismiss this view and say that non-cancerous nDNA mutations do not cause health problems in normal people since the genome can absorb a lot of damage thanks to redundancy and sheer size. But you also add that, if SENS were successfully developed and human lifespans were extended into the hundreds of years, non-cancerous nDNA mutations would have time to build up to lethal levels in people. A cure for this would therefore have to be found at some point in the distant future. So, after SENS were implemented, what sorts of medical conditions would people still die from? What would “SENS II” look like?
AdG: Because SENS has so many components, it’ll be undergoing enhancements continuously after its first version arrives. Most of these enhancements will be conceptually quite minor – one more enzyme to get rid of a slowly accumulating target junk molecule, one more cell type that we need to replenish because too many cells have died, etc. But you’re right; occasionally there will need to be more major enhancements. I don’t know in detail how we’d cope with non-specific mutation accumulation – if I did, I’d suggest that we deal with it now, just in case my analysis of the non-importance of those mutations in a currently normal lifetime is wrong – but I expect it’ll involve an increased use of tissue engineering for most tissues, and in those where that’s impractical (especially the brain) a very mild stimulation of cell death combined with cell replacement from stem cells.
H+: What do you mean by “tissue engineering”?
AdG: It’s not my term…see http://en.wikipedia.org/wiki/Tissue_engineering
H+: In Ending Aging, you are quick to caution that SENS won’t impart true immortality since people will still die from accidents, homicides, and suicides, though such fates might not be met for hundreds of years. If one’s objective is to live as long as possible and in as good a condition as possible, wouldn’t it be the logical next step after SENS to go beyond the frailties of biology and to start using cybernetics, which would make one less vulnerable to fatal injuries? After all, even a SENS-engineered heart will have a much shorter useful life and will be much more damage-prone than some type of advanced mechanical heart, just to cite one example. Wouldn’t cybernetics solve the problems of aging and death more conclusively than any biology-based therapy could?
AdG: Yes, certainly — and I do indeed expect that humanity will work harder than it does today to reduce the risk of death from causes other than aging, once it no longer has aging to worry about. Even simple things like spending more money on vaccine development will make a big difference. But even a completely cybernetic human will not be immortal: a nearby star can still explode and suck us into a black hole, or vaporize us…
H+: At one point in your book, you criticize the Food and Drug Administration’s (FDA) drawn-out medical approval process and suggest that drugs should instead be approved after completion of Phase 2 trials. Why do you want such a change, and won’t it lead to more deaths thanks to unsafe drugs and medical procedures becoming available?
AdG: I want this change because it will save more lives than it costs. This question has been carefully analyzed by experts and it’s clear that we are vastly over-cautious now in approving drugs. That over-caution is not the fault of the FDA or the government, because it reflects public attitudes: every death from an unsafe medical treatment causes an outcry and a lot of legal action, whereas we turn a blind eye to death from the unavailability of good drugs. But when aging is recognized as defeatable, public opinion will become more rational in this regard, and so will public policy.
H+: In Ending Aging, you complain that the biggest hindrance to antiaging research is the widespread belief that aging is not curable. Unlike you, most people simply don’t think that aging can be slowed or reversed, and they will either ignore or try to fight the science underlying your ideas. This also cuts potential public funding for your research since most people consider it a hopeless cause. You say that the only way to overcome this will be to conclusively demonstrate in the lab that mammalian lifespans can be greatly extended. “Robust Mouse Rejuvenation” (RMR) as you call it, would involve using SENS therapies to make mice live for five years instead of the normal three. You believe that, once this is accomplished, scientists and average people all over the world will be forced to realize that aging is, in fact, a treatable disease, leading to shifts in medical spending priorities and attitudes that would favor your cause. To encourage research into mouse longevity, you have created the Methuselah Mouse Prize (MPrize), which metes out monetary rewards to scientists who find new ways to make mice live longer. Research inspired by the MPrize could lead to RMR.
H+: However, the lab studies cited in Ending Aging repeatedly show how medical mouse research has limited usefulness since human and mouse biochemistries are very different. So certainly, even if RMR were achieved, many scientists would publicly protest that the antiaging therapies could not be applied to humans owing to different biology. With that in mind, why do you put so much value on the Mprize? Aren’t you worried that mouse life extension still won’t convince people that the same is possible in humans?
AdG: Actually the Mprize is not quite the point here: its main value is shorter-term, raising the profile of longevity research in the minds of people who don’t like to think about science but are excited by world records and such like. What you’re referring to, the RMR milestone, is not the subject of a prize (though it may be in the future. So, to answer your question: you’re quite right that when RMR is achieved most biogerontologists will (correctly) say that this doesn’t tell us that RHR (the human equivalent) is just around the corner. But they will change their stance somewhat from what they tend to say today: they’ll accept that the achievement of RMR makes it only a matter of time before RHR is achieved, whereas today most of them are not persuaded that the repair-and-maintenance approach to postponing aging will ever work. Yes they’ll mostly decline to say how long, and indeed there will still be a substantial chance that RHR will take 50 or more years after RMR. But I feel sure that a public expert consensus that achieving RHR is only a matter of time will be enough to induce key opinion-formers (Oprah, for example) that humanity must prioritise making that time as short as possible. And that’ll be all it takes to make the public adopt that same view, which will immediately alter public policy accordingly.
H+: Can you explain how the immediate and ultimate goals of the MPrize differ, and how short-term MPrize-inspired lab results will eventually lead to RMR?
AdG: The short-term work inspired by the Mprize will probably not be a major contributor to RMR, in my view, because it will be focused on “magic bullets” — ways to “tune” the mouse body to make the most of its existing genetic makeup. RMR will only happen when we have pretty comprehensive repair and maintenance, which is a very different approach.
H+: Can you go into detail describing the sequence of changes (behavioral, attitudinal) that will sweep the general public, scientific academia, influential celebrities, and politicians during the period between the achievement of RMR and the start of RHR (Robust Human Rejuvenation)? How will the different groups feed back with one another during this process?
AdG: I think almost all the changes will happen very quickly as soon as RMR is achieved — or maybe even sooner. The trigger will be when laboratory studies convince most biogerontoloists that the “repair and maintenance” approach to combating aging has really become feasible. As soon as that happens (and, as I said, it may happen as a result of earlier, less impressive results than RMR), they will start to say so on the television. I don’t think it will take more than a day before Oprah and other popular opinion-formers respond by saying that society has an unprecedented moral obligation to make that happen for humans as soon as possible. It will probably take no more than a week before people who are worried about looking stupid, such as politicians and religious leaders, follow suit (after seeing that there is no alternative). And by then, the public will be in uproar, the FDA and its counterparts elsewhere will be in the process of complete reconstruction to accommodate society’s changed priorities, and all the other changes to public policy will be underway just as rapidly as things change at the beginning of a war. (I mean a “real” war, of course, i.e. a war that threatens to kill large numbers of people on both sides.)
H+: Wait a second. You complain about how traditional attitudes towards aging seriously impede efforts by yourself and some other scientists to gain support for new antiaging research. (Somewhat ironically considering the topic of your book, you cite the quote: “Science advances funeral by funeral” to summarize your point and to express your frustrations.) Specifically problematic are conservative scientists who peer review funding requests and turn down proposals for things like SENS because it sounds unorthodox and risky. Aren’t you worried that, in a SENS-enabled future world full of 1,000-year-old people and relatively small numbers of fresh-minded youngsters, this problem of orthodox attitudes arresting progress will become all the worse?
AdG: No, because society will be able to respond if that happens by inducing senior scientists to switch to other careers. That will probably be a useful thing to do for all professions, not only science.
H+: Wouldn’t longevity disrupt natural parent-child human relationships? After all, if you have a child when you’re 30, and then both you and your child live for hundreds of years — with your biological ages fixed at a certain youthful point — the advantages of experience and maturity naturally held by you as the parent would become vanishingly small over time. And without death, your children wouldn’t function as replacements for you, but rather might become vaguely like siblings. Do you agree with this assessment, and do you think they stand as arguments against developing life-extending technologies?
AdG: I think this argument is very true – children would indeed rise to the equivalent of siblings. But that’s just what happens to a lesser extent today: 60-year-old parents usually treat their 35-year-old children as equals. I can’t see anything wrong with that, nor with taking it further.
H+: Going back to the aforementioned scenario, how do you think longevity-related changes to the parent-child relationship might, over time, affect peoples’ decisions to reproduce?
AdG: I think the main change will be that we will see an extension of the current trend to have kids later in life. The main reason so many women have their first kids in their late 30’s is surely because it’s then or never. One of the things we’ll do by defeating aging is to remove that deadline, so a lot of women will probably delay their child-bearing even more.
H+: The BBC recently did a documentary about you entitled: “Do you want to live forever?” Towards the end, the interviewer had you present SENS to a neutral scientist named Dr. Martin Raff for evaluation. During the scene, Dr. Raff was critical of SENS and of you, and he said that you were scientifically inexperienced and “too bloody ignorant.” Is there anything you would like to say about the documentary and its conclusions or about this particular exchange?
AdG: The documentary overall was pretty positive. Like any such programme it needed to demonstrate “balance” — so it needed to give a fair amount of air-time to my critics, since there’s no question that I have quite a few – but I felt it gave my side of the story very effectively, so that was fine. (There was a major blooper near the end, where the film-makers gave the impression that I’d been fired from the University of Cambridge for using my department’s web site to promote SENS — for the record, I had clear written permission to use that website in that way and I certainly wasn’t fired, I gave four months’ notice when I went full time with the Methuselah Foundation — but that was an isolated error.) Regarding Martin Raff: clearly my proposals are highly radical and I come to very dramatic conclusions, so it’s entirely appropriate for scientists to be very skeptical at the outset; what’s less appropriate is for them to state that skepticism publicly when they know they’ve heard hardly anything about the logic by which I reach my conclusions. All in all I think that was reflected well: Martin was shown not giving me a chance to answer his points properly, and he was quoted saying immoderate things like “he should be sent to jail,” so I think he was portrayed as not quite the model of objectivity one might have wished for.
H+: In Chapter 3, you talked about how the availability of food in the environment alternatively favors either low-reproduction, long-lived organisms or fast-reproducing, “sloppily constructed” organisms. What does “sloppily constructed” mean, and can you elaborate on the whole theory?
AdG: I use this phrase quite broadly, because it surely has quite a lot of manifestations, but I’ll focus on the most obvious one. Cell division requires DNA replication, and also the preservation of the epigenetic state (which genes are turned on and which are off) of the genome via chemical modification of the DNA bases and the proteins that the DNA is wrapped around. DNA replication is extraordinarily accurate, but it still makes occasional errors, and these errors are mostly repaired by “proof-reading” mechanisms. But if cell division is very fast and furious, there is that much less time for those errors to be caught, and they become undetectable (for example, because after one replication with an error there is a base-pair mismatch, but after two replications there is only heterozygosity).
It’s even worse for epigenetic errors (epimutations), because there the cell is often required to make deliberate changes to daughter cells relative to the mother cell that divided, due to the cell’s requirement to differentiate. So the faster an animal grows (and thus divides its cells) the more mutations and epimutations will occur per cell division. The mutations may not matter too much in most ways, but they’ll definitely cause the animal to get cancer at an earlier age than otherwise. But the epimutations will affect all aspects of the animal’s metabolism – all its tissues will behave just slightly (or maybe not so slightly) sub-optimally, with the result that the animal can’t quite run as fast, or isn’t quite so able to fight off infections, or whatever. For evolution, this doesn’t matter much to the individual’s offspring, because the epigenetic state is reset and rebuilt after fertilization. But that’s only true if the individual lives long enough to HAVE those offspring! So when there’s lots of food around, the thing to do is to grow as fast as possible and start having offspring before you’re eaten – you may be a bit more susceptible to getting eaten because you grew sloppily, but that’s outweighed by the opportunity to have offspring at a young age. But when there’s not much food, there’s not much point in having offspring, because they’ll probably die of starvation before having their own. So it makes sense to take the time to build yourself really carefully, so as to have the best chance to survive the famine in a good enough state to be able to have offspring when food returns.
H+: Caloric restriction (eating a low-calorie diet daily for years on end) is something that has been proven to reliably extend lifespans in many different types of animals. Scientists also strongly suspect that it does the same in humans, and drugs that chemically mimic the effects of caloric restriction are being developed (notably, by Sirtris pharmaceuticals) as a way to prolong human life. What do you think of the life-extension potential for caloric restriction drugs in humans, would you recommend that people take such drugs once they become available, and what is the relationship between SENS and caloric restriction (particularly, would one impede the effects of the other in the same person)?
AdG: I think calorie restriction will indeed work in humans – but not very well. I expect it to give people a year or two of extra life (and of course proportionately less when started later in life, just as we see with rodents). This is because (a) we see a much more extreme life-extension response to nutrient deprivation in really short-lived organisms (such as flies and worms) than in longer-lived ones like mice (and even less in dogs, though that’s only been tested once), so by extrapolation we’d expect even less in humans, and (b) from a theoretical standpoint, the evolutionary pressures I describe above for slow versus sloppy growth apply less to longer-lived organisms. But I figure that even a year or two is better than nothing, and far from impeding SENS it would synergize with it, in the sense that some people would live long enough via CR to be able to benefit from first-generation SENS therapies, when without CR they’d be dead (or too nearly so) by the time those therapies are developed. As for CR mimetics, I think there’s a good chance that we can indeed develop drugs that confer as much or nearly as much longevity benefit as CR itself. There’s a big challenge in terms of making sure that any drug that one is going to take for many years has no long-term side-effects, of course, but once that has been determined I think it would indeed make sense to take such drugs.
H+: But just to be clear, calorie restriction and SENS are two, separate things that could be done in the same person for additive health benefits, right?
AdG: Right, absolutely.
H+: Do you think that consumption of antioxidants or alkaline water improves health or extends life? If yes, then to what degree?
AdG: Alkaline water is quite definitely useless, because it stops being alkaline essentially as soon as you ingest it. Today’s antioxidants are probably useless too, because they do good in some parts of the body but harm in others – they have hardly ever had beneficial effects in rodent studies. People are working on cleverly designed antioxidants that may preferentially localize to the places where they’ll do good, and we’ll have to see how useful they are.
H+: Though you advocate the use of radical technologies to improve human life, you responsibly note that traditional practices like good diet and exercise are the surest ways to long life and health. What specific lifestyle choices and habits do you most recommend? Are there any particular diet/exercise books you like?
AdG: The only big thing I can say about this is that books are not the whole answer. If you want to do better than you would just be doing what your mother told you—not smoking, keeping a constant weight, and eating a balanced diet. Beyond that, the biggest thing is to pay close attention to your body and do what your body seems to like. No two people are metabolically identical, so what works for one person may be bad for another. So books can tell you some basics, but they’re never the whole story.
H+: What is an average day for Aubrey de Grey like? First of all, when you wake up in the morning, are you in the U.S. or the U.K. (i.e. — Where do you live)?
AdG: I am based in the U.K., but today I woke up in the U.S…I spend a lot of my time traveling, especially to the U.S.
I don’t really have an average day. When I’m traveling, my day is full of lectures, fundraising meetings, interviews, and keeping up with my email. When I’m in Cambridge, U.K., my day is full of, well, keeping up with my email… and also interviews: I do over 100 per year.
H+: Thanks a million for joining us, Dr. de Grey! Best of luck with SENS and all your endeavors!
AdG: My pleasure. Thanks for your interest!
This interview was conducted via email. The interviewer was Eddie Germino.