ENDING AGING

AN INTERVIEW WITH AUBREY DE GREY

BY MARK SACKLER

Looking at Aubrey de Grey for the first time, his long bushy brown whiskers and sage countenance might remind you of Methuselah. How appropriate. That look is probably intentional. Though he originally trained in artificial intelligence, he has emerged as one of the world’s leading researchers in the field of human biological rejuvenation.

In fact, he founded the Methuselah Foundation in 2004 to endow human aging and rejuvenation research. He followed that up by authoring Ending Aging, The Rejuvenation Breakthroughs That Could Reverse Aging in Our Lifetime in 2008, and co-founding the SENS Foundation a year later. SENS, which stands for Strategies for Engineered Negligible Senescence, is a non-profit organization that researches the science of aging and possible means to reverse it. He serves as its chief science officer.

In Ending Aging, de Grey cited 7 types of intra- and extra-cellular damage that accumulate in the human body as it ages. Nine years later, he still sees those same 7 as the critical issues in understanding—and eventually reversing—human aging. But two significant things have changed in the ten years since he published that volume.

First, research into human biological rejuvenation has moved into the mainstream of research from the fringes. Any number of for-profit biotech ventures have started up, a longevity venture fund has received backing from some of the top names in Silicon Valley, and even some clinical trials are on the cusp of launching. The SENS Foundation itself has received backing from the likes of Peter Thiel and Ray Kurzweil.

Second, the emergence of breakthrough genetic editing techniques, such as CRISPR/Cas9, have pointed the way to accelerated progress in developing age-reversing genetic therapy. At least two individuals have tested genetic therapies on themselves within the past two years, both with initially promising results.

I spoke with de Grey recently in an interview for my Seeking Delphi™ podcast, regarding progress since the 2008 book, and the current state of the anti-aging art.

Mark Sackler: You wrote the book Ending Aging in 2008. You identified seven areas of cellular and intracellular damage that you think need to be reversed as the best process for reversing aging. In the nine years since you wrote that book, what has changed? Are we where you thought we’d be by now? Have there been any breakthroughs?

Aubrey de Grey: People often ask me, “When are you going to write a new book—when are you going to update Ending Aging?” It’s not a priority right now. It could easily be presumed to be saying that it’s not my priority simply because I haven’t made much progress and there’s not much to say. But it’s just the opposite of that—there’s been massive progress, but it’s been pretty much exactly the progress that we were predicting in the book. So essentially the plan is the same 7 points. There’s no problem number 8 or 9 that came along and had to be added.

“There have been some surprises, but they have all been good surprises in the form of innovative technologies­—new discoveries that have allowed us to pursue the same approaches but more effectively and more rapidly than we otherwise thought.”

And furthermore, the solutions that we discussed in the book are still the same solutions. There’s nothing that has come along that has made us have to revisit it and say, well, OK, the approach that we thought was going to be the right way to go is actually much harder than we had expected and therefore we need something else­­—none of that has happened. There have been some surprises, but they have all been good surprises in the form of innovative technologies­—new discoveries that have allowed us to pursue the same approaches but more effectively and more rapidly than we otherwise thought. Now there is one downside, though, which I also want to deal with here. Which is, back then—in fact a couple of years before I wrote that book in 2004—I started making predictions about the time frames of how long this will all take. And of course, I was always making a lot of caveats emphasizing that a prediction of time frames was very speculative for any pioneer in technology. However, the fact is we haven’t hit the time frames I was saying that we would.
I said there was a 50–50 probability of reaching a milestone that I specified and that I named robust mouse rejuvenation within 10 years—from that point of around 2004. And so that’s what’s gone wrong. But what’s gone wrong is not the science, but something else. The answer is the money. The fact is that my predictions were always very strongly conditional on the ability to bring in funding that was sufficient so that the rate of progress would only be limited by the sheer difficulty of the technology, the actual science and practice. I believe we’ve been going along three times more slowly than that initial prediction simply because it’s been so much more difficult than I had expected to attract sufficient funding.

Mark Sackler: You mentioned robust mouse rejuvenation as one of the key milestones along the road to reversing human aging. I’ve read some stories lately that some scientists have claimed to slow or create some minor rejuvenation in mice. Obviously, it’s not what you define as robust. So how do you define it?

Aubrey de Grey: I have defined robust mouse rejuvenation to be taking mice that are already in middle age, before anything has been done to them, and doubling or trebling their remaining time. What that means is you take normal adult mice, with no preexisting problem or had any prior therapy applied to them­­—you want those mice when they’re already two years old and you have done nothing to pharmacological and nothing genetic to them—that would typically live an average of three years (that’s on the long side for mice). And then you throw a whole bunch of interventions at them to turn their last year into three. That’s the definition that I gave to robust mass rejuvenation. Now the things that have been happening recently have been exciting but they’re definitely not doing robust mass rejuvenation at the moment. We still can’t extend the lifespan of mice by more than a couple of months by interventions that are initiated at two years of age.

Mark Sackler: There’s a second critical milestone you cite, that’s LEV, or longevity escape velocity. So obviously we’re nowhere near that. But what is it, and how far away are we from getting there?

Aubrey de Grey: First, let me summarize the definition —it all arises from the fact that progress buys time when you are doing rejuvenation. In other words let’s talk about humans: If we were to take someone who was 60 years old, let’s suppose, and at some point in the future we were at the stage of rejuvenation technology whereby we could buy people 30 additional years of life—so that we would take them and throw a whole bunch of therapy at them that would rejuvenate them reasonably well so that they would become biologically sexy again until they were chronologically 90—if we could do that, then the reason why they would become biologically 60 again at all is because the therapies are imperfect. There will be a huge number of different types of damage that happen that fall into the 7 categories; some of them are just more difficult to manage than others.

So, we end up mending the easy stuff. And we can do that as often as we like. But eventually the initial therapies don’t work, and damage will accumulate to the point where damage is again the same as at 60 years. But because you have those 30 years way before you got to be biologically 60 for the second time, you’ve had time to improve the therapies.

“The definition of longevity escape velocity is simply the minimum rate which we need to improve the comprehensiveness of the therapies to stay one step ahead of the problem.”

And improving means improving the comprehensiveness. It means getting to a point where you can fix some of the difficult damage. Maybe you’ll never be able to effect repair on 100% of the damage, but you’ll be able to fix some of it, which means you will be able to rejuvenate the same people with what we might call SENS 2.0. Perhaps by the time this rejuvenation decays to be biologically 60 a third time, they’ll actually be 150. And so on. The definition of longevity escape velocity is simply the minimum rate which we need to improve the comprehensiveness of the therapies to stay one step ahead of the problem. And longevity escape velocity turns out to be a trivial thing to maintain. The rate of progress that we’re talking about here is minute as compared to the rate of progress that we always see in other technologies historically after the initial breakthrough that solves the fundamental problem. So, the uncertainty of time frames consists entirely of the question of how soon we will reach SENS 1.0. Soon will we do that, and originally my time frame over the past 13 years since I started talking about it has come down only by about 5 years, which is sad, but the reason again is entirely because of a lack of funding.

Mark Sackler: What about using pharmaceuticals or supplements to slow the aging process—to buy more time before we reach SENS 1.0? There are several agents out there now. Metformin is about to go into human clinical trials, Rapamycin is in trials with dogs, and NAD+ supplements are all the rage right now. What’s your take on all of this?

Aubrey de Grey: So I’m all for this work. I think that it’s very valuable in helping people to stay healthy longer. However, there is a very important feature of all of these supplements which is very often swept under the carpet by the researchers and companies that are working on them. They’re all hypothesized to work by calorie restriction memetics. In other words, drugs that trick the body into thinking it’s not getting as many calories as it would like, even though it is getting them. The reason such drugs are so interesting is because 80 years ago it was established that if you feed, say, a mouse or a rat less than it would, like then, it will live longer than it would otherwise live.

And that’s a really important result. And by the 1970s it had become the single most studied phenomenon in the whole of gerontology—and it continues to be. But not eating as much as you would like is not fun. So, if one could develop the drugs that mimic this effect, then you’ve got the best of both worlds: you’ve got the longevity extension and you also don’t have the hunger. So that’s wonderful. Except that there’s a huge catch, and it has been a totally incontrovertible message in the animal data for decades. It is a fairly scandalous thing that has been swept under the carpet.

The problem is that different species respond by different degrees to this kind of restriction. Specifically, long-lived species respond less than a short-lived species. The world record for how much you can extend the life of a nematode worm that normally lives about three weeks is by a factor of five. But then if you go up and look at organisms that live a couple of years, like mice, you can only get a factor of one and a half. That’s still very impressive but it’s definitely not five. But unfortunately, this trend persists as you go higher up the chain.

For example, about 20 years ago you’re in a very thorough and rigorous trial made with Labrador dogs, which normally live about 11 years, and on the whole, it resulted in only about a 10% increase in lifespan. And over the past 20 odd years, two groups in the US have performed extraordinarily expensive and time-consuming experiments of calorie restriction on monkeys, and depending on how you interpret that, it yielded maybe a couple of percent increase. So, the prognosis for humans is not terribly good.

Now again I want to emphasize I’m fine with the fact that people are excited by these drugs, because they do seem to keep people healthy; they are protective, but it is critical not to make the extrapolation that they are the foundation to extending life—because in no way has that happened. We want to pay proper attention and give proper priority to the stuff that will really works.

Mark Sackler: One of the hottest biotech topics lately has been genetic editing, and there have been at least two individuals who recently had genetic editing therapy performed on themselves. They are Elizabeth Parrish, CEO of Bioviva, and Brian Hanley, who has his own one-man biotech operation. I wonder what you make of those two efforts.

“But there are things that CRISPR can’t do—specifically it can’t insert new genes into the genome, and we actually have a very important project that is designed to get around that limitation.”

Aubrey de Grey: Well, first let me talk about gene targeting in general. CRISPR is a fantastic breakthrough. When I was talking at the beginning about the surprises that we’d had, that’s probably the single biggest one—because the fact is that before it came along, there was very little that we could do to change genes. We had methods for gene targeting, for modifying the genome, but they were very laborious and expensive, and it didn’t seem they were going to become any less so. So CRISPR was a huge revelation. But there are things that CRISPR can’t do—specifically it can’t insert new genes into the genome, and we actually have a very important project that is designed to get around that limitation. But yes, basically we can do genetic editing with CRISPR more easily and cheaply and it is getting better all the time—getting more high fidelity and so on.

Now as for self-experimentation—what Liz and Brian have done—one can look at it in a whole bunch of ways. First, one can be curmudgeonly about it and say, well okay, this is very unsafe. God knows what’s going to happen if bad things happen if these people die as a result of that therapy; it is going to set back the whole field to a large degree.

That’s all true up to a point. But at the same time, we have to remember that self-experimentation is not new. It has a long and very distinguished history in biology. JBS Haldane, the distinguished and respected British biologist from the 1930s, was rather famous for doing things to himself that I certainly wouldn’t dare to. So we have to acknowledge that it’s double edged. Certainly, the scientific information that will come from this sort of experimentation effort is probably very limited, simply by the fact that it is a sample size of 1. But on the other hand, the high-profile news that arises and the fact that people are talking about what is happening and a discussion is actually occurring, has its own value. If people are not interested in something, it’s very hard to get them to think about it, whereas if they are interested, even for an unusual and rather tangential reason, you can educate them. In a sense, people like Liz and Brian are helping me.

Mark Sackler: Earlier this year I interviewed David Wood of the London Futurists on his book The Abolition of Aging. You may be familiar with it, since he did mention you more than once in the book. In it he forecast that by 2040 there is a 50–50 chance of there being widely available affordable rejuvenation therapy. How do you feel about that forecast right now? Is it overly optimistic? Is it well within reach if there’s enough money, or is it totally uncertain?

Aubrey de Grey: It’s pretty much exactly the same as my prediction. That may not be a coincidence.

Aubrey de Grey Biography
Dr. Aubrey de Grey is a biomedical gerontologist based in Cambridge, UK and Mountain View, California, USA, and is the Chief Science Officer of SENS Research Foundation, a California-based 501(c)(3) charity dedicated to combatting the aging process. He is also Editor-in-Chief of Rejuvenation Research, the world’s highest-impact peer-reviewed journal focused on intervention in aging. He received his BA and PhD from the University of Cambridge in 1985 and 2000 respectively. His original field was computer science, and he did research in the private sector for six years in the area of software verification before switching to biogerontology in the mid-1990s.

His research interests encompass the characterisation of all the accumulating and eventually pathogenic molecular and cellular side-effects of metabolism (“damage”) that constitute mammalian aging and the design of interventions to repair and/or obviate that damage. He has developed a possibly comprehensive plan for such repair, termed Strategies for Engineered Negligible Senescence (SENS), which breaks aging down into seven major classes of damage and identifies detailed approaches to addressing each one. A key aspect of SENS is that it can potentially extend healthy lifespan without limit, even though these repair processes will probably never be perfect, as the repair only needs to approach perfection rapidly enough to keep the overall level of damage below pathogenic levels. Dr. de Grey has termed this required rate of improvement of repair therapies “longevity escape velocity”. Dr. de Grey is a Fellow of both the Gerontological Society of America and the American Aging Association, and sits on the editorial and scientific advisory boards of numerous journals and organisations.

Postscript
This has been an excerpt from Ending Aging in the January-February 2018 issue of Age of Robots. In the next issue of Age of Robots, part two of this article will feature an interview with the first person ever to have genetic age reversal therapy procedures tested on herself, Bioviva CEO Elizabeth Parrish.

The complete audio podcast of my interview with Aubrey de Grey is available at https://seekingdelphi.com/2017/12/13/podcast-19-ending-aging-with-aubrey-de-grey/ and on iTunes and PlayerFM.