At our fourth annual Ending Age-Related Diseases conference, Dr. Aubrey de Grey discusses the transition of rejuvenation biotechnology from proof-of-concept to companies engaging in clinical trials, and he outlines the challenges inherent in such a move.
It’s great to be here, of course. I just thought I’d start by saying that some of you may have heard perhaps of a complication that’s going on in my life right now. I just wanted to say that there is an independent investigation, which was started at the beginning of July and is still ongoing. That, of course, means a couple of things.
First of all, it means that I am on administrative leave, which means that I am not representing SENS Research Foundation here today; officially, I am here in a personal capacity. I should mention that I just noticed I have the SENS Research Foundation logo at the bottom of all my slides, so please pretend that that isn’t there.
Apart from that, I can’t say anything more at all about what’s going on; of course, this would be the wrong place anyway. I just want to say how overwhelmed I am for all the love and support that I’ve received from hundreds and hundreds of people, and it shouldn’t be long now. So you know, watch this space. So, having said all that, let me share my screen.
I thought I would talk today about the changing priorities that I see that we have in this field at the moment, because it’s very easy to get very optimistic and excited about how things are going. No question, things are moving much faster than they were even a few years ago, but I believe that those of us here who are really at the forefront of this crusade need to be absolutely clear that there is an awful lot still to do.
I thought I would start in illustrating that by using some of the slides that you’re very familiar with but with different titles than you may have seen. Of course, you know about this, it’s the increase in life expectancy that has happened over the past couple of centuries, and, of course, that’s a wonderful thing.
It is the result of progress that we have made initially in the elimination or virtual elimination of infant mortality from things like tuberculosis. And subsequently, as we’ve gone on, the reduction in mortality rates at older ages, which has been absolutely wonderful. And it has certainly resulted in greater quantity of life and quality of life.
But as we all know, the result is that more and more people are reaching ages at which they suffer from the chronic progressive health problems of late life. As usual, I’m just putting up this slide showing the economic outcome of that, which is completely catastrophic, in terms of the rate at which we are having to increase the proportion of the economy that is allocated to medical care. It’s completely terrifying, and something better be done about it.
Of course, that is very much in the minds of people across the board, policymakers, the private sector and so on. But, what to do about it is something that, of course, we have rather less consensus on as things stand. I mentioned all that because it kind of illustrates how priorities change, that when you identify a particular problem or a particular bottleneck, and you make progress on it, other ones pop up in their place.
If we look at the maintenance approach, the damage repair approach, that, of course, I founded more than 20 years ago now, that has become very much the focus or one of the major focuses of the anti-aging research field. We can see that potentially, there is a bit of an issue, because there are lots of different types of damage that we have to go after.
Of course, the whole reason why geriatric medicine was originally seen to be a non-starter that would never really have all that much effect on the healthspan of the human race was because of that precise problem that there are so many things you have to fix. The maintenance approach kind of sidesteps that; it makes the divide-and-conquer problem more manageable in ways that I’ve talked about many times and I won’t reiterate now.
But still, it’s a divide-and-conquer problem. And that means that we have to make quite sure that the most difficult parts of that divide and conquer approach are not left behind and neglected. Of course, SENS Research Foundation was set up more than a decade ago, with exactly that in mind; we set it up as an independent charity, an independent nonprofit funded almost entirely by philanthropy.
We did that precisely in order to avoid the constraints that forced both industry and mainstream academia into short-termism into focusing on low-hanging fruit and neglecting the harder but equally important problems that otherwise they might work on. Of course, the past decade of work that we and others have done, has had great successes, and certainly some of those successes constitute progress in the most difficult areas of damage repair.
For example, in the area of mitochondrial mutations, in the area of extracellular matrix stiffening, these are areas which were completely stalled when we started, and they’re not stalled anymore. But they’re still nowhere near as far along as getting into clinical trials, for example. So we’ve got to make absolutely sure that that does not persist, that these things are continuing to be pushed forward.
That’s where emerging challenge number one is: it is extraordinarily hard to get most people to not focus on the low-hanging fruit. In industry, of course, we know that people who want to make money, they want to make it soon, and therefore they are going to put pressure on to cause that to happen.
Some of you who have long memories may recall a company called Elixir Pharmaceuticals, which were founded by two absolute demigods of gerontology, Cynthia Kenyon and Leonard Guarente. The reason why those of you with short memories will probably not remember Elixir is because it ended up being a complete waste of time. That was why: they took the wrong money, they got pressured into doing stuff that wasn’t useful, and nobody remembers them at all.
It’s, of course, exactly the same in academia, that short-termism arises from the need to publish or perish. And same result. The worst of it is that it’s quite easy in biology in general, and certainly in our field, to identify areas where you can make quick progress and make a big splash and get a terribly interesting paper on the front page of Science Magazine. Unfortunately, it doesn’t go anywhere, because there is no actual way to take it forward to something that would have clinical relevance in the long run.
And the final problem, a final aspect of this problem, is that most of the real visionaries who have money are actually capitalists: they are people who made their money in the private sector, and they believe in that kind of way of doing things. Many of them simply do not believe in philanthropy, or in charity in general.
Now, some of those people have been visionary enough to recognize that they have to bite that bullet. Of course, the person who gets the greatest credit for that in our world is Peter Thiel, who started funding Methuselah Foundation back in 2006. But the fact is now that these people have the opportunity to invest rather than to donate, they are very, very tempted to do exactly that. So we absolutely need to be vigilant in making sure that the most difficult components of the damage repair portfolio are not neglected.
Another problem arising from the divide-and-conquer nature of damage repair is that there are lots and lots and lots of different types of damage. Some people often oversimplify what I say and they say, “Well, he’s saying there’s only seven types of damage.” That’s nonsense, of course, that’s not what I’m saying. What I’m saying is that there are seven types of damage repair but within each of these categories, there are many examples, like different types of stem cell therapy that are needed for different types of cell loss in different tissues, for example.
What this means from the point of view of those of us who are developing these therapies is that it’s absolutely critical to find out, as soon as possible, what bad things might happen when we simultaneously administer a bunch of different damage repair therapies to the same people at the same time, and that is something that is very hard to get anybody to do. Because the fact is, it’s antithetical to the way that medicine is normally done: medics just like to keep things simple because they understand that unforeseen interactions are really hard to anticipate.
It’s worse than that, because the thing is, it’s boring. In other words, it does not fit the incentive structure of other groups; we have more or less the same problem I talked about before, in terms of low-hanging fruit, but perhaps even more so in this case, because in industry, everyone’s got their own intellectual property, and they want to try and make money out of that, and there is not much of an incentive to actually work together.
There are, of course, eventually incentives of that nature, so as to bring therapies together and do cross-licensing and suchlike, but it takes a hell of a long time to put that kind of structure in place. There is a huge barrier to this, absolutely a central component of our mission, when we look at industry.
Unfortunately, the same is true in academia. Basically, if you have a therapy that in mice, for example, causes them to live a bit longer, and you have another therapy that also does so, then you’ll get really good papers, publishing each of those things. But you sure as hell won’t get a good, high-profile paper just putting the two things together and finding out that yes, everything’s okay. That’s just yawn-inducing to the people who make the decisions about what papers get published in high-profile places.
That is a problem that we, this community, need to be very, very serious about and to compensate for. So at the Foundation, there is now a very nascent effort to do that. We are putting together a program to put just two therapies together, a stem cell therapy and a senolytic therapy, and there’s going to be a lot more of that.
I believe that one of the biggest consequences of the enormous windfall that some of you may know we received recently is that there’ll be a very big expansion of work at SENS Research Foundation on combining therapies. It may end up, in fact, being our main focus over the next few years, but we shall see.
Now I want to talk a little bit about the steps that companies make; there’s been a huge emphasis, of course, over the past few years in our world, on startups, and there’s literally hundreds of them now, and that is absolutely wonderful, no question. I mean, half a dozen of them were spun out of SENS Research Foundation, but the number that have sprung up independently but doing very much damage repair work, it’s just breathtaking.
That’s wonderful, but the thing is, the reason why these companies exist is because they got investment. The reason they got investment was because the investors were looking ahead to the point where they could get their money back, which of course happens as a consequence of things like IPOs, and acquisitions, and suchlike, and that is all very well.
But the thing is that when those things happen, you’re talking about different kinds of investors coming in, and that is a problem because those different kinds of investors are far less mission-focused than the angels and seed investors to get these companies going in the first place. I’m sure all of you are familiar with many of the main people who have made these investments and who are absolute heroes who have saved the most enormous number of lives, in the future as a result of accelerating research by putting that money in.
The fact is, when you go IPO and suchlike, you’ve got people coming in who are only interested in the money, and they really don’t have much interest at all in the longevity crusade. Unfortunately, what has already happened a few times is errors of judgment, in hindsight anyway, of when to go and how to go public or to do something like that.
I’m sure many of you are familiar with the company Ajax, which is headed by the absolute granddaddy of private sector, longevity work, Mike West, they’ve had a very, very tough time, then there’s resTORbio, which collapsed completely and ended up just disappearing off the face of the earth, basically, as a result of one negative clinical trial, and it wasn’t even really their fault. They kind of had the goalposts move under their feet, and it was enough to kill them.
I, of course, am in no way pretending to be any kind of, you know, knowledgeable person, let alone guru in terms of Investment judgment and such things. I know nothing about that kind of world, really, but this is what I see; don’t shoot the messenger, but this is what has been happening.
Those of you who are in a position to influence the timing and the structure of the steps of the later stages of growth of these startup companies, this is what I want everybody to be thinking about and be aware of. We could end up having things slow down and go less rapidly than they could if we allow too many companies to make this kind of mistake.
I want to talk a bit more about thought leadership, especially thought leadership from the scientific community, because here, we also have a difficulty. Let me, first of all, draw your attention to the line immediately under the red one.
In 2003, when I ran my first conference in Cambridge, UK, I gave two talks, and one of them was a kind of call-to-action kind of talk. The title was something like “Gerontologists have a duty to make timeframe predictions publicly.” That was focused on the principle that if the thought leaders, especially the small minority of thought leaders who are willing to do a whole bunch of public outward-facing stuff, talking to the general public and suchlike, if those people are too cautious in talking about timeframes, they are going, by omission, to leave their audience with the assumption that nothing is ever going to be doable about aging. Which, of course, is an assumption based on thousands of years of failure to do anything about aging, and therefore, it’s rather deep seated.
I understand very strongly that scientists hate making timeframe predictions across the whole of science. And I understand why: scientists do not want to over promise and under deliver, they think it’s going to hurt their funding in the future, and so on. But it’s our duty; we have no choice if we do not stick our necks out, and take risks for peace, as someone said, then we will suffer really badly in terms of the enthusiasm, the credibility that we have as a result, in the sense of timeframes that the public sees, and things won’t happen.
Now, of course, we know that there are now some examples of other thought leaders following the lead that I’ve been giving all these years and coming out and saying pretty optimistic things. I often highlight the title that David Sinclair gave to his book of two years ago, “Why We Age and Why We Don’t Have To.” But, of course, that’s just one illustration.
There are a few other people saying the same kind of thing these days. But we must say it louder, louder and louder, because that’s the only way that people are going to really get the message that now we really are on the brink of bringing aging under comprehensive medical control.
So let me now talk about my fourth emerging challenge, it comes down to the regulatory environment. So you all know what TAME is, the clinical trial for metformin against aging. I’m sure that all of you or at least most of you will be familiar with the enormous amount of work that had to be done several years ago now, to actually get the FDA to say “Yeah, this trial sounds like a good trial.”
If you do this trial, then, you know, we will recognize the results and all that. The difficulty, of course, was that in order to create a clinical trial, they had to define a very clear, crisp, clinical endpoint, and they wanted the clinical endpoint to be aging, and everybody had their own personal definition of aging. It was a complete non-starter.
An enormous amount of work was done by Nir Barzilai and a few colleagues in conversation with the FDA to gravitate to a definition of the clinical endpoint for TAME that, from the gerontologist perspective, was synonymous with aging in all but name but, from the FDA standpoint, was crisp enough to actually be a genuinely binary thing that the trial would either succeed or fail at.
That was massive. I mean, like there is no overstating what how massive that regulatory breakthrough was. There was a bit of a problem, however, which was that because metformin was off patent since before most of us were born, there was no way that anyone from the private sector was going to pay for this trial. It had to be paid for from other sources, a lot of the money was pledged by a foundation, but it also required other money.
The NIH rejected the proposal twice. I am perhaps the first person to actually name names in that regard, there is one person who, at least behind the scenes, has received most of the opprobrium that I have heard for the reason why that that trial was never funded by the NIH.
But anyway, here we are, the trial is, so I gather, very likely to be funded this year. However, we cannot ignore the fact that it should have started years ago, and that the delay in actually doing the trial has also delayed the recognition of TAME’s significance in the wider world and especially in Big Pharma.
Of course, the significance I’m talking about here is the regulatory breakthrough, because we are all very well aware that, for the longest time, Big Pharma has been extremely uninterested in developing therapies that will have a broad-based impact on the health problems of late life.The reason they have is because they did not see a path through the FDA to actually get something approved so that they could make money out of it.
The TAME trial, as it currently stands, before it has been actually done, just because of the nature of that clinical endpoint, has, to a very large extent, solved that problem. But getting people, decision makers in Big Pharma, to actually recognize that, while TAME is still actually just a twinkle in the eye of the people who are supposed to be getting on and doing it, that’s really tough.
Decision making in Big Pharma inherently has serious inertia, just as it would be the case in any industry. So this is hugely problematic. So the sooner we get TAME going, the better, but even before we get TAME going, we’ve really got to drill into the decision makers and Big Pharma that now is the time to be putting really proper money into investing in anti-aging therapies.
I haven’t got much more to say. Actually, I’ve just got one breakthrough that I want to talk about again, but I’m going to talk about it at some length. The last emerging challenge is at the level of policy, and here, I don’t just mean regulatory, I mean beyond that.
I’ve mentioned in the past, I may even have mentioned a year ago at this meeting, that COVID is a bit of an opportunity, in the sense that it has hit the elderly extraordinarily preferentially. As we know, most infectious diseases are worse for the elderly than for young adults, but it’s particularly extreme in the case of COVID.
What we have not, I believe, said nearly loudly enough and focused policymakers nearly strongly enough on is the fact that among all of the damage repair rejuvenation technologies that we’re interested in, rejuvenating the immune system is really going rather well. It’s one of the ones that’s furthest along.
All of us are familiar, I’m sure, with the TRIIM trial led by Greg Fahy, even if you can’t pronounce Fahy, immune rejuvenation is doing really well. Thymic rejuvenation especially, and other parts. If policymakers were to understand that really not very much additional public money thrown at this kind of area could have a significant impact on the immune function of the elderly, that could have a very significant impact on the likelihood, let alone the severity, of any future pandemic, then we would be in a better position than what we are now.
What this fundamentally means, because, of course, policymakers ultimately care about the economy more than anything else, what this ultimately means is that we need a really aggressive revival right now, of that thing that came along, best part of 20 years ago originally, led by Jay Olshansky and a few other people, called the Longevity Dividend.
This was a really aggressive and articulate initiative. Trying to drill home into policymakers’ minds the fact that even a really modest postponement of the health problems of late life would have the most indescribable, astronomical, impact on the economy. That was coming from really authoritative people. Four of the authors of the original longevity dividend initiative, are very, very, mainstream grantees of the field, biologists and economists and sociologists or lobbyists. These are the right people to have done that.
And the impact of that initiative was exactly zero. Of course, I don’t really need to explain to you why the impact was zero. It was zero because it was not accompanied by, what do you know, any timeframe predictions from the biologists. So it was all received terribly courteously, as an appeal for more money that would be poured down the drain.
It’s in a revival now, because progress has been made in all of the laboratories around the world, and, of course, that progress could accelerate with more money. The good news is that it is being revived.
A British economist named Andrew Scott has led a new study that was published quite recently, in which he explores the economic benefits of progress against aging. And unlike the original longevity dividend, Andrew has gone as far as to incorporate rejuvenation as an actual part of the study; in other words, one of the scenarios that might actually occur in the foreseeable future. And he’s given it this wonderful name, we’ve called it the Wolverine scenario, I think that will catch people’s attention.
Now, very cool thing about this is that it’s only the start. Andrew’s paper looks at an extremely half-hearted version of the Wolverine scenario, in which people, at some point in the relatively near future, receive rejuvenation therapies at the age of, I think, 60, but they only receive them once, and then they just age and die anyway.
Of course, that’s the absolute ultra minimal, minimal version of actual rejuvenation, he knows it perfectly well. Right now, there is, of course, follow-up work going on to broaden this and to look at other variations on the Wolverine theme, and I believe that this is the way that we are going to get policymakers’ attention really seriously.
He’s just one guy, one research group. This is not enough. We have to be, all of us, out there in our own ways with our own communities and our own networks, our own areas of influence, telling people, “Listen, this is really coming and you can make it come faster, and you will get votes for it because people will be wealthier as a result.”