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Aubrey de Grey: Longevity as Emerging Megatrend

Monday, September 21, 2020

Aubrey de Grey was born 20 April 1963 in London, England. He was educated at Harrow School and studied at Cambridge Universityís constituent college of Trinity Hall where he graduated with a BA in computer science in 1985. After graduation, de Grey joined Sinclair Research Ltd as an artificial intelligence and software engineer. In 1986, he cofounded Man-Made Minions Ltd to pursue the development of an automated formal program verifier.

At a graduate party in Cambridge, de Grey met fruit fly geneticist Adelaide Carpenter whom he would later marry. Through her he was introduced to the intersection of biology and programming when her boss needed someone who knew about computers and biology to take over the running of a database on fruit flies. He educated himself in biology by reading journals and textbooks, attending conferences, and being tutored by Professor Carpenter. From 1992 to 2006, he was in charge of software development at the universityís Genetics Department for the FlyBase genetic database.

Cambridge awarded de Grey a PhD in biology based on his 1999 book The Mitochondrial Free Radical Theory of Aging, in which de Grey wrote that obviating damage to mitochondrial DNA might by itself extend lifespan significantly, though he said it was more likely that cumulative damage to mitochondria is a significant cause of senescence, but not the single dominant cause.

For over twenty years now, de Greyís work focuses to identify and promote specific technological approaches to the reversal of various aspects of aging, or, as he puts it, ď... the set of accumulated side effects from metabolism that eventually kills us.Ē Starting in 2005, he has been working on a detailed plan called Strategies for Engineered Negligible Senescence (SENS), which is aimed at preventing age-related physical and cognitive decline.

Matthias Knab: Probably since the dawn of humanity, humans were looking to live forever and avoid the decay thatís coming with old age. Today, we are looking for the proverbial fountain of youth with the help of science and immense research budgets and we are doing this globally. So, I wonder Aubrey, have we made progress? Where are we today?

Aubrey de Grey: Well, we have made progress for sure and the progress is accelerating but I would like to take issue with your suggestion that there is an immense budget allocated to it. That is indeed most of the problem. It has somewhat alleviated over the past few years, but itís still a really bad problem. At the moment, we are still in the mindset as a society of thinking of aging as something very distinct from diseases and we have invented this completely fictitious notion of age-related diseases like Alzheimerís or most cancers and atherosclerosis and so on, as if they were actual diseases that could be cured like infections when in fact they are simply parts of aging.

Now, you may ask why have we done this? Why do we cling to this fictitious notion that there is some distinction between the so-called diseases of late-life and ďaging itselfĒ (whatever the hell thatís supposed to be)? I believe that is part of the edifice of irrationality that we have constructed over the whole of civilization in order to just keep aging out of our mind and get on with our miserably short lives and make the best of it, rather than be preoccupied with this terrible thing thatís going to happen to us in the future.

Now, of course, that used to make sense. That was a perfectly rational thing to do when we had no clue about what to do about aging, about how to bring aging under medical control, but over the past 20 years or so, it has become increasingly untenable. It is an unquestionable fact that we are within striking distance of being able to really address the root causes of aging and bring aging under medical control, and therefore this irrationality is a huge part of the problem. In particular, this irrationality and failure to properly understand and address aging are slowing things down, largely because it diminishes peopleís enthusiasm for having tax payersí money spent on this research.

Matthias Knab: Right, but research is and has been happening, also via your Methuselah Foundation, which put us, as you said, within striking distance of being able to bring aging under medical control. I understand that for you more money and more funding has to happen. But letís also look at what has happened over the past decades, maybe you can share with us what your Methuselah Foundation and your SENS Research Foundation have been focusing on and achieved?

Aubrey de Grey: The Methuselah Foundation was the first charity that I created jointly with a businessman from Virginia way back in 2003. We managed to bring together a little bit of money basically by raising the profile of this work and offering prizes for progress in extending the lifespan of mice in the laboratory, and that was enough to allow us to start doing a little bit of research and funding a few Ph.D. students here and there.

Then in 2009, we created SENS Research Foundation which is the main thing that I work on, and that has grown progressively. Here we have done quite a lot of research and have made considerable progress in kickstarting a number of critical areas of research that contributes to the eventual defeat of aging, but our budget is still $5 million dollars a year Ė not billion, but million Ė and thatís exactly the problem.

As I said over the past few years, things have improved in one way, namely that we now have a very rapidly increasing interest from the private sector in this area. Investors have started getting involved and we at SENS have in fact been able to spin out half a dozen of our projects as startup companies that are moving forward and towards clinical trials and so on. So, from that side, the funding situation is slowly improving because there are a lot of people out there who are visionary and wealthy and generally willing to support this work. However, at the same time, they really donít like just giving money away. So, even if itís very early stage and from that perspective more a high-risk proposition, nevertheless they also have a chance of eventually getting their money back, and so they are much more willing to write checks with one more digit on them.

At the same time, the foundation still exists because there are some equally critical areas of research that havenít yet reached the point of investability even for these high-risk, high-reward early stage investors. So, the foundation is still just as short of money as it was.

Matthias Knab: Can you give us some examples of the spin-outs of your SENS Research Foundations?

Aubrey de Grey: Sure, there are quite a few. Last year one of the projects that we spun out into a startup company is called Revel Pharmaceuticals. It is focused on restoring the elasticity of tissue which is important for addressing high blood pressure in the elderly, for example. Also, from a nonlife-threatening aspect, it turns out that the same chemistry is part of an underlying process that is largely responsible for wrinkles. So, itís got cosmetic relevance as well.

Now, the underlying molecular basis for this has been reasonably well understood already for some time, but nobody had figured out any way to do anything about it. We worked on this for over six years funding a research group at Yale University, and they eventually cracked it. They made some nice progress and figured out how to break these molecular crosslinks that form between the proteins that give the tissues like the major arteries their elasticity. We still need some more time until clinical trials can start, but it was something that would never have happened at all if it hadnít been for our foundational funding of this work. Thatís just one example.

Matthias Knab: Thatís impressive and underlines a comment I have read in the review of one of your books that applauded you for your focus of combatting aging in a lab rather than the usual ďeat healthy and exerciseĒ sort of advice.

Aubrey de Grey: I think exercise or a good diet and so on are worth it, thatís not at all put into question, and so following a healthy lifestyle and taking care of yourself is definitely worth doing, but we must always keep a sense of proportion as thatís not the fountain of youth as they are definitely only going to postpone the health problems of late life by a small amount and even by different amounts in different people.

For example, I am just lucky: I am one of those kinds of people who can eat and drink pretty much what I like and nothing happens, and I donít even need to get much exercise, but everybody has to pay attention to their body and listen to that body and do what it takes to keep themselves healthy and youthful as best they can. But, whatever you do on that level, you are still going to go downhill in the end and the maximum you can do here is to postpone things a little bit. Of course, when it comes to health, even a little bit is better than nothing, so thatís why Iím definitely not against any of this. But, again, at the same time, it makes sense to do what you can to hasten the development of therapies that donít yet exist, that will actually deliver a great deal of more postponement of the health problems of late life, and of course, thatís what I do.

Matthias Knab: How can people or specifically investors and donors get involved with what you do?

Aubrey de Grey: Of course, there are many ways to get involved and we want to grow this community as much as possible and we really need people of all kinds. If you are a biologist, in your work you can start emphasizing the right areas of research that have the greatest potential for impact on longevity. If you are a wealthy individual, you can donate to the foundation or of course you can invest. If youíre a journalist, you can do what youíre doing right now and get the word out to people by interviewing me or interviewing other people and making sure that there is more quality of information out there about our research.

If you are a policymaker, you can influence everything around it.

Even though my main affiliation is as chief science officer of a non-profit foundation in California, nevertheless, because I have been in the field for a long time and I have a high profile in this area, people approach me all the time wanting to know what to do. I spend a lot of my time making introductions, whether itís between investors and founders of startup companies or to match investors with other investors. People who want to get involved look for some guidance also about things like co- investing in consortia or investing in some venture funds that is focused on this sector. So, there are many ways and every kind of flavor of investment opportunity that exists in any other sector we also have in this sector.

Matthias Knab: Futurist Ray Kurzweil predicts that The Singularity is coming in 2045 and he plans on living long enough to see it, which means heíll be 97 at the time.

Kurzweil has also gained some fame for his exhaustive list of supplements he takes, with coenzyme Q10, phosphatidylcholine, and vitamin D as the most important (https://www.quora. com/Which-150-supplements-does-Ray-Kurzweil- take-daily). Do you follow a special physical or nutritional regime to help you live longer?

Aubrey de Grey: Well, different people need different things, different people can have very different diets in the first place and then, of course, different genetics and physiology that can influence the exact amount of micronutrient that they need.

We do know that genetics and physiology determine their processing of macronutrients, especially carbohydrates and fat. Some people will put on weight if they eat a certain amount of something that would not cause other people to put on weight, and so on.

The only recommendation that one can give that has any general validity is that you have to pay attention to your body. You just have to do what your body is telling you to do and resist to go with the flavor of today when it comes to what you put into your body or do with it. Thatís all we can really say. Everyone is different.

The role of supplements varies so much. You mentioned Ray Kurzweil, and indeed, I am often compared and contrasted with him as he is another high-profile person in this field. Ray is well known to take an impressive list of supplements a day. Now, thatís not as different from me as it sounds because you could also say he is doing what I said before, which is he is paying attention to his body, and therefore he also knows that there is a lot of cardiovascular disease in his family. He came down with type 2 diabetes in his 30s, which is pretty rare, and over time he ended up developing this regime which appears to be working well for him. Heís now I think 70 and he has not had any signs of diabetes since he started doing what he is doing.

Now, this is of course very positive and congratulations to him. But at the same time, that is in no way any evidence that alone can prove that the same kind of regime would be good for other people. It has somewhat normalized his accelerated accumulation of certain types of damage associated with sugar metabolism, but other people who donít have those deficiencies in the first place, if you are aging normally or especially someone like me who is aging unusually slowly for their age, you know, we have to take a more conservative view.

Matthias Knab: One of the fundamental questions in longevity research is whether humans and other species possess an immutable life-span limit. The debate on this is still going on.

Jeanne Calment, a French woman who lived for 122 years and 164 days still holds the ďworld recordĒ for the oldest recorded human who has ever lived. She died in 1997, so just from that perspective, it seems that since then we havenít really pushed that limit. Or are we about to?

Aubrey de Grey: A lot of people are fascinated by the absolute world record holders and looking at the trend in the statistics and so on. It is actually pretty curious and quite an anomaly that there are three people who died in the period 1997 through 1999 and who still hold the record for the oldest three people in the world. Actually, I think the person in third place was beaten by a few days a year or two ago.

But if you simply exclude those three or four people and just look at everybody else, then the records have been going up at a rather smooth pace of about one year per decade or something like that, maybe a little more, which is pretty much the same pace than the general human life expectancy where the average lifespan in the industrialized world has been going up. So, statistics are hard work when you are talking about very small numbers of people. However, what is important to take into account is the more general trend that we see over a longer period of time.

Letís have a closer look at how the lifespan of humans has developed. In the 1700s, the 1800s, life expectancy was very much lower, it was in the 30s or something like that. And the reason was because so many children would die very young. In fact, even in the worldís wealthiest countries, the incidence of infant mortality was like one in three or more. In other words, more than one- third of babies would die before the age of one. And of course, with the help of science we fixed a lot of that by figuring out that hygiene is a good idea and we developed vaccines and antibiotics, very simple medicines. Now, of course, these issues are still the main driver of the increase in life expectancy today in the developing world and the reason why the average lifespan worldwide has now reached I think 72 or maybe even 73, which is really pretty good. Thereís not a single country in the world with a life expectancy lower than 50 any more.

But letís also reflect a moment what does this mean and whatís next from here? Well, in the industrialized world, that major push in life expectancy had mainly been accomplished by World War II already. But, once you have driven down the incidence of a particular cause of death to almost zero and thus increased a particular average age of death for that particular cause, you canít do it again.

The only reason why life expectancy has continued to rise at all in the industrialized world since World War II is because of progress in other areas and so we have seen that the risk of death, or the mortality rate, has continued to decline. In other words, life expectancy after the age of letís say 50 has continued to increase.

Of course, there are many causes for that and thereís still some debate as to which are the biggest ones. For example, itís pretty clear that some of it come from things like the decline in smoking, but most people think that the biggest single is simply prosperity. When people become more prosperous, they are also better fed and have a better diet in general and especially really early in life and even prenatally. It turns out that lots and lots can go wrong in the very early part of life to the extent that some people can end up essentially being biologically older throughout their whole life because of certain deficiencies in their nutrition in early life and pre-birth. Conversely, if you can have better nutrition when you are in the womb, then you are going to live longer. Most people think that these are some of the main reasons why things have improved over the past 50 or 70 years.

What we need to consider next is that all these factors are eventually also going to have diminishing returns, and in fact, most people would say that this has already happened and that we need to look at other things that are coming in that also can bring down life expectancy and work in the other direction. Take, for example, the obesity epidemic that is particularly bad in the U.S. but not so good elsewhere either. Already in a number of countries, certainly in the U.S., that trend of ever-improving life expectancies is basically leveling off, we are just not seeing an increase any more. That is bad news and itís not surprising that life expectancy even in other countries in the industrialized world is therefore going up only very slowly now.

But hereís the thing. We will eventually see another wave of increase from another source. Again, when we look back, we didnít have this nutrition-based improvement I talked about until World War II or so. But eventually, the kind of things that I work on Ė regenerative medicine, damage repair to really stop people from accumulating the damage that makes them sick when they get old Ė that is whatís going to drive the next wave of longevity increases.

Matthias Knab: Letís look at the investment opportunities again in this field. You are also active on the Venture Capital side and funding research for the development of medical innovations that can postpone all forms of age- related ill-health.

How can investors interested in his field participate, and what would be some recommendations for investors in longevity? Or, can you already point to some success stories?

Aubrey de Grey: Sure! The spin-outs from SENS Research Foundation are just the tip of the iceberg. There have been half a dozen of those, but I also work with dozens and dozens of companies that have sprung up independently of SENS Research Foundation that are doing very closely aligned and very valuable work. Usually those companies are also just starting out, so they still have only like seven- or eight-digit valuations and they are looking for seed money or Series A funding, so there are plenty of opportunities. So many, of course, that most people donít know how to choose and thatís why itís also been important that there are people coming in helping them to choose either their direct investments or their venture funds specifically focused on the longevity with the scientific due diligence skills that are required as well as the business due diligence skills that will be the same in any sector.

There are even companies whose business model is simply to snap up other companies: to have a whole coterie of daughter companies that cover several different areas of damage repair. At the moment I am working with four of those companies, and I think they are all very attractive propositions. They have also all been very successful in bringing investment, especially from wealthy investors who are new to the field. Those investors know that they canít really make good choices themselves and that the best way for them to limit their risk as early-stage investors is to have a diversified investment portfolio, which is what those acquisition companies provide as well as the venture funds provide. You asked about success stories, which for me happens first on the research side, and, indeed, thereís a huge number of success stories there. But, at the same time, you canít expect those companies to demonstrate large amounts of revenue because at the moment those firms are built on things that were still just basic science and linked to the laboratory only a couple of years ago. However, you can certainly measure success in other ways, for example, companies that have gone through multiple rounds of investments with valuations increasing sharply round on round.

Companies that have gone into clinical trials and the early stage of clinical trials have gone really well. One company, for example, that I work closely with called Unity Biotechnology reported last year on a phase 1 clinical trial of their first drug to get rid of what are called senescent cells, which are cells that accumulate in the body and they do damage. So, as you probably know, phase 1 trials are normally only about safety, not about efficacy, but this trial did so well that even though the number of patients was very small, it was also becoming clear that the drug is actually working.

This is the area I am personally most interested in: focusing on damage repair, so not just slowing the aging clock down but actually turning it back. Thatís where the future is and where we are going to see the biggest effects.

Matthias Knab: What I hear is that while you are coming from and are firmly rooted in the research world, you are also in close contact and working with the financial ecosystem that supports your research work. It appears to me that you seem content with the evolution of that financial ecosystem and how it is surrounding and supporting your work, is that so?

Aubrey de Grey: Content would be too strong a word, but the truth is that Iím always an optimist and a glass half full kind of person. I am delighted that things are moving faster than they were before, but at the same time in my mind is the knowledge that we could be going much faster still if it werenít for the crazy irrationality that surrounds this whole area of aging that I mentioned earlier. And, just to make that point, I am of course not blaming anyone, I understand that this is rooted in the history since the dawn of civilization with people being terrified of aging and not being able to be rational about it. But, the sooner we can wake up and start actually treating this as the medical problem that it is and addressing it in the same way that we addressing COVID, the sooner weíll actually start saving lives.

Matthias Knab: Well, it is sort of understandable that people in a way have given up hope when it comes to aging and try to avoid addressing it. They see itís around them, even their pets suffer from it, and it seems just a law of nature that everything needs to end and disintegrate in some form. My sister has a dog and right now the dog has started to turn gray and we already know that the next thing is that heíll start walking slow, so I can also understand why people see the decay of old age as inevitable.

Aubrey de Grey: Well, at the same time, lots of things used to be inevitable. We think that itís okay to spend large amounts of public money on research designed to cure cancer or to cure Alzheimerís. But, if you think about it, these things are still inevitable too, right? But that doesnít stop us from trying to fix them. So, the problem is this fallacy that there is something kind of off limits to medicine which is called aging, that is somehow wound into the fabric of the universe in some way that prevents us from actually ever doing anything about it. And, again, that train of thought, that perception and that paradigm is for me completely nonsense.

Let me come back to pets, as, for sure, a lot of people would want us to develop these medicines for pets. Itís something that will get people really excited and weíd love to do that, for sure. Apart from anything else, the regulations around developing medicine for animals are somewhat easier to navigate than regulations from medicine for people. However, it turns out that pets Ė foremost cats, dogs or horses Ė obviously donít live so long as people; herein also lies the the problem in the sense that it is more difficult to get them to live a lot longer. Basically, there are more gaps in their own inbuilt anti-aging systems, and thatís why they donít live as long at the moment.

However, work is moving in that direction. There are some projects already in progress, a very important one at the University of Washington in Seattle which is looking at feeding certain promising drugs to dogs to try to extend their lifespan. Let me also point out that this work has been done within the dog owner community Ė in other words, these are dogs that actually belong to people and not in a laboratory anywhere. This means that a lot of diversity is being considered as well, not only on what kind of drugs are being used but also what kind of diets, lifestyles and so on that dogs have. So, a lot of information is being gathered and we hope to see some progress.

Still, also this work is not as much of a solution to the irrationality problem as it might sound. The defeat of aging is no more and no less than the ultimate goal of medicine. All the other goals of medicine are ethically uncontroversial. For example, no one tries to argue that it would be a mixed blessing to have a cure for Alzheimerís disease or cancer. The only reason we feel differently about aging is because, through a necessity that existed from the dawn of civilization until only 20 years ago, we have made our peace with aging so as to put it out of our minds. Now is the time to re-engage that battle.

In 2007 de Grey published the book ďEnding AgingĒ where he argued that defeating aging is feasible, possibly within a few decades, by eliminating aging as a cause of debilitation and death in humans, and restoring the body to an indefinitely youthful state. De Grey points to seven of the most significant known causes of human aging, and what is known about how those causes can be addressed and combated:

1. Cell loss, tissue atrophy

2. Nuclear (DNA) mutations (cancer)

3. Mitochondrial DNA mutations

4. eath-resistant cells (cells not dying when they are supposed to)

5. Tissue stiffening (glycation: stiffens tissues leading to stroke, heart disease, etc.)

6. Extracellular aggregates (or ďjunkĒ, e.g. beta amyloids)

7. Intracellular aggregates (or ďjunkĒ, e.g. lipofuscin)

De Greyís main line of research is into mutations in mitochondrial DNA that cause increased cell stress via production of free-radicals. In other words: something that will need to be addressed in a lab rather than in your kitchen or following ďeat healthy and exerciseĒ sort of advice.

He also elaborates on the essential distinction between preventative/ rejuvenating and or curative or palliative treatments: Aging damage will inevitably accumulate, so masking or slowing it, alone, is insufficient to extend life dramatically.

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