What is life extension?

KB: Thanks so much for being here. I'm sure people will have a lot of questions to Aubrey. Thank you to you and your beard for being here. First, let's define things. When people talk about life extension, they mean a lot of different things. What do you mean when you talk about life extension?

AG: I want to applaud you for starting with that. There's so much bullshit spoken in this space about the whole thing that we do. It all comes down to a failure of definition. For me, first of all, we have to define what we mean by the word ageing. An enormous amount of the failures that we have seen really throughout our whole history surely our past century with regard to the attempt to bring ageing under medical control, has arisen from a failure to understand what we mean by the word ageing. People think there's some kind of distinction or fundamental biological difference between the things that we think of as the diseases of ageing, like Alzheimer's or most cancers or arthritis, versus this thing called ageing itself. What the hell is this thing called ageing itself? Nobody can actually tell you. They come up with things like... fraility. People have come up with precise definitions, but not just one definition, it's like-- it's crazy. The reason why it's crazy is because there's no actual definition. The thing that we call the diseases of old age are not diseases of old age at all. They are not diseases at all. They are simply aspects of aging that we have chosen to give disease-like names to. Once we understand that, that the word "disease" should be narrowed in use, to apply only to the health problems that people have earlier in life, then things get much more clear.

KB: How would you define success in this realm?

AG: Success in combating ageing by medical means in this area is defined as keeping people healthy irrespective of how long ago they were born. By healthy, obviously I do not mean healthy for your age, because that would be circular. I mean healthy in terms of physical function-- as healthy, as functional as someone who was born only 20 or 30 years ago.

KB: Just to clarify, in this version of this success, then we could potentially live indefinitely?

AG: Right. Certainly what we know, obviously, is that today most people what they die of is being sick. Not being healthy, right. Not usually an asteroid impact, although we're working on that too. The main purpose of working on self-driving autonomous vehicles is so that people don't die on the road, besides the efficiency gains. This is going to be as much as an emphasis as it becomes the main reason why we die, rathe rthan the current main reason which is having been born a long time ago. We will only have the same causes of death at 120 years old as we presently do at 20 years old.

KB: I worry about dying of a shark attack.

AG: I have a fine method of preventing that, which is not going into the water. The fact is, people worry about this. About 12 years ago, I wrote a general audience book called "Ending ageing". One of the things that happens when you write a book like that, is that Coblert asked me to come on his show. That happened to me. I went on Colbert, and he said-- and you know the way he does things, so, he said like, how about risk? I'm not going to want to cross the street because it's going to be such a huge risk. I just said, look, that probably means your grandmother is going to be able to help you cross the stree tbecause she is still going to be healthy. This is the right way to think about it. We're actually going to take risks more seriously when there's unlimited longevity potential, but that doesn't necessarily mean that we have to be risk adverse as in staying in bed or avoiding anything that is currently risky because we have the second option of simply throwing money at the problem, in other words making the risky thing less risky so that we can still do it. Autonomous self-driving cars was my first example of that.

Modern medicine

KB: Before we get into some of your ideas, what about all the things that have already happened that we hoped would extend our lifes? Modern medicine, antibiotics. All of these things should have helped extend our lives. But have they measurably done so? What makes you feel like your ideas will solve these problems and all of these other things, which are low tech in comparison but should have solved some of the problems?

AG: Fine question. I think the simple answer is that these things did significantly improve the situation. 200 years ago, the child mortality rate was 1/3rd even in the United States. Many people would die during child birth. This doesn't really happen anymore in the industrial world. Even in the developing world, those statistics are diminishing at an astonishing rate. The overall life expectancy in the world today, including all of the poorest countries of the world, is 72 years, which is 1 decade lower than the country with the most advanced life expectancy which is Japan. We are only just now putting proper effort into wondering how to address the problem of old age, now that they have only recently become the main problem.

Lifespan vs healthspan

KB: I think the life extension field is bifurcated into two spaces. One is people interested in healthspan, and some people who have your views-- and some people call you immortalists. What do the healthspan folks have wrong?

AG: This pisses me off like nothing on earth. The fact is that, yes, there's a huge amount of political bullshit about some sort of alleged dichotomy between the emphasis on healthy lifespan versus the emphasis on total lifespan. It's utter bullshit. The fact is, everybody should and really does know it's bullshit. It's just rhetoric. Everyone knows that lifespan is a side effect of health span. The main thing that people die of is, not being healthy. Therefore, you can't get away from the fact that on the one hand if you're not extending healthspan then there is no risk of extending lifespan. It's complete nonsense to suggest we shouldn't try to do this, because we should be scared that we'll become a "global nursing home" and we'd keep people alive in hospice everywhere around the world. It's just not going to happen. We have to look at the other side, too. Some people will want to be politically correct and say, we don't want people to live longer in total, we just want "compressed mortality". It's bullshit: if you can keep people healthy longer, then you are absolutely going to keep people alive longer. And that's a great thing, hello! People who are healthy, don't want to die tomorrow, irrespective of how long ago they were born.

The seven types of damage accumulation

KB: So you have seven molecular and cellular processes that you want to fix. Not everyone here is probably familiar with them. Why do you think these are the key to solving aging?

AG: Ageing is a combination of two processes. There's a process that goes on throughout life, literally throughout life, even before you are born. The entire huge complex network of processes that keep us alive from one day to the next, that network of processes generates changes to the molecular and cellular structure of the body. Those changes are harmless for a very long time until we're 50 years old or more. The reason why they are harmless is because the body is setup to tolerate that. But it's only setup to tolerate a certain amount of that change, because by the time we're 50 or 60 years old, evolution doesn't care about us anymore because we would have already reproduced by then and our genetic information has passed on. That progressive accumulation change to the microarchitecture of our bodies eventually exceeds the tolerance of our body and then it starts to decline until we can't function at all and then we die. That's all that ageing is. It's a lifelong process accumulating these changes, and I call those changes damage. The reason why I call it damage is because once they have exceeded that threshold of tolerance, then the second process kicks in and there's the emergence of pathologies or the decline in mental and physical faculties. The paradigm for dealing with this, for essentially uncoupling metabolism from this other-- like uncoupling being alive from being dead, that is all about repairing the damaging by doing periodic comprehensive preventative maintenance. In order to do that, you have to characterize and understand reasonably well what you're trying to target. What is the damage that accumulates? What changes are occurring in the molecular and cellular structures of the body? Nearly 20 years ago, I put forward a taxonomy of that damage or classification of that damage, which I thought was reasonably useful. It was a reasonably manageable taxonomy, with only 7 different categories, and secondly the reason why that classification was useful was because for each category we could actually describe a generic therapy or generic approach to eliminate that damage and repair that damage. When I say generic, I say that within each category there might be many examples in different tissues or organs of the body, where different cells undergo different chemical changes, but the approach to fixing it would be more or less the same. Once we would have done it a couple of times, we would have a handle on how to do it the next time more quickly for other types of damage. In more concrete terms, let me talk about stem cell therapies. One of the 7 types of damage back then that I talked about was cell death, and not being automatically replaced by the division of other cells. So there, you know, the number of cells is going down gradually over time and then eventually not growing enough cells to do the organ's job, and this drives some important aspects of ageing like Parkinson's disease. Stem cell therapy is the solution: you put stem cells into the body that are of the right type. I don't need to go through the other examples; this is just a simple illustration of what it's about. We're restoring, in that case, the number of cells to how it was in youth or young adults. In all of these cases, it's about restoring hte state, whether it's the number of cells or the contents inside of cells or the contents between cells. This concept was very heretical when I first put it forward 15-20 years ago. Over the course of the 2000s, I spent a lot of time educating my colleagues and bringing them to understand what I was really saying. This decade, it's been very heartening. A number of people have essentially reinvented the same idea and now it's totally mainstream. I am now pleased to say this is going to happen, although it's a question of how quickly.

KB: More than 15 years ago, you put a pretty aggressive timeline out there. You said, once we have a robust mouse model, it would be 15 years until we solve these problems. Right now I don't think we have that robust mouse model.

AG: Right, yes, this was another area where I took on my colleagues. It wasn't just a new paradigm. But I also felt my colleagues were being irresponsibly cowardly with regard the potential timeframe for progress. Many of my colleagues would say, one should not go out there and actually make predictions about how soon progress will be made, because that will engender unwarranted optimism or get people's hopes up. They wanted instead to underpromise and overdeliver. My view is the opposite: it's irresponsible to not put forward one's best guess about how these procedures are going to take or how long. If we don't, then non-experts are going to make up their own impressions and they are going to be even more wrong than we are, and they are going to be more pessimistic than us. We have spent the entire history of civilization kind of resigning ourselves and accomodating the fact that ageing is inevitable and immutable and all that. We're not predisposed to think otherwise, really. If you don't tell people, listen, things have changed, then people are going to carry on thinking things haven't changed. This means they aren't going to be particularly supportive of tax payer money being used on this research, because they would have no reason to believe the money would achieve anything. I believe experts in this area have an absolute duty to come out and say how long it is going to take. I started doing this maybe 15 years, like 2003-2004. I defined a milestone- "robust mouse rejuvenation", taking middle aged mouse and increasing their remaining lifespan. I said that we had a 50/50 chance of getting to the equivalent situation with humans within 25 years from that point. So what actually happened? We are 15 years ahead, and I now think that we're 5 years away from robust mouse rejuvenation. We've only achieved 5 years of progress, in 15 years, in other words. Not good, eh? But you have to take into account that people from the beginning-- not only did I say 50/50 chance, which is a bit of a weasel way of getting out of it, but I also said it's subject to funding and we didn't get that funding. I said, what we need to make sure that funding is not the rate limiter, is $100 million per year. Realistically, I think we could have got away with $50 million. What we had instead was $2-3 million/year, not so good. The good news, though, is that things have been changing especially over the past 3-4 years. Now a lot of the work that needs to be done is being funded much more aggressively than before, simply because our efforts and other efforts from curageous early stage people have been able to push things along to a suffiient proof-of-concept that angel investors are starting to get interested. Half a dozen of our projects, and many others, have been spun out into startup fcompanies that are getting far more money than we have been able to ever provide philanthropically. So that's really moving forward. If we look at how things have been changing over the last 5 years, it's been rapid. Three years ago, I was saying robust human rejuvenation would be 20 years away. But now I am saying 17 years. Over the last 3 years, we haven't slipped at all.

Successes so far

KB: Can you talk about the places where we have been successful so far? Your researc...

AG: Senolytics is one example. It's not to say that we invented this. This is all wonderful, and it's moving forward brilliantly. The first clinical trial for such a thing happened just a year ago. Results were announced a few months ago, and it's moving forward rapidly. There's a number of other areas, including the elimination of indigestible waste products in adipose cells. That's really good news. What I really want to say is that this is not just cherrypicking. Even the most difficult areas-- the areas that have not yet been spun out in companies, those areas are still moving forward much faster than they used to. There's a good chance that they will all be well along the way in 3 years from now.

KB: Are there any specific biological roadblocks in the way of progress on other fronts?

AG: Actually, there's really not. The big thing that I have been scared of and looking out for are roadblocks, and htey haven't happened. What's happened is that, back then when I was talking about 7 types of damage, well I'm still talking about only those 7 types. There hasn't been any major discoveries that there's a new category that we need to tackle. We have not had to abandon any previous approach to repairing any particular type of damage because we found bad news that indicated it wouldn't work and we needed a plan b; that hasn't happened. All of the surprises over the past few years have been good surprises, like CRISPR and induced pluripotent stem cells, which have provided new technologies to give us a shortcut to make it easier to do the things that we need to do.

History of biogerontology

KB: You talk about the body in the context of being a machine that needs to be fixed. In biology, that analogy can break down pretty quickly. That might be why your work has attracted skepticism. In the 90s, there was c. elegans and the worm, and they thought there was one variant that seemed to impact ageing and then we found out no it's more than 500 things. What do you think is the best argument against you?

AG: There aren't any. I've heard them all, and they are all wrong. At the end of the day, it comes down to misunderstanding. The body really is a machine, no matter how much you ascribe to being alive. The only practical difference between a living organism and a vehicle is that, with regards to ageing, we don't have the plans for the organism. We have to work from a position of profound ignorance about the ways that the machine works. That is a meaningful challenge. But it's a challenge that most scientists overinterpret, because scientists are all about finding things out for the sake of finding things out. Their training and inclination is all about understanding nature. This is a really big deal. My wife's lack of interest in ageing was one of the motivations for me to be getting into this field. We had conversations and I asked her why she isn't interested in ageing; she would say, it's just decay, what fundamental truths about the universe is one going to establish by studying decay? I would say, well sure, but decay is bad for you. She would say, well that's not my problem, and I would say, uh it kind of is. There's this profound difference of mindset, inclination and training, between basic scientists who have the goal of understanding nature, versus technologists whose goal is to manipulate nature. What technologists do, at the end of the day, pioneering technologists sidestep ignorance. They figure out ways to do stuff to systems that they know that they only partly understand. That's what it's all about here. When 25 years ago, .. discovered that by making one mutation in one gene in C. elegans you could double its lifespan, this was a huge revolution and it drew a large number of smart scientists into the field which was great. But we can't do that to humans, because that same genetic pathway has almost no effect in humans. This was obvious even back then; it didn't become more obvious over time. It's a small community. I know the senior people of the field really well; and we all understand the science pretty well, but we all have different understandings of what to do next. I have huge respect for what Cynthia did, and how vocal she was, even when she was a junior professor without tenure, going out there and saying "we should probably fix this". It was even harder to say that back then, than it was 10 years later when I started to say it in public as well. She is fixated on the paradigm she came up with, and doesn't want to listen to the stuff that we have come up with since then.

Ageing is really bad

KB: You've put out an idea about a global trance where we're in denial about ageing. I think you could really apply that to any sort of community calamity like climate change. It seems like the bigger hurdle to get people to care about this stuff and fund it, and getting people to fund it, is them knowing about it. That's really a communication problem. How do you fix that?

AG: You're quite right. There is a difference, though. With climate change, I think that a huge part of the difficulty is complacency. The people feel, it's okay right now, climate change is only getting worse slowly, people are working on how to fix it, and it will be alright in the end. The situation with ageing is kind of the opposite. People feel it's natural and universal and inevitable and it's never going to be alright, which is the opposite of climate change. But it's equally bad, because it has the same consequence. And people argue we should do other things with our time and money. People need to view that the problem is between those two things. Effort can make a difference, it's difficult not impossible. That's what I keep trying to get people to understand. That's the place that I am at right now. Michael Rose became prominent in gerontology back in the 1980s; he said something a long time ago, which I completely agree with and feel it needs to be repeated: there will come a point when we bring ageing under comprehensive medical control, and when we do, we will as a whole society globally we will be unimaginably ashamed that we didn't do it quicker. I completely believe that this is true. I'm doing my very best to minimize that unnecessary delay, and thereby to minimize that shame.

KB: At the beginning of our chat, you alluded to some areas of this field that are kind of bullshit. I live in San Francisco where people love fasting, metformin, if you have enough money then young blood. What do you think of these potential ageing interventions?

AG: We need to luck at things like metformin, rapamycin, resveratrol, and these vairous small molecule supplements and drugs for which there is some evidence of anti-ageing efficacy. Many of these things call under the category of calorie restriction memetics. These are drugs that trick the body into thinking that you aren't eating enough, even though you are. How effective these drugs are, this varies, and it also varies depending on the person. How good would it be to trick the body into this? The answer is, well actually, a little bit. It's been nearly a century since we've figured out that if you feed mice or rats maybe 30-40% less than what they would like, then they would live 30-40% longer than otherwise. It turns out that long-lived species contain a considerably less benefit than shorter-lived species from such approaches. That's a shame. It's not the holy grail. That doesn't mean that these approaches are useless; not at all. There's plenty of evidence that these drugs confer a health benefit, especially for people not living a optimal health diet or lifestyle. But I am interested in the actual holy grail, bringing medicines into existence that actually get this problem completely solved. None of those drugs are going to do that, they are a stopgap towards what I am trying to do.

KB: Do you want to plug any products that you use?

AG: People ask me about my beard a lot, yes. I'm a lucky guy. I'm well-built, somehow. I have good genes, or whatever. I have to be conservative, if it's not broke don't fix it. But this might not be the case for the average person to do the obvious things. The most important thing that you ought to do today that are available are just the things your mother said, like don't smoke, don't get seriously overweight, have a nice varied diet. A minority of people will draw a short straw of one kind or another where one supplement or regiment might be useful. People often point to Ray Kurzweil because of his huge supply of supplements. But he took on type 2 diabetes in his 30s, and he has cardiovascular disease in his family, so you shouldn't draw too many analogies from him.

KB: Has this idea matured in the past two decades?

AG: No, for me, of course not. I was already right. For everyone else, absolutely. It's very gratifying to me to see that the community has strengtheend and grown so much and this is so much more mainstream now. I had to have thick skin a few decades ago to keep going. But as you know, there are many pioneers in this room. It's easy to be thick skinned when you're right, though. So here I am. Things are going well now. I obviously wish things would have went well sooner.

KB: It must be nice to be right all the time.

AG: I am not right all the time, the things that I am wrong about are often the details. I am the chief science officer of a research organization, and research is about figuring out what's wrong quickly. The overall paradigm that I have been using for the past 20 years, it turns out that that paradigm has stood the test of time and it is now mainstream and I'm very proud of that.

What biohackers should do

KB: I have one more question. There are people here who are I assume interested in knowing how they can contribute to your work and contribute to the field of life extension. What are your thoughts here?

AG: Sure. The current istuation in the field is that we're still pursuing this damage repair strategy. But as I already summarized, and as some of you know, it's very much a divide and conquer strategy. There are many types of different damage accumulating in the body. Any of these types of damage can kill you on its own, more or less on a schedule, however well we fix all the others. That's why it's divide-and-conquer. Different types of damage have different types of repair and thus entail a different level of difficulty. This is why SENS Foundation has not declared victory yet. There's still a number of extremely vital areas that have not reached the point of investability and spun out into companies with angel investors and so on. So we are still critically short of the adequate funding to get this stuff to go as fast as the science would allow us. If anything, the emergence of the private sector side with the startups to invest in, have made it even harder to bring money into the non-profits because now the people who are historically investing in the philanthropies are now investing in business. Originally, they were donating only because that was the only option, and now they have the option to invest instead. We are still critically short of money. I would like to encourage you to do anything you can to help in that regard. But since this is a conference about biohacking, people who know something about biology, and therefore all of you need to think about what you can do in America not just in terms of biohacking but also in terms of contributing in the lab to research knowledge. That's not a dichotomy. We absolutely understand that people who are self-administrating this or that, can provide great information that can be used more broadly. I am sure all of you know that I want to empathsize that the way you do self-administration really matters enormously. The quality of your baseline data and how much you have measured about yourself before you start an intervention is utterly critical. It is pathetic how badly people do this. How rarely people do a good job of figuring out what state they are in, before they begin. Also, do follow-up. If you have done something and you think it has worked for you, then that doesn't mean it's one-off for everybody. It might be one-off for you. But everybody needs to know what state you're in after you've done it. And also, six months after you've done it, and 2 years, and 5 years after you've done it, which is what tells people how useful this is. This is not ever going to be as good in terms of information as standard randomized double blinded clinical trials. But that doesn't mean it's unrelated to that kind of work. People like myself, we aggregate this data both formally and informally, and we get information from it that determines the priorities of our research and that eventually saves lives. Everybody here who is a biohacker needs to remember that you have responsibility not only to yourself but to the rest of humanity, as a result of what you're doing.

KB: Let's take questions. Do folks have questions?