FightAging!
8-11-19

https://www.fightaging.org/archives/...ng-aging-2019/

Much of the proceedings at Undoing Aging in Berlin earlier this year were recorded, but of course it takes a few months for everything to process through the queue. I briefly escaped from the conference for an ad hoc, unstructured discussion with Adam Ford of Science, Technology, and the Future, who, like the Life Extension Advocacy Foundation folk, was interviewing as many people as he could during the event. It wound up a monologue on topics that were at the top of my mind at the time, particularly the present state of funding and the transformation of our community from a primary focus on advocacy and academic research to one in which a great deal of important work is now carried out in startup companies, and the utilitarian ethics of treating aging as a medical condition. The resulting video is now up at YouTube, and is here accompanied by a transcript for those who prefer text.

I'm Reason. I've been around in this community for quite the long time, going on I guess twenty years now, rather shockingly. I seem to have become old in my own lifetime; I'm not as young as I look, unfortunately. I run Fight Aging!, the blog, which I've used as a platform for advocacy for some time, the aforementioned going on twenty years, though more like fifteen now for that site. Recently, last year, I cofounded Repair Biotechnologies with Bill Cherman to actually jump into the industry and do some things. Prior to that I was investing as an angel in a few biotech startups focused on aging, where I felt it was a better choice than giving to the SENS Research Foundation or other groups to do the research, because companies have the chance to attract a great deal more funding more rapidly than non-profits do, unfortunately - that is just the way of the world.

That is very much the transition of our community right now. And as that happens, I think it becomes much more important to think about why the hell are we doing this thing? Sudden influxes of vast amounts of funding are consequential. There are several hundred million funds right now, focused on longevity, and there will be more next year, because it is a land rush right now. If you lose sight of why you are doing this, and thus what is the most effective approach, then you wind up with a bunch of idiots doing stupid things that won't work, and the upshot of that is that funding will be wasted. It is to a certain degree unavoidable, I mean look at the dot com era; every new industry has its peak of hype, a bunch of stupid things happen, a bunch of charlatans come in and take funding from investors who don't know any better. It will happen, but I think that those of us who are here now, and have been here in this community, have something of a duty to try to reduce the size of that problem, down to some nominal minimum, to the degree that that is possible to achieve.

So why do we do this? The fundamental philosophy of the problem is that death is bad. Suffering is bad. That death is bad is the more debatable of those two. It is quite possible to construct an ethical position in which we say it is fine to be dead, you didn't exist for quite a long time prior to existing, and you will not exist for quite a long time after you cease to exist. That is the way of the universe; the Stoics were good with this position. But I think it is very hard to argue that suffering is acceptable, at least above the sort of "maybe I should get out of bed and do something today" level of suffering needed to motivate the human animal to go and do something constructive. Anything much more than that level of angst I think should go away - and certainly that includes the level of pain, physical decrepitude, loss of function, and horrible things happening to the people around you that comes with aging. That should go away.

The world just hasn't quite got there yet in terms of thinking about this in the right way. People think about malaria in the right way. Malaria is something like one six hundredth of the cost to humanity of aging, depending on how you want to measure all the little fripperies around the edges. So if we really feel up in arms about malaria, willing to spend billions on getting rid of it, which some people clearly are, then we should be spending trillions on getting rid of aging. We should be, but we are not, and that is why the advocacy community came into being. We have this weird mismatch between our capabilities and our goals. The world is a crazy place, I think everyone acknowledges that; there are many, many insanities that the human condition contains, be that politics, be that the way that some people like peanut butter, pick your poison. The present relationship with aging is just another one of these insanities: the world is insane with respect to aging, because accepting aging is insane. Why would anybody accept that he or she is going to crumble and die, and not want to do something about it? Plain, basic utilitarianism says that we should do something about it if we can do something about it. And we can do something about it!

So is the population of the world asleep at the switch because next to no-one realizes that we can do something about it? That will change pretty soon. Senolytics will wake up everybody. What if you can take one pill that makes your arthritis go away? That is basically what senolytics will do, when they are truly effective. The ones we have right now, that are available right now, appear to be fairly good at getting rid of arthritis, based on the results of trials yet to be published. Once this realization happens, I think there will be an interesting phase change. People will start to somewhat wake up from this business of "oh well, aging is just a fact of life, wherein we're all going to die horribly, let's just get on and try to paper over that." So no, instead let us go full on utilitarian and try to do something about it. That is essentially the philosophy of action here. It is that aging is so terrible that there is really no amount of effort that humanity could spend on this problem that would be too great. Of course we're so far away from anything that even approaches a reasonable amount of effort, given the level of death and suffering caused by aging, that for the foreseeable future we can keep on advocating and building hundred million funds. If investors build another hundred of those hundred million funds, that would be a nice start, but by no means the right amount of funding in order to reasonably address the problem, given what it actually costs.

The cost is enormous, and, sadly, most discussions about aging, when they do get going, really skate over the utilitarianism of it in favor of "wow, we're spending a lot of money on entitlements, we need to do something about this." That latter expression seems to be what passes for ethical thought in policy circles these days. It is a matter of "well, we're spending a bunch of funds, we should find a way to stop doing that." Then of course, the nihilists seems to be mostly in charge now, because their idea of spending less is to not treat old people for their conditions, rather than building rejuvenation therapies that stop old people from getting those conditions. As I said, it is insanity. This really just needs to change. So this is why the advocacy, and now that we're at the point at which funding can be raised for startup companies working on rejuvenation biotechnologies, these startups are just another form of advocacy, really, if you look at the bigger picture. We're not building therapies because we can do something with our small slice of the pie of aging, we're building therapies because if we show people that we can do something with our small slice of the pie of aging, then soon enough there will be another hundred companies over the next decade, working on their small slices. People will see success and attempt to replicate it themselves.

There are a hundred, two hundred, three hundred programs out there languishing in the research community that could be turned into companies, turned into therapies, doing useful things in and around aging. As you know, the research community is just not good at raising funding. They are not good at translating their research to the clinic. They are poor at a lot of things other than just advancing the science. I think it falls to the rest of us, where "the rest of us" means anyone who might be an entrepreneur, or in venture capital, or an advocate, to set forth and sift through these programs, the output of the scientific community, and say "look, we should do something with these things." If the research community isn't pushing a program forward, well, this is a time in which anyone can wrap a company around a project, say "I think we can do something with this," go to venture capital and get a few million in seed funding.

That will be the case for the next twenty years, on and off, as the market cycles up and down. So we should have a thousand startup companies working on a thousand projects related to aging. While there are only seven categories of fundamental causative damage, per SENS, some of those categories are very, very broad in terms of their little individual components. We have to fix all of lipofuscin, and we don't even have a good catalog of everything that is in lipofuscin, just the major pieces of it. We have to get rid of all the amyloids, and that is a good few dozen projects right there. Replacing aged stem cells: a different cell population, different recipes for therapy for every tissue. And so on and so forth all the way down the list.

Then after we've worked through the SENS list of causative damage as it exists today, there will be all the things about aging that are problematic but are hidden by the fact that people presently die before they become problematic. Such as nuclear pore proteins in long-lived neurons. Some of those molecules never change after they are initially created. It is the same molecule for your entire life, and if it gets damaged, well, that is kind of a problem. How do we build the nanotechnology to go fix our nuclear pore proteins? That is a problem that no-one should much care about today, because there are fifty other things that will kill you before that will become an issue. But it will become an issue, eventually. If we come to live to 150, I'm willing to believe that your nuclear pore proteins becoming corroded and corrupted and reacted with is actually a serious issue, at least in neurons.

We can in principle replace everything except the brain. So the worst case scenario for the ultimate future is that they open your skull, take out your brain, and put it into a new body. I'm sure it will actually be somewhat more sophisticated than that, but this is just a thought experiment - what is the most radical thing you can make work in terms of replacement, in principle? That is moving the brain to a new body. What will probably happen instead is that your new body will be rebuilt from your old body: regeneration and rejuvenation by delivery of cells and therapies and control over cell behavior. But the brain itself? A really challenging problem, because you have to fix it without breaking it. I think we are along the way towards understanding the mechanisms to target for the early, preventative reductions in inflammation, to avoid supporting cells in the brain going crazy, to get rid of the protein aggregates. To try to keep things the way they were during your 30s. But that is just a starting point. There is so much to do after that. It is a big project. When I say trillions in funding, I'm serious. This is a very big thing, this is reinventing architecture when you are a caveman, going all the way up to the Renaissance, and building huge palaces. That is the scope of the project for us. I don't think it will take as long as it took the cavemen, but I think that we're definitely in for the long haul. To the extent that we can incrementally build meaningful rejuvenation therapies along the way, then many of us will also be in for the long haul, and this turns into someone's life's work. That life might be rather long.

I don't know how long people will live. I am a late 40s individual, and if you can just run the thought experiment of the biotechnologies that will be available to me in my 80s, I won't look anything like an 80 year old person today. I will have no chronic inflammation; no senescent cells; probably no cross-links in my body; my stem cells will have been replaced; my immune system gardened; and so on and so forth through a long list of treatments that are going to happen in the next few decades, and are very plausible right now. So you can add these things up and say, right, if an 80 year old has no inflammation, no senescent cells, no cross-links, no atherosclerosis, what does that do to health? Do you still look like an 80 year old? Can you go run a mile? No-one knows, and we get to find out by doing it. That is the great adventure.

The big problems in aging are all comparatively simple to solve, and it is all benchwork in the lab to get your programs going. You don't need the massive computational, big data, machine learning projects that are popular right now. The only place where present artificial intelligence might be useful is in improving the state of small molecule drug discovery, and my belief is that small molecule drug discovery will go away, largely, in favor of gene therapy. So maybe your AI is looking for genes or proteins that are of useful effect, but the present process of finding genes that have useful effects is not terrible. It is having good results. The upshot is, ok, where do you use AI in this process outside of small molecule development? And I don't see anything in which AI is absolutely necessary, useful in any way other than incrementally improving the infrastructure, reducing costs. Targeting senescent cells with senolytics, that is where small molecules might be useful, but the best projects there don't involve small molecules. Dealing with mitochondrial DNA damage? No, that is benchwork, and it seems unlikely that small molecules can do anything meaningful there - that is gene therapy territory. Stem cells? Again, it is just a matter of developing the methodologies that can lead to successful therapies, and deep down under that development, you find a role for AI in anything where there is a lot of data to be analyzed, but it is only incremental improvement in cost and efficacy.

Infrastructure makes the world turn, and incremental improvement is not to be sneezed at, but it is just a part of the technology background. You can't just jump up and say "we're going to do AI for longevity", no. You are going to do AI for biotechnology in general, and biotechnology is then applied to longevity. So AI will vanish into the tool space. It won't be a major category that is up there on its own in the fight against aging. Right now it is because it is novel and because investors throw funding at AI like there's no tomorrow, and entrepreneurs and scientists follow the funding. So you get In Silico Medicine, for example, and they are doing small molecule discovery AI, which is what most other people are now following on to do nowadays, because that is where the funding is in the present phase. But I think this will just fade into the background, it will be another tool in the toolkit. It isn't exciting, it is not category changing. It is an incremental advance, using computers a little bit more to help you do things when there is a lot of data involved.

Let's talk about Effective Altruism. That community is doing smart things, in the sense that Big Philanthropy is thoroughly corrupt, and one should ask the question: if I want to do good in the world, versus conning myself into thinking that I did good in the world, what should I in fact do? You don't give to the Red Cross, because the Red Cross is a thoroughly corrupt organization. The same for most large entities in philanthropy; they have enormous overheads, and most donated funding doesn't go to the projects you would want it to go to. The Effective Altruism movement in that sense is great, and a very overdue examination and critique of philanthropy as a whole. Secondly, if the effective altruists can find convincing ways to convince high net worth individuals to actually give sensibly, this will be a good thing. I suspect that reason many of high net worth individuals don't give sensibly is because they have absolutely no idea how to do good, and it is a big project to figure out how to do good at scale. If Effective Altruism can lead to more people in the high net worth category putting their funds into projects that actually have a good chance of improving the human condition, then that is a public good.

The third strand is obviously that the Effective Altruism community includes people who are quite concerned about which projects to fund from a utilitarian point of view, and to the extent that anyone takes even a cursory look at aging, it is obviously the case that aging is far worse than anything else that happens anywhere. Pick your favorite cause in the third world, and I can tell you that those people are suffering more from aging than from the target of your favored cause. Even for war, even for famine, it is still the case that aging is much, much worse. This is a sad thing, because we could be dealing with all of these issues, but when it comes to prioritization, yes, if you want to solve famine because it is terrible and causes people to suffer, then you also be willing to work on solving aging in that same population, because it causes a far worse outcome to far more people. So the Effective Altruism community should logically work its way to advocacy for the treatment of aging as a medical condition, because it is undeniably the case that it is the worst problem facing humanity, and it is the most cost effective point of intervention to reduce suffering and death in the world. Even when intervening in tiny ways, the outcome is an enormous return on philanthropic investment in the cause.

So I think that the effective altruists do good, and I think that there are not enough of them, and I think that they are not talking about aging to the degree that they should. But they are coming at it largely from an outsider perspective, and except for a few, they don't understand the science, they don't understand the degree to which rejuvenation is possible. Effective Altruism is a young movement, it has a way to go yet, but it has the potential to be very important. We shall see how it develops. In terms of our community engaging with effective altruists, it is all just advocacy at the end of the day. To the extent that the aging research and development community needs funding, then we set forth and engage the effective altruists to the extent that they have funds, or can influence sources of funding. If it is more effective to talk to effective altruists, then we aging advocates will do that, trust me.

That might be challenging as an argument right now, as right now it is clearly more effective to talk to venture capitalists, because they are very incentivized to put funding into these projects. Very large amounts of funding, in fact, to the point at which it would be very hard to raise that level of funding through any sort of philanthropic program. Unless of course you are talking to high net worth individuals. But convincing high net worth individuals to go and put funds into work on treating aging is Effective Altruism, whether or not you are cloaking it in that name. Certainly, I and others are guilty of poking high net worth individuals to say "have you thought about this a little bit? Do you want to get old? You can do something about it. So go do something about it." But it is an incremental process. You can't just flip a switch and have all of the trooping masses of the Effective Altruism community go off and spread the desired message. So we shall see. It will go where it goes.

There is an enormous waste right now in development and deployment of ineffective ways to treat age-related disease, those that don't target the causes of aging. Further it will cost a great deal to develop functional rejuvenation therapies that do target causes of aging. But if you look at the enormous amounts that are spent on merely coping with the consequences of aging, then making it go away is highly efficient. But of course it is not just about funding and cost, it is about effective reduction of suffering. Funding spent on anti-aging research is an enormously cost-effective way to reduce suffering, providing it is spent on the right anti-aging research, rather than the programs that are not likely to produce more than a small effect. So mTOR inhibitors are great compared to previous technologies for dealing with age-related diseases, because they influence a lot of processes, but the effect size is really not large in the grand scheme of things. If you are going to put funding into developing mTOR inhibitors, then fine, that is happening, then you should spend that same level of funding on aspects of the SENS program that can actually repair underlying damage, rather than trying to tweak the body to be a little more resilient to damage. People taking mTOR inhibitors are still going to die on the same schedule as the rest of us. That aren't that much more resilient. People with senescent cells removed, on the other hand, well, who knows. We will see what that does to life span. I think that the pensions and insurance companies are going to be in for a rude awakening. Personally, I think that five years of additional life is not an unreasonable guess, and that will break a lot of insurance companies if they haven't prepared successfully.

Regarding what will convince the world that meaningful progress is happening and further meaningful progress is possible, I think that recent developments in the laboratory, particularly around senolytics, are convincing to scientists. That is helpful. But I don't think that it convinces the world at large in a useful way. Things have to leave the lab for that to happen. The thing about senolytics is that even those initial compounds available now seem to be quite good at making a sizable impact on quality of life in older people, and possibly for autoimmune diseases, and a bunch of other things. To the degree that we can say "guys, we're giving you a rejuvenation pill, your arthritis is probably going to go away" and then if even half of the patients lose their arthritis, or their symptoms are greatly minimized, and they lose their other inflammatory conditions, and we turn back early Alzheimer's disease - and all of these are plausible things that senolytics should accomplish, based on the mouse studies - then if that happens, then suddenly rejuvenation therapies are a real thing, and people can stop saying it is impossible to rejuvenate humans. Then we can go from there to explain that this is just one part of a larger program. We're just doing one tiny thing, and not even that well, and look how good it is.

Senolytics will be the point at which an awful lot of things change. The early stages are happening right now. The self-experimentation community is doing interesting things with senolytics. Once the first studies that actually have large effects are published, it will be hard for regulators to keep these early senolytic drugs out of peoples' hands. There are 60 million people in the US alone who would benefit from senolytics because they are old enough to have conditions that are inflammatory. This should happen. It will happen. And that would be the moment, I think. Senolytics, not anything else. Aging is a huge burden. Effectively treating aging will solve many problems. Old people are old people because they are aged. If you rejuvenate them, then they are no longer old. They will have a better time of it, and if you have an aging population of 80 year olds who are physiologically like 65 year olds, then you have an aging population of 65 year olds, effectively. After that it is very easy.