Hybrid Approaches to Substantially Slow or Reverse Aging - Kamil Pabis

All right, good morning everyone. Thanks for coming in so early on a Saturday to listen to our science. I will today start the event with just a random assortment of ideas how we can be more efficient and trying to slow aging and sort of an overview of things I find interesting. view of things I find interesting. And for those who don't know me, so I'm helping to organize this event, I've been interested in longevity for 15 years, sort of always working in the field.

Currently I'm in NUS Singapore. I work on, for example, the NRF2 pathway for stress resistance, combinatorial approaches. I'm also interested in very foundational questions, so including controversies in the field. And personally, I'm also interested in supplements, so ever since I got into longevity, I always wanted to do something immediately to improve my health, whatever was available. I also like to do outreach, blogging, tweeting, things like that.

And I thought, so I grouped this talk loosely into those seven categories, sort of starting with like wellness supplements in the beginning and then going into like more substantial or more like long-term strategies strategies how we can affect aging so maybe I'll just start in the beginning first sort of the pros of using supplements or grass Compounds that can be sold over-the-counter to slow aging or improve population health, of course You know if you gave this to millions of people hundreds of of millions of people, even small benefits would save, like, billions of dollars. And if you take a compound over decades, even if it has a small benefit, it could have a compounding benefit. So there is a certain logic. And they're cheap. Time to market is fast.

So supplements are safe. So they're certainly attractive as one weapon to slow aging or at least improve population health. But often the problem is whenever we test them in animals or human studies, when they work, if they work, the effect sizes are really tiny. Many studies are badly designed. If you run a company, it's a problem because it's hard to get IP on any of those compounds.

And many supplement companies, their marketing is at best slightly misleading. And it also leads us to the question of healthspin versus lifespan because most of these compounds are, would rather improve healthspin rather than slowing aging, which might still be beneficial, but this is actually not the same as the idea of the geroscience hypothesis, which is to substantially slow aging. And maybe later a few words about that. When we were in Singapore, we had a nice meetup where I analyzed part of Brian Johnson's famous supplement stack at that time. I noted which drugs or supplements I find promising, which I find questionable, which I find so-so.

And he does take a lot of stuff. Some of it I would consider evidence-based or at least with good risk-benefit ratios. Other things I found questionable or useless. So, for example, it doesn't hurt that he's taking vitamin D. There are a lot of studies, some suggest minor benefits on cancer incidence.

It's extremely safe. And if you don't get a lot of sun exposure, right, it will be beneficial. And I'm not going to go through the list of compounds. Maybe later we'll talk briefly about taurine or some others. But basically you can go from taking nothing to taking like dozens of supplements.

It's quite interesting the range of what people take. And since we were mentioning biohacking yesterday and like what do people take, how do we improve our life currently, so this is sort of my minimalistic stack. Most of these supplements, I would say, will not slow aging, but they might improve my health. So I got really interested in cocoa powder recently because there was a very large study that showed in around 20,000 participants that it reduces cardiovascular mortality. So it's a supplement and it still has a really substantial benefit when you consider the totality of evidence.

So just because something is a supplement doesn't mean it cannot be useful. But from this list, actually, the only maybe one or two things have also real sort of evidence for slowing of aging. For example, taurine was found to extend lifespan in healthy, long-lived, well-husbanded mice, which is one of the standards we use to decide whether something affects aging. And sulforaphane is an activator of the NRF2 pathway, which has very strong implications in longevity. pathway, which has very strong implications in longevity.

But we don't have, for example, on this one yet, even solid mouse lifespan data. So it's very hard to say whether it's just a health supplement, right, or whether it will slow aging. But for example, just a few words about sulforaphane, because I work on it. So there are large studies in China showing that it does increase the liver's capacity to conjugate and detoxify all kinds of carcinogenic species, benzene and carcinogens found in smoke, right? So it is very plausible that it would decrease human cancer rates, but these studies have not been performed yet.

But a lot of these things, they're safe, they're found in the diet, right? So it doesn't hurt to take them. The risk-benefit ratio is certainly positive. And if I were to extend my, you know, my supplements, like so to say I have a may... Well, how does this work?

Maybe not. Anyway, on my maybe list are things like rapamycin. This is, maybe it has a higher risk, but it has also potentially higher benefits, so this is currently sort of the gold standard drug that seems to work in both mice and primates to slow aging, so if I were to experiment further, right, I might be tempted to take rapamycin, and I also do all these nice things, you know, like sun avoidance, exercise, to live healthier. But the problem is... Male Speaker 1 in audience 2 inaudible 007 Sorry?

This... Male Speaker 1 in audience 2 inaudible 007 Yeah. All right. It's going to be fine. Male Speaker 1 in audience 2 inaudible 007 Yeah, the clicker.

Yeah. So maybe just a few words how you could rationally select supplements. What I like to do is I like to take things that have some efficacy in mouse, like on really hard outcomes like lifespan, and at least some efficacy in, you know, medium-sized human studies on relevant strong outcomes like lipids, blood pressure. So this is, for example, why I came to like taurine, because it has both lines of evidence. But there is fundamentally a problem with most of these supplements that if they do not slow aging, due to Tuber's paradox, as we discussed yesterday, because multiple causes of death increase in parallel, if you just improve your health slightly, you decrease cardiovascular mortality, you will still die from cancer, and it will probably substitute for cardiovascular mortality.

So it will not even affect your lifespan, just even though it's healthy and health-promoting. And I like this picture to the right, which shows a person being executed, multiple bullets being fired at the same time. If you just stop a single bullet, it will not delay the death of that person. And I think that's a nice way to visualize the Toybus paradox. So what we want to do is we want to like really substantially slow aging.

And this is also just another example of Tuber's paradox. Recently a study on prostate cancer. So the prostate cancer death in that study was halved, but it only led to like at best marginal differences in lifespan. And the prostate cancer is in the dark blue here. And you can see how the other causes of death quickly substituted for the prostate cancer death in older men.

So what we really, really need to do is to slow aging. And this is just to show you the changes. And that's the idea of the geroscience hypothesis. It is that you can slow aging and it would have substantial benefits. And again, a funny picture to symbolize it, if an elephant is falling on your head, if you have an umbrella, it will not really protect you.

And that's basically aging. And we're trying to do something about it as scientists. And I'll briefly talk about some of the work I'm involved with, partly through the NUS and through our longevity community. So I was trying to compare exercise with rapamycin to really write a paper that makes this stark contrast between improving health and slowing aging. Because after I looked at the mouse data and other data, I realized that exercise barely has any benefits on lifespan in most models, but rapamycin has really substantial benefits.

And then I also noticed as these charts show, when you ask people whether rapamycin or exercise likely slows aging, the general opinion even among health professionals and many even geroscientists is they think exercise is perhaps likely to slow aging. It has a very high, very good reputation. I think exercise is great to promote health, but there is very, very little evidence that it actually affects the process of aging. And maybe one or two figures to show this comparison. So I looked at data and then I compared the lifespan extension under rapamycin exercise and rapamycin led to like threefold higher lifespan extension in mice.

So that already suggests rapamycin is much better than exercise. But the situation gets actually worse. We recently published a paper showing that most studies in mice, they're hampered by very short lifespans of the control, so the mice are not healthy. If you look at really, really healthy mice that die mostly from real age-related causes, and then you compare rapamycin and exercise, exercise does nothing. But the effect size of rapamycin is basically unchanged.

So that means rapamycin, because it slows aging, is an order of magnitude, at least, better than exercise, which already is probably quite beneficial in humans. So it would be tremendous if we could slow aging and if rapamycin translated to humans. Yeah, that's what we found also doing our own experiments. The benefits, the health benefits might be very dependent on the protocol. And since the mice don't talk, they're not very friendly when you handle them.

It's hard to figure out what is the optimal protocol to do them. Most of them are voluntary wheel running. But I also looked at forced wheel running. It did not look much better. running, but I also looked at forced wheel running, it did not look much better.

And there are no protocols for like strength training in mice where lifespan was looked at. But whenever different protocols were compared, there did not seem to be substantial differences, at least in mice. And also strains in mice that tend to naturally run longer, they don't necessarily live much longer as a sort of correlative data, that's what I can say. But I agree, there is probably some optimal mix of different kinds of exercises that would help humans and maybe mice. Now let's talk about more pharmaceutical approaches.

So there are a lot of incremental improvements that we've made to improve human life. And I just list a few of them, many vaccines, HIV therapies, and something like cancer immunotherapy. And they lead to very substantial gains in a single domain, but this probably still won't improve lifespan and it won't increase age-related healthspan that much due to Tauber's paradox. But some of these inventions, some of these drugs are still very important, and they might pave the way for applying them to age-related diseases or combining them so that they would cover different aspects of aging and actually extend lifespan and age-related healthspan. And I'll just show one example of those incremental but still substantial improvements we've made.

So recently those immunotherapies for cancer, especially for cancers where it works, like melanoma, the immunotherapy is at least as important as surgery for this cancer. And survivals have improved substantially. for this cancer, and survivals have improved substantially. So we're definitely making gains, improving human healthspan, but we can do better than just these therapies. And one thing I'm working on, as I briefly mentioned, is the NRF2 pathway and sulforaphane, which is an activator of this.

It leads to multistress resistance. which is an activator of this. It leads to multi-stress resistance. It upregulates hundreds or dozens of antioxidants plus other proteins that help the body excrete various toxins. It improves iron handling.

And there is very preliminary data in mice that it does decrease mortality. And we would really want to test this in longer-term mouse studies and also in large human studies. And this is one of those molecules that is sort of at the intersection of preventing cancer and slowing aging, so it could be repurposed for both, and I think we could do very nice hybrid trials on this, which I'll later explain as one approach for the field forward. And again, sulforaphaneane nicely for human supplementation. It nicely fits this intersection idea.

It has some good mouse data and it has some good human data on inflammation, carcinogen detoxification. If you combine the two, for me it means the risk-benefit ratio is positive. And that's why I myself also like to take sulforaphane and I liked researching it. And now maybe more about gerontology itself. There have been some substantial, you know, findings in the last hundred years, you could call them paradigm shifts, where we've learned how to better deal with aging, how to get slower, closer to slowing aging, starting with the famous caloric restriction experiments made famous by Clive McKay, among others, where it was first shown that diet can actually slow aging.

But for a while, people thought it only works in young mice. So then the big breakthrough was to show that it also works when you start it in adulthood, among others done by Walford and Weindrück. But then this was just a diet diet and it was an extreme diet. It's not applicable to humans, so people could criticize the field for not having nothing substantial to show yet. And there was also for a long time a debate, you know, how many genes are involved in aging, how multifactorial it is.

And some people really thought aging is so complex, you just cannot slow it. There can never be a single gene mutation to extend lifespan. But then in the 90s, in two different models, C. elegans and myosid, it was shown that actually single gene mutations in some pathway can substantially extend lifespan. So this was another great breakthrough.

So we're really getting somewhere. Then eventually, we found what to me is perhaps the biggest finding of all so far, that a drug can actually extend lifespan. And this was rapamycin, and it also even worked not just in adulthood. It worked in late middle age. So this is like a dream come true if this were to translate to humans because we don't want to intervene too early since this might be inconvenient.

You know, young people don't show signs of disease yet. So we made real progress. But still, to some extent, investors are not taking the field that seriously. But I think rapamycin should have shown that there's a lot of promise. And there are also other interesting sort of paradigm shifts showing that intermittent rapamycin even works.

So there could be therapies which you don't have to take them for your whole life. You can maybe take them for a few months, like senolytics or rapamycin even works. So there could be therapies which you don't have to take them for your whole life. You can maybe take them for a few months, like senolytics or rapamycin, and it would still slow aging. So this would make it even more practical in terms of, you know, translation.

Then we got some studies showing that caloric restriction and rapamycin might work in primates. I know there are certain controversies, but this is also amazing. And now we're just working on those biomarkers and showing that aging can be really measured. Still, it's imperfect, but now we're getting the biomarkers. And maybe this will enable clinical translation.

And then there are these, there's a whole series of approaches which I title as hacking aging. It's sort of sidestepping the classical problems of pharmaceutical science and of aging. I won't talk too much about any technological approaches here, ranging from AGI over advanced technologies. But if you go back a few hundred years, our today's technology looks like magic compared to what we had back then. So you can't predict what we will have in 50 to 100 years.

There are also interesting approaches in terms of like embryo selection and things like that. You could select for SNPs that slow aging a little bit. What I don't fancy about this approach, among other challenges, is that it doesn't benefit the 7 billion people who are alive now. So I like to focus on, you know, give you a list of approaches where people are thinking about substantially slowing aging now. What could be done?

And one is, of course, reprogramming. And I think reprogramming is part of a very cool group which is sort of gaining an understanding of privileged tissues and states in the human body. One was development, but the other one was also the germline, which has an unusually low mutation rate. And people, Björn Schumacher's group, found that the dream complex might be a master regulator of DNA repair in the germline. So really understanding what makes these privileged states so, you know, beneficial that these tissues show slow aging or whatever, it has led to a lot of progress.

So people knew or thought for a long time that there must be an, you know, embryonic, some sort of rejuvenation event and now using reprogramming we've shown that this might be partly responsible for why our germline is sort of immortal, like why older parents can give birth to relatively normal, young, perfectly fine children if you ignore chromosomal abnormalities and stuff like that. But that's amazing. And then, of course, there are cell and gene therapies. I don't want to talk too much about this. I will highlight one approach that I like, some sort of the hacking aging category, which is like filter and select.

So I already mentioned senolytics. So the idea is that you might have certain cells which are dysfunctional. And if you could find a marker for these cells, you could remove them. And they tend to accumulate with aging. And the idea is to do this.

And there is actually something very cool. There is a study, which most people don't know. It was about mitochondrial disease. And it was found that a ketogenic diet in patients with mitochondrial disease led to selective destruction of these red fibers. So those are fibers that accumulated a lot of mitochondrial DNA deletion.

And it immediately struck me as being really similar to the senolytic approach. It's sort of a filter and select strategy. You find a marker or some way to push these damaged cells out of equilibrium and then get rid of them. Now, this is amazing. You get rid of the damaged cells.

Now, the only question is whether regeneration will take place and whether they can be replaced with healthier cells. But this is, I think, one important and necessary step. And yesterday I mentioned, I mean, not everyone was here yesterday, mitonioid DNA deletions also increase in natural aging exponentially. So eventually they will limit human lifespan. And here we have an approach to remove muscle fibers that have those mitral DNA deletions.

So it could perhaps pave the way for treatments for aging as well. And here I just show some slides of this patient study, like when they gave the diet, right, they saw an acute increase in muscle damage. And that showed that the diet was lysing these red fibers and what was interesting is there was evidence over like two years of follow-up after this two-week treatment that the patients improved in function and this study also shows another problem it was a nice beautiful small pilot but afterwards people got really scared and IRBs would not look fondly on those who suggested to try this again. But there were actual hints of improved muscle function afterwards, but I've not seen follow-ups. And if anything, in reviews I've read that, you know, ketogenic diet are contraindicated in patients with myopathy, but there was actual muscle improvement.

So I think we have a problem with the whole regulatory system being a bit too conservative. And I have a few slides about this later as well, but this study highlights this nicely. But of course, when you remove cells, you always run into this question, maybe in some tissues, these sort of damaged cells still serve functions. So, also with mitochondrial DNA accumulations, like, you don't want to, you know, destroy your dopaminergic cells because they also have DNA accumulation damage and that contributes to Parkinson's. So, one has to be very careful with these removal strategies, but they're extremely promising.

And also a few words about some sort of engineering-like approaches. I looked at vascular aging 10 years ago and yesterday I had a slide about this as well. So calcification in the human arteries increases exponentially with age and if we could remove this, it would be probably beneficial. It would probably improve vascular resistance, left ventricle heart failure and there are actually companies that are sort of working in this space, like Elastrin. They have this beautiful idea of using antibody-coated, some sort of vectors that will recognize elastin, and then you can deliver a payload.

And I think this could be beautifully applied to vascular aging. But again, we run in some limitations that these companies, in the best case, they work on age-related diseases and not aging per se. So they won't take a healthy 70-year-old with vascular stiffness and test a therapy in them, although this would be a perfect population. They go to these extremely rare diseases or extremely dangerous diseases where you find calcification and they first test in there. But there is often no path forward how to test these therapies in regular older people.

And I think the PROSPERA approach was quite nice one that maybe you could in parallel also run sort of heroic studies in volunteers who don't mind testing these therapies so that we would actually get data from real, healthy, older people instead of spending 10 years in disease populations. I mean, it's important to target these diseases of allostin and calcification, but ultimately we have to find a way to get into real patients. And I think there are a lot of approaches that we can talk about. How can we reform the system, IRBs, our own approach to risk and benefit. But I think this highlights some of the complexities and promises in the field.

And yeah, just the question here. Can't we find people willing to take these drugs? I think we can. But we need to also find an IRB, a university willing to take on the risk of testing this in healthy age people. But I think it would not be a problem to find the volunteers.

So why do you distrust healthy age people? Because we don't really have sufficient evidence to say that they're not as anti-tank and anti-shock, that they're not anti-interventionist, but what about Absolutely. You could also test things in middle-aged adults, but that makes the study even harder from the perspective of the IRB, because these people don't have any disease, and they're not even close to developing a disease. So prevention approaches are beautiful, but the risk-benefit ratio is also tricky because a lot of these people will never go on to develop the target disease. Some of these people will never die from cardiovascular disease, but you're still targeting trying to prevent cardiovascular disease.

I mean, I like the approach and I think we should explore it, but again, we run into the whole idea that the system is very conservative and very disease-centered. All right, and there are like maybe two, three chapters left. So one way to improve, which is now totally outside of science, is to get, of course, more funding into the system. And it is also the question for everyone who wants to do something about aging, what kind of job should I take to help to make the field better? Should I become a VC?

Should I become rich and donate? Should I be a scientist? And I think it's, so that's my opinion, it's very difficult to make a choice and I think many different jobs can of course contribute to the ecosystem and we need all of them. So as we have in Asia, sort of the idea of the icky guy, you should choose not just the thing that will contribute the most to the field, but also something that will make you happy in the long term. Because if you burn out, well, that's maybe won't be beneficial to the field.

Or if the things never materialize that you're hoping for, you still want to have lived a good life, right? So, choose whatever job you think is beneficial to the field, but also a job that will make you happy. But we really need to understand also the philanthropy system. It has been like perplexing for me for a while, why the big donors are not interested in longevity, why they do not believe in the geroscience hypothesis that slowing aging would be beneficial. So here are like some of the biggest foundations or donors.

And down there, I've written about their focus. So their focus is often public health, climate change, governance, and democracy. So a lot of it is linked to poverty alleviation. Now, the question is that we can brainstorm at some point is how do we make geroscience more attractive to big donors? But actually, I that over-aging of societies will very soon, if not already, affect poorer countries, like India will eventually in the second half of the century, the population pyramid will be very unfavorable.

The number of older people will grow there rapidly even before they have become rich. So after you elevate poverty, right, immediately the fertility crisis and the over-aging of the population will be the next drag on those developing countries, as we already see with China, right? They went from rich, sorry, from very poor to being sort of a middle-income country, but now they reach peak population and people are getting older and birth rates are very low. So now aging has become actually a pressing issue for this once poor country. So I think even if your poverty alleviation is your, like, goal as a philanthropic donor, I think you still have to consider that geroscience is important.

And now there's also, of course, the debate, do we understand aging well enough to intervene? I have my own opinions on this. I think we can get far enough without understanding aging, and once we have the first drug, we maybe can acquire more funding. But there are certainly reasonable arguments to be made that we really don't understand aging very well. So just to give you a flavor of this, there has been a debate for 20 years where the caloric restriction actually works.

We always say it really works, and I think it is quite robust, but it does not seem to work in all strains of mice, for example. And we've also done some reanalysis of this in our own papers. Nevertheless, you know, despite these controversies, I think there are some cornerstones of the field. Caloric restriction does something in the strains where it works, and we want to understand it., but certainly as my colleagues say, you know, we really need a deeper understanding of aging to get more than a couple of decades lifespan benefit.

And there is also a nice colleague or a person that I would like to highlight is Dan Eninger. He has written a lot of controversial papers. So he, for example, makes the claim that the treatments that extend lifespan in mice maybe do this only for like very limited pathways. And I agree, right? We need to start looking for treatments that are not just mimics of caloric restriction because everything seems to affect those anti-anabolic pathways.

And now we need to find some novel, maybe more substantial treatments. And I think it's important to highlight and discuss these problems, but still to the outside, to the public, to emphasize correctly that geroscience is the most promising way to improve population health in the long term. And so this is a slide that I made for my blog, right, about this, can we make progress without understanding? I think if we had one drug, let's say rapamycin translated to humans with 50% of the effect size in mice, this would be already the best blockbuster drug ever found and it would be a trillion dollar industry. And I think this would lead to, you know, Nobel prizes, VC money.

So if we get this one primitive drug on the market, it will help us to, you know, Nobel prizes, VC money. So if we get this one primitive drug on the market, it will help us to, you know, start this cycle of further improving, refining, understanding aging. That's my hope. And another candidate for this are, of course, the GLP agonists. So they could also potentially slow aging even in healthy people.

And we need to test them. So for those who are interested, I'm on Twitter as TheAgingScience, so please follow me. If you want to learn more about longevity, I'm also on Substack on the geroscience blog. So yeah, we can always keep in touch. And now I'll just highlight a few approaches in my last slide.

So we also need to do better advocacy. And I also still don't understand why the public at large is so skeptical towards longevity. But we certainly need to explore novel avenues, the modern media where we could reach younger audiences. We also have to understand that targeting different audiences requires different messaging. So when I talk to specialists, right, I want to have a different message and use different words than if I talk to the lay audience.

And this is just something to keep in mind. It doesn't mean that you're lying. It just means that you have to be mindful of the people you're speaking to. Then, of course, there's some incipient political advocacy. It would be great if we could make longevity a non-partisan issue that all parties are interested in.

And there is some progress in the U.S. with the Alliance for Longevity Initiatives, right? But of course, there are other parties like regulators, insurances that we also have to talk to and get on board. And one of the most promising advocacy avenues is actually, I think, the fertility discourse.

People are now realizing that in a lot of developed countries without immigration, populations are absolutely collapsing. People have calculated that, you know, Korea will basically cease to exist in 100 years, given their fertility rates. So I think this is really troubling, and I think longevity could make two contributions here. It could extend the healthy, fertile window of women, and it could also compress morbidity, extend lifespan, decrease the dependency ratio, right? So maybe we can use this discourse to combine it with geroscience and explain to people how important this is and how we can help with the fertility problem.

And just a few slides about the typical influencers. And what I just found very striking is you can see to the right, you know, most people will know Matt Cabala and he is like very evidence-based. He's an amazing guy. He has done good work. But he only has 20,000 followers who are people like Brian Johnson who are more controversial.

Sometimes they say bullshit, sometimes they say smart things, you know. They have more followers. And I actually like Brian Johnson a lot. I think he has done good things for the field by attracting people. He has attracted people to my own meetup where I explain to people the importance of true hardcore geroscience.

So I think he has been in many ways beneficial to the field. But he does also risk polarization, especially on the left wing. I noticed recently debates that maybe lifespan extension is right wing or that somehow it's only for billionaires. So there's a real risk there. If it turns into a partisan issue, we will immediately lose like 30% of the population because they will think it's a political thing when it's not.

And of course, if we could get the hyper-influencers on board somehow with millions of followers, they would be beneficial. So you could be an influencer who tries to influence the influencers, right? There are so many jobs in the field that could be beneficial, and it's up to us to find something. So yeah, I do my contribution in Singapore. We run a longevity meetup there.

And as I mentioned, Brian Johnson had a positive impact on my meetup so it helped me to get more people with whom I could talk about geroscience. And we just, this was an example of a recent opinion piece where, you know, people were saying it's, we're right wing and we're horrible people. So we really need to avoid this kind of politicization, negative politicization of geroscience. And if we could find some thought leaders on the left that support geroscience, that would be certainly very amazing. Okay, I think I don't have that many slides.

So these are now the summary slides, sort of what do we do with this knowledge, the ideas, what are ultra high impact ideas that I identified for myself. So I mentioned sulforaphane. I think it could be used for these hybrid trials where we test sulforaphane or rapamycin in sort of populations that are a little bit sick, maybe like smokers. So at the same time, we would test it for cancer prevention. But we would also get these very, very large studies with hard outcomes.

And there is certainly money to do this. Often the candidates chosen for these studies are inferior, although we only find this afterwards, like beta-carotene famously increasing cancer rates in smokers. I think a combination of rapamycin plus sulforaphane or another NRF2 activator would be really nice for a large trial in smokers with hard outcomes. I think we really need to also push for GLP agonists to be tested in much broader populations So we know whether they improve heart outcomes in regular people with right normal body mass index The fertility debate is mentioned. I think we can link this with geroscience.

This could be very beneficial other people of course from the Environment they had other cool approaches. So I think these special economic zones where treatments can be tested with slightly less oversight can be quite valuable, although I'm not a specialist on this. But I see some promise there. And then just there are many other ideas, right? As mentioned, influencing the hyper-influencers and the meager philanthropists.

Like, if we found a way to understand. Yeah, and, like, how do we make longevity the next climate crisis? Because it's, like, a really urgent thing. Climate will certainly affect millions of people negatively. Aging will affect almost everyone negatively.

So, if we have time, thanks for listening. Thanks for all our supporters who made this possible. And maybe we can just briefly brainstorm what kind of ideas you have to improve geroscience and slow aging.