My attention was drawn today to a recently published presentation by James Peyer. He heads up Apollo Ventures, one of the new crop of investment concerns focused on funding companies that are developing means to treat aging. These include the Longevity Fund, first out of the gate some years ago, as well as Juvenescence and the Methuselah Fund, created this year, and a repurposing of existing funds, such as Michael Greve's Kizoo ventures. Apollo Ventures is the source of the Geroscience online magazine that helps to advance and explain the position taken on aging by this group; this is something that more investors should do. It is a cost-effective means of talking up one's industry and positions, of reaching out to the community that includes founders and potential founders of companies to invest in, and so forth. In the best of worlds it does all of that and also provides a service that is useful.
So, my grandfather was kind of my hero, growing up. He was kind, smart, super-passionate about every little thing he was doing. And really argumentative about it too. He was happy, successful, loved his family, and if you asked me what living a good life meant when I was a kid, I would have told you it was to be like my granddad. So when he was diagnosed with cancer when I was 14 it shattered my world. We were going to go on vacation that summer, but his doctors found two tumors at the same time, one in his throat and another in his brain. So instead, I spent that summer watching week by week, month by month, as he got sicker and frailer, and also, heartbreakingly, forgetful and paranoid. He was given medicine that kept him alive a little bit longer, but he never really was himself again. And in my last conversations with him, he talked with me about how terrifying it was, knowing that, day by day, he was slipping away. Knowing that he wasn't getting better.
When he died I fell into a depression. I couldn't stop thinking about the fact that no matter how good of a life we live, every one of us has the same thing waiting for us that my granddad did. Months or years of suffering of some terrible disease, like cancer, or dementia, or a stroke. What was the point of getting 'A's in school or scoring the winning goal in the big game if that's all we have to look forward to? I spent months feeling this way, and it wasn't until I stumbled across an idea that I was finally able to crawl out of that depression. I latched on to something that gave me a purpose. What if I spent my life fighting against those diseases, so that other people didn't have to suffer from them the way that my granddad did? That purpose has been keeping me going until this very day.
So there I was, I had my epiphany, the big idea, but I had no idea how to go about doing it. How could I fight against the diseases that had killed every single person I knew who had died? I started casting around and learning as much as I could, and it didn't take me long to find something interesting. While cancer and heart attacks are today's biggest killers, they haven't always been. As recently as 1900, most people died of infectious diseases. The leading causes of death were pneumonia, tuberculosis, and influenza, and the average life expectancy was 45 years old.
Doctors and scientists spent the last century struggling heroically against these diseases - and we invented antibiotics and vaccines in order to fight them. Those were the biggest challenges of the 20th century. We've been so successful fighting them that now we live in a world where the average life expectancy is 80. In developed countries all ten of the leading causes of death are caused by simply living long enough to not die of anything else. The 21st century will be defined by our struggle against these diseases of aging, and it is not going to be an easy one. For 75 years, these have been the leading causes of death for humanity, and everything we've done to fight them has barely made a dent in the number of people dying of any one of them. In fact, they are rising as a fraction of total deaths in the world, as we continue to make strides against infectious disease, malnutrition, and violence around the world.
You see, as a society we look to medicines to make us well when we're sick, and so far almost everything that we've designed to treat the diseases of aging has fit in that paradigm. We wait for someone to get cancer, to have a stroke, or start losing their memories, and then we try to do something about it. But this approach hasn't really been working. Since 2000, we've done 200 clinical trials in humans just for Alzheimer's disease, and 99% of those have failed. The two that succeeded haven't even given us a drug that does much to treat Alzheimer's disease. We spend over $20 billion a year on cancer research and trials, but most of the gains we've made against cancer since 1970 have come from better diagnosis of cancer, not from curing the disease.
This should tell us that we're doing something wrong in our approach to the diseases of aging, because, unlike infections, the diseases of aging are caused by the slow, gradual build up of damage to our bodies over a lifetime, before they ever cause enough of a problem for us to go see a doctor. And by the time that we go to see that doctor, so much has happened inside of our bodies, that there is not much that they can do to help us. So this is how I started my academic career. I was one of a small group of scientists, and we were all thinking the same thing: if we ever wanted to eliminate Alzheimer's and cancer, the way that we eliminated smallpox, we would have to take a different approach to healthcare. We would have to treat the diseases of aging by anticipating them, building medicines that could remove damage caused by getting old before it ever accumulated enough to make us sick.
And this kind of makes sense, right? Because we all feel the effects of getting old right now, even when we're not sick. I mean, who here can run as fast as they could when they were 18 years old? Or maybe bounce back up after falling out of a tree like they could when they were 12. I am by no means old, and even though my risk of osteoporosis or cancer is diminishingly small, I am getting older, just like all of you are. My blood vessels are hardening. My neurons are starting to get tired. My DNA is mutating. I'm losing the battle to keep my cells and tissues in good condition. Right now we only think of this progressive accumulation of damage as a problem when everything goes to hell, and it erupts as some kind of disease. If we want to stop this gradual build up of damage in our bodies, we're told that the old things we can do are eat better, exercise, avoid smoking, hope that we've gotten lucky with our genes. It's not exactly a hopeful message. We're not leveraging the power of modern medicine to prevent us from getting sick from the things that are killing us the most.
But that is all changing. Because for the first time in history, we understand what makes us get older. We've traced to the biochemical level the diseases of aging and what causes them, and we've been able to categorize the damage of aging into nine buckets. Things like the random mutations of DNA, or the exhaustion of our stem cells. Our understanding is now at the cellular and molecular level, which means that we can actually design medicines to target and treat these things. And those medicines actually exist. We have a repository of over 50 interventions, whether a small molecule drug or a genetic change, that can extend healthy life by as much as 50%. Think about that: 50% longer without getting Alzheimer's disease, or cancer, or having a stroke, or having our bones and muscles wear down. 50%! In mice. And so the mice are super-excited about this. But what does it mean for us humans?
Well, luckily this is how new medicines are usually born. We take a piece of research and test it in mice to see if it works, and if it does then we advance that to human trials. And the good news is that we have 50 things that are ready to test. But making the jump from mice to humans for these sorts of diseases won't exactly be straightforward. You see, a trial to prevent a disease instead of to treat it has some additional challenges. It is more time-consuming and more expensive, which means the companies that would have to pay the tens of millions of dollars for these trials are often hesitant to do so, when they are used to doing the more traditional reactive trials. However, we have a glimmer of hope here too, that may be able to fast-track some of these preventative medicines into the clinic. You see, if you build a medicine that does a good job preventing damage that could eventually cause disease, it turns out that the same medicine can stop a disease from getting any worse by halting that same damage. And sometimes we can even repair the damage, reversing the effects of a disease.
Now, if you caught yourself thinking "but wait, that sounds completely obvious!" I might forgive you for that. It does seem reasonable that if something is going wrong with my cells, and I fix that thing, then it would help whether or not I've labelled my cells as diseased. But until very recently we just didn't know that, because it hadn't really been tested. The people who are working on studying what goes wrong in an old mouse and the people who are giving treatments to Alzheimer's patients weren't really talking to each other. But now they are, and armed with this new knowledge of what makes us age, and what we can do about it, we're able to pursue two ambitious goals at the same time. First, we have the ability to create new medicines to treat patients suffering from diseases of aging. This is what motivates me and the people that I work with, every single day, using this new research to come up with a medicine that can impact millions of people who are sick right now.
But there's also a second thing we can be doing. As we create new medicines for these diseases, and test them in the traditional way, we have to remember that what we really want is a medicine that can prevent disease instead of just treating it. And to get there, we're going to need to have proven, safe, effective medicines targeted at treating the damage of aging, and there has been progress on this front as well. One of the 50 interventions I told you guys about before happens to be an approved drug that's already been used in humans for decades. So after results in mice came out showing that we could extend their healthspan, a group of researchers started combing through hundreds of thousands of patient records who had been taking this drug, and they found something incredible. This drug - that people didn't take to prevent the diseases of aging, they took to prevent their blood glucose from going up, because they had diabetes - but when then were on this drug, they had a lower incidence of both cancer and Alzheimer's disease. Even compared to healthy people that didn't have diabetes.
So this thing may actually be working. This drug, which is called metformin, can extend mouse life span on average by 5-10%, which, if it works the same in humans, would mean 4 to 8 extra healthy years. And that's a lot, because if we invented a pill that miraculously cured all cancer in all of humanity right now, we would expect an average life span gain of about three and a half years, because we would succumb to another disease as we got older. So based on this research, a new clinical trial has started to test whether people who are healthy can take metformin and avoid cancer and Alzheimer's disease. So you might want to wait for the results of that trial before you go and beg your doctor for diabetes meds.
So now you may be asking yourself, whether it's this trial or another medicine that gets approved, who is going to pay for these preventative medicines? And it's worth pausing here for a moment to reflect that insurance companies are actually already paying for something very similar. Many of us in this room may be taking medicines that lower our cholesterol, which reduce the chances of getting stroke. When we invent new medicines that can not just reduce your chances of getting a stroke, but also Alzheimer's disease and cancer, which are way more expensive for those insurance companies to treat, you can bet that they'll be lining up to pay for those drugs too. With insurance companies in the game, this means that pharma companies are going to pay top dollar for the rights to test and sell these medicines. And that means that scientists working at universities or at biotech companies are going to be competing with each other to create the next greatest preventative medicine. It's a positive feedback loop, and the cycle can be kicked off with just one victory. Even a drug that extends healthy life span by a year or two can start a cycle of investment and research and testing that can change the way we do healthcare forever.
And I have good news, because there are 50 interventions that we already have ready to go. We just need to get to work. As I close up here, I think it's worth addressing one little thing, which is that I get asked all the time if we even should be trying to treat aging or extend life. I think that this is absolutely the wrong question. I think that the question we should be asking ourselves is "when do you want to get Alzheimer's disease?" When do you want to have a stroke? When do you want your muscles to break down? For most of these, I think everyone that I know would say "never". It's like asking someone in 1900 at what age they'd like to get tuberculosis. Or polio. "No thank you!" The evidence we have suggests that we can make new medicines based on our understanding of aging that can help people who are suffering from today's biggest killers. Yes, this will change healthcare. It will redefine medicine in the 21st century in the same way that vaccines and antibiotics redefined medicine in the 20th. But that's good! That's progress. Because I want to be able to enter the 22nd century and face our newest medical challenges, whatever those may be.
We have the opportunity in our lifetimes to flip healthcare on its head, by wedding the power of modern medicine with our understanding of what makes us age. We're going to invent new medicines that can treat the damage caused by getting old before we ever get sick. And that? That's a future that I can look forward to.
Peyer's position on aging incorporates the views of the Hallmarks of Aging authors and the Longevity Dividend scientists, in that while he views aging as damage accumulation, and our responsibility as being to build the means to repair and prevent that damage, he has enthusiasm for moving ahead with approaches to slow aging that I consider to be largely a waste of time and effort. Take metformin, for example. To my eyes the animal data is shabby and unreliable, with studies showing all sorts of outcomes, and the effects in humans are too small to spend any time on in a world that includes the SENS rejuvenation research programs and the senolytic therapies to clear senescent cells currently under development.
For Peyer, the present TAME metformin trial is a useful step on the road towards obtaining more funding and attention in order to build better therapies: it is a wake up call. I'm dubious, however, that all it will take to start the avalanche is just a little success in the matter of life span, health, and mortality. We have plenty of examples from past years of what I would call a little success: the effects of statins on cardiovascular mortality, the bisphosphonate studies showing significant reductions in mortality, and so forth. The revolution hasn't happened in response to any of this; 99% of medical research and development is still business as usual, creating expensive and marginal patches that fail to address aging in any meaningful way. So why would it happen over a modest reduction in rates of age-related disease for people taking metformin?
I think we need bigger and better successes. Marginal improvement won't cut it. We need outright, obvious, sizable rejuvenation. Will senolytics wake the world if they produce a reliable five year gain in healthy life expectancy, as well as reversing numerous diseases and conditions of aging? I don't know. It may be that even that will just be absorbed into the current state of things, and 95% rather than 99% of medical research and development will continue to be business as usual. Inertia is an impressive thing in these large institutional scientific and regulatory communities. Nonetheless, we need to keep aiming high. If we aim low, then all we'll get in the end is poor results on the only metric that matters, the degree to which health is restored and extended.
View the full article at FightAging
