To me, damage repair is a first and foremost a new, fundamentally different approach to medicine, one that emphasizes fixing things that are obviously broken, which I expect to work much better than the old paradigm of treating diseases separately. The whole “ageing” thing is almost secondary to me. We’ve literally not been fixing people’s bodies this entire time, and now people are finally trying to fix a bunch of obviously broken things, that’s why I’m excited.
I like the parts of the post I’ve read so far, and I’m just making a local argument to this specific bit.
People have been fixing people’s bodies insofar as they can, since the dawn of medicine. They’ve been setting bones, stitching wounds, treating or preventing inflammation and autoimmune reactions, and more recently, destroying or removing cancer and transplanting organs.
What unites SENS interventions is that they require sophisticated cellular and subcellular therapies that depend on the stack of biomedical technologies we’ve produced at an accelerating pace over the last century. Cellular senescence was discovered in vitro a little over 60 years ago, and as recently as 1996, a Berkeley cancer biologist was still writing in Cell that “a limited number of in vivo experiments… strongly suggest that cellular senescence is not an artifact of culture,” i.e. that it takes place in the body, not just in a dish, though the potential mechanistic links between senescence as a tumor suppression mechanism and driver of aging were already well-known. We only sequenced the human genome in 2003, and Crispr-CAS9 has only been around since 2012.
Point being that we’ve been trying to fix people’s bodies for millennia, but we’ve only had the scientific knowledge and bioengineering technology that might potentially allow us to treat the cellular and subcellular precursors of homeostatic breakdown (“aging”) for a matter of years.
Yes we’ve always been trying to fix damage—anything that restores function must fix damage somehow—but it’s a matter of what we consider to be damage, i.e. “bad stuff that we should try to fix because it would restore function”. Historically we’ve focused on trauma, infection and cancer, and although we’ve known about age-related changes like lipofuscin accumulation for a long time, it’s only recently that we started thinking of them as potential targets. Gerontology has historically been a field of basic science, with few gerontologists willing to venture that we could even in principle do something about age-related changes until very recently. They were too afraid to challenge the deeply held notion that ageing is normal, natural and fundamentally immutable. I’m not without sympathy though—anyone who had made that claim would have been attacked and likely would have lost their livelihood—Aubrey de Grey was only able to do it because he was financially independent.
If you look at things like atherosclerosis and AMD, both of which have long been known to be driven by the accumulation of toxic metabolites, I think we could and should have started working on the root causes of these diseases much earlier than we did. Sure, we’re only now figuring out how to remove 7KC and A2E, but that’s because we only just started working on it! Likewise, we’ve known about thymic involution for a long time and it’s always been clear that it damages your immune system in the long run, so why is it that only Greg Fahy is working on fixing it, and why does he get so little funding that his trials have to be funded by their own participants? We declared war on cancer long ago, when our models and tools were still hopelessly crude, and because of that we are further advanced now than we would have been otherwise.
Point taken that this is all extremely difficult and ambitious, and it’s not entirely unreasonable that researchers have been intimidated by that. Rejuvenation is indeed highly dependent on very recent technological breakthroughs, and those new capabilities are a huge part of why this shift is occurring. In my defense, there is a bit where I say
I don’t mean to imply that prior researchers had been stupid here; humans don’t come equipped with enzymes capable of degrading A2E so it wasn’t exactly obvious how to get rid of it.
Perhaps I could have stressed that more. To whatever extent there is blame, I place it more on grant committees than on medical researchers. The stuff SENS works on is all high-risk high-reward, which public purse-holders and investors are both cagey about—that’s why it all has to be philanthropically funded. For example, the idea to copy mitochondrial DNA into the nucleus where it is safer (which I ignored completely in the post) has been around for a long time, but SENS had to work on it because no one else would.
Anyway, I don’t want to fixate on whose fault things were. The point is that for whatever reason, we were pursuing a broken paradigm of “one disease one target one drug”, which was never going to work because the diseases were not naturally separable things and their root causes mostly lay in fundamental age-related changes, which we are now beginning to target, and it seems likely to work.
Agreed, I like this elaboration. As I see it, the argument really is that we’ve been neglecting preventative medicine in favor of treating disease after it has become symptomatic. This is a familiar critique that normal doctors and laypeople already subscribe to, and showing that anti-aging medicine is really just another familiar form of preventative medicine (which we have historically neglected) will make more immediate sense than claiming that “we haven’t been fixing people’s bodies” which is only true in the specific sense you just articulated.
Along with that is emphasizing that it’s normal and natural to use preventative medicine. You brush your teeth, you try to eat a good diet and get enough sleep and exercise, you might stake preventative statins or blood thinners or get LASEK. If you’ll do all these things to maintain your health, then why not take low-dose rapamycin? It’s really going to be about normalizing the use of pill-form preventatives at an earlier age, and breaking the association between pills and “being sick.” Instead, it’s about creating an association between pills and “maintaining health.”
It’s both prevention and cure—prevent disease by reversing damage before it gets bad enough to cause problems, but if you already have a chronic disease, then reversing the damage that causes it will be the only way to cure it (though prevention is better of course).
I agree the preventative medicine angle is a good one that people will buy easily, but you can make the same argument against it—that we’ve always been trying to prevent disease just as we’ve always been trying to fix damage.
It’s important to note that statins, blood thinners and rapamycin are not damage repair—they’re not useless, but I think damage repair will make them obsolete. These approaches focus on slowing the buildup of damage rather than reversing damage that’s already there. The problem is that a) this tries to modify human metabolism to “run more cleanly”, which is super difficult and prone to unforeseen consequences and b) you have to take these medicines every day, which makes it all the more dangerous. Statins are well known to have side effects, and rapamycin is an immunosuppressant, which unsurprisingly has a lot of side effects too. You don’t want to take this stuff every day.
The reason people associate things like statins with “being sick” is that they don’t actually make you less sick, they just slow the progression of a disease while causing side effects. Damage repair is far less prone to side effects because it targets stuff that’s definitely not supposed to be there instead of trying to change the way the body works. You won’t get side effects from removing atheromatous plaques (so long as that’s all the treatment does do), but you do get side effects from mucking around with liver chemistry. And because ageing damage accumulates so slowly, you’ll only have to take these therapies every 10 years or so (eventually, once they’re mature). And of course, because it reverses damage instead of merely slowing it, you’ll actually feel, look and be healthier and fitter after the treatment. That’s why I say it’s a new kind of medicine—the public are absolutely not used to medicine that makes them feel younger after they take it.
That’s a reasonable point of view. I don’t think we should be certain that the effects of rapamycin at high doses will be reflective of its effects at low doses, which is why we need to test it. This era is all about precision medicine, figuring out how to control dosing, release, and specific delivery in the context of much better knowledge of how these drugs affect the body to cut side effects and enhance benefit.
The heuristic of leaning toward occasional damage repair by engineered interventions rather than continuous damage slowdowns by manipulating evolved biochemistry makes sense, but so does the heuristic of focusing on an available tool that we have extensive data works pre-clinically right now. I think the “don’t mess with evolution” heuristic is oversubscribed for antagonistic pleiotropy and declining selection pressure with age reasons when it comes to anti-aging medicine.
All the same, I expect that over time we’ll come up with a wide range of both preventative and damage reversal interventions, perhaps along SENS lines. But in that context, a damage-slowing drug (perhaps rapamycin) that might reduce the frequency of the need for damage reversal therapies will be highly valuable, and particularly because it may well be the cheapest and most accessible option to get started, especially in countries that don’t yet have fully developed medical systems..
I like the parts of the post I’ve read so far, and I’m just making a local argument to this specific bit.
People have been fixing people’s bodies insofar as they can, since the dawn of medicine. They’ve been setting bones, stitching wounds, treating or preventing inflammation and autoimmune reactions, and more recently, destroying or removing cancer and transplanting organs.
What unites SENS interventions is that they require sophisticated cellular and subcellular therapies that depend on the stack of biomedical technologies we’ve produced at an accelerating pace over the last century. Cellular senescence was discovered in vitro a little over 60 years ago, and as recently as 1996, a Berkeley cancer biologist was still writing in Cell that “a limited number of in vivo experiments… strongly suggest that cellular senescence is not an artifact of culture,” i.e. that it takes place in the body, not just in a dish, though the potential mechanistic links between senescence as a tumor suppression mechanism and driver of aging were already well-known. We only sequenced the human genome in 2003, and Crispr-CAS9 has only been around since 2012.
Point being that we’ve been trying to fix people’s bodies for millennia, but we’ve only had the scientific knowledge and bioengineering technology that might potentially allow us to treat the cellular and subcellular precursors of homeostatic breakdown (“aging”) for a matter of years.
Yes we’ve always been trying to fix damage—anything that restores function must fix damage somehow—but it’s a matter of what we consider to be damage, i.e. “bad stuff that we should try to fix because it would restore function”. Historically we’ve focused on trauma, infection and cancer, and although we’ve known about age-related changes like lipofuscin accumulation for a long time, it’s only recently that we started thinking of them as potential targets. Gerontology has historically been a field of basic science, with few gerontologists willing to venture that we could even in principle do something about age-related changes until very recently. They were too afraid to challenge the deeply held notion that ageing is normal, natural and fundamentally immutable. I’m not without sympathy though—anyone who had made that claim would have been attacked and likely would have lost their livelihood—Aubrey de Grey was only able to do it because he was financially independent.
If you look at things like atherosclerosis and AMD, both of which have long been known to be driven by the accumulation of toxic metabolites, I think we could and should have started working on the root causes of these diseases much earlier than we did. Sure, we’re only now figuring out how to remove 7KC and A2E, but that’s because we only just started working on it! Likewise, we’ve known about thymic involution for a long time and it’s always been clear that it damages your immune system in the long run, so why is it that only Greg Fahy is working on fixing it, and why does he get so little funding that his trials have to be funded by their own participants? We declared war on cancer long ago, when our models and tools were still hopelessly crude, and because of that we are further advanced now than we would have been otherwise.
Point taken that this is all extremely difficult and ambitious, and it’s not entirely unreasonable that researchers have been intimidated by that. Rejuvenation is indeed highly dependent on very recent technological breakthroughs, and those new capabilities are a huge part of why this shift is occurring. In my defense, there is a bit where I say
Perhaps I could have stressed that more. To whatever extent there is blame, I place it more on grant committees than on medical researchers. The stuff SENS works on is all high-risk high-reward, which public purse-holders and investors are both cagey about—that’s why it all has to be philanthropically funded. For example, the idea to copy mitochondrial DNA into the nucleus where it is safer (which I ignored completely in the post) has been around for a long time, but SENS had to work on it because no one else would.
Anyway, I don’t want to fixate on whose fault things were. The point is that for whatever reason, we were pursuing a broken paradigm of “one disease one target one drug”, which was never going to work because the diseases were not naturally separable things and their root causes mostly lay in fundamental age-related changes, which we are now beginning to target, and it seems likely to work.
Agreed, I like this elaboration. As I see it, the argument really is that we’ve been neglecting preventative medicine in favor of treating disease after it has become symptomatic. This is a familiar critique that normal doctors and laypeople already subscribe to, and showing that anti-aging medicine is really just another familiar form of preventative medicine (which we have historically neglected) will make more immediate sense than claiming that “we haven’t been fixing people’s bodies” which is only true in the specific sense you just articulated.
Along with that is emphasizing that it’s normal and natural to use preventative medicine. You brush your teeth, you try to eat a good diet and get enough sleep and exercise, you might stake preventative statins or blood thinners or get LASEK. If you’ll do all these things to maintain your health, then why not take low-dose rapamycin? It’s really going to be about normalizing the use of pill-form preventatives at an earlier age, and breaking the association between pills and “being sick.” Instead, it’s about creating an association between pills and “maintaining health.”
It’s both prevention and cure—prevent disease by reversing damage before it gets bad enough to cause problems, but if you already have a chronic disease, then reversing the damage that causes it will be the only way to cure it (though prevention is better of course).
I agree the preventative medicine angle is a good one that people will buy easily, but you can make the same argument against it—that we’ve always been trying to prevent disease just as we’ve always been trying to fix damage.
It’s important to note that statins, blood thinners and rapamycin are not damage repair—they’re not useless, but I think damage repair will make them obsolete. These approaches focus on slowing the buildup of damage rather than reversing damage that’s already there. The problem is that a) this tries to modify human metabolism to “run more cleanly”, which is super difficult and prone to unforeseen consequences and b) you have to take these medicines every day, which makes it all the more dangerous. Statins are well known to have side effects, and rapamycin is an immunosuppressant, which unsurprisingly has a lot of side effects too. You don’t want to take this stuff every day.
The reason people associate things like statins with “being sick” is that they don’t actually make you less sick, they just slow the progression of a disease while causing side effects. Damage repair is far less prone to side effects because it targets stuff that’s definitely not supposed to be there instead of trying to change the way the body works. You won’t get side effects from removing atheromatous plaques (so long as that’s all the treatment does do), but you do get side effects from mucking around with liver chemistry. And because ageing damage accumulates so slowly, you’ll only have to take these therapies every 10 years or so (eventually, once they’re mature). And of course, because it reverses damage instead of merely slowing it, you’ll actually feel, look and be healthier and fitter after the treatment. That’s why I say it’s a new kind of medicine—the public are absolutely not used to medicine that makes them feel younger after they take it.
That’s a reasonable point of view. I don’t think we should be certain that the effects of rapamycin at high doses will be reflective of its effects at low doses, which is why we need to test it. This era is all about precision medicine, figuring out how to control dosing, release, and specific delivery in the context of much better knowledge of how these drugs affect the body to cut side effects and enhance benefit.
The heuristic of leaning toward occasional damage repair by engineered interventions rather than continuous damage slowdowns by manipulating evolved biochemistry makes sense, but so does the heuristic of focusing on an available tool that we have extensive data works pre-clinically right now. I think the “don’t mess with evolution” heuristic is oversubscribed for antagonistic pleiotropy and declining selection pressure with age reasons when it comes to anti-aging medicine.
All the same, I expect that over time we’ll come up with a wide range of both preventative and damage reversal interventions, perhaps along SENS lines. But in that context, a damage-slowing drug (perhaps rapamycin) that might reduce the frequency of the need for damage reversal therapies will be highly valuable, and particularly because it may well be the cheapest and most accessible option to get started, especially in countries that don’t yet have fully developed medical systems..