I appreciate the detailed and thoughtful reply. :)
I and others think that anti-aging and donating to SENS is probably a more important cause area than most EA cause areas (especially short-term ones) besides X-risk for the reasons below.
I agree that anti-aging is neglected in EA compared to other short-term, human focused cause areas. The reason is likely because the people who would be most receptive to anti-aging move to other fields. As Pablo Stafforini said,
Longevity research occupies an unstable position in the space of possible EA cause areas: it is very “hardcore” and “weird” on some dimensions, but not at all on others. The EAs in principle most receptive to the case for longevity research tend also to be those most willing to question the “common-sense” views that only humans, and present humans, matter morally. But, as you note, one needs to exclude animals and take a person-affecting view to derive the “obvious corollary that curing aging is our number one priority”. As a consequence, such potential supporters of longevity research end up deprioritizing this cause area relative to less human-centric or more long-termist alternatives.
I wrote a post about how anti-aging might be competitive with longtermist charities here.
Again, this is nice, and I think it’s good evidence that we could achieve modest success in the coming decades. But in the post you painted a different picture. Specifically, you said,
The ‘white mirror’ of aging is a world in which biological age is halted at 20-30 years, and people maintain optimal health for a much longer or indefinite period of time. Although people will still age chronologically (exist over time) they will not undergo physical and cognitive decline associated with biological aging. At chronological ages of 70s, 80s, even 200s, they would maintain the physical appearance and much lower disease risk of a 20-30-year-old.
If humans make continuous progress, then eventually we’ll get here. I have no issue with that prediction. But my objection concerned the pace and tractability of research. And it seems like there’s going to be a ton of work going from modest treatments for aging to full cures.
One possible response is that the pace of research will soon speed up dramatically. Aubrey de Grey has argued along these lines on several occasions. In his opinion, there will be a point at which humanity wakes up from its pro-aging trance. From this perspective, the primary value of research in the present is to advance the timeline when humanity wakes up and gets started on anti-aging for real.
More likely, we will see gradual progress over several decades. I’m unsure whether the overall project (ie. longevity escape velocity) will succeed within my own lifetime, but I’m very skeptical that it will happen within eg. 20 years.
In addition, in the past 2 years, human biological aging has already been reversed using calorie restriction, and with thymic rejuvenation, as measured by epigenetic (DNAm) aging.
I don’t think either of these results are strong evidence of recent progress. Calorie restriction has been known about for at least 85 years. The thymic rejuvenation result was a tiny trial with ten participants, and the basic results have been known since at least 1992.
The recent progress in epigenetic clocks is promising, and I do think that’s been one of the biggest developments in the field. But it’s important to see the bigger picture. When I open up old Alcor Magazine archives, or old longevity books from the 1980s and 1990s, I find pretty much same arguments that I hear today for why a longevity revolution is near. People tend to focus on a few small laboratory successes without considering whether the rate of laboratory successes have gone up, or whether it’s common to quickly go from laboratory success to clinical success.
I understand that the number of longevity biotech companies may (wrongly) suggest that the field is well-funded. But this number is not an accurate proxy for the relative funding received by basic geroscience to develop cures for aging, from which these companies are spun-out of.
If the number of companies working on rejuvenation biotechnology did not accurately represent the amount of total effort in the field, then what was the point of bringing it up in the introduction?
I think many EA’s assume academia is an efficient market that will self-correct to prioritise research with the greatest potential impact
Interestingly, I get the opposite impression. But maybe we talk to different EAs.
Aubrey de Grey who has significant insight into the landscape of funding for anti-aging believes that $250-500 million over 10 years is required to kickstart the field sufficiently so that larger sources of funding will flow in.
I don’t doubt Aubrey de Grey’s expertise or his intentions. But I’ve heard him say this line too, and I’ve never heard him give any strong arguments for it. Why isn’t the number $10 billion or $1 trillion? If you think about comparably large technological projects in the past, $500 million is a paltry sum; yet, I don’t see a good reason to believe that this field is different than all the others. Moreover, there is a well-known bias that people within a field are more optimistic about their work than people outside of it.
For example, a drug or cocktail of therapies that extend life of all humans on Earth by 10 years essentially allows 10-years’ worth of people who would otherwise have died of aging (~400 million people) to potentially reach the point at which AI solves aging and hence, longevity escape velocity.
This is only true so long as the drug can be distributed widely almost instantaneously. By comparison, it usually takes vaccines several decades to be widely distributed. I also find it very unlikely that any currently researched treatment will add 10 years of healthy life discontinuously. Again, progress tends to happen gradually.
I agree that anti-aging is neglected in EA compared to other short-term, human focused cause areas. The reason is likely because the people who would be most receptive to anti-aging move to other fields. As Pablo Stafforini said
I agree with Pablo’s reasoning as to why anti-aging has not taken off in the EA community.
If humans make continuous progress, then eventually we’ll get here. I have no issue with that prediction. But my objection concerned the pace and tractability of research. And it seems like there’s going to be a ton of work going from modest treatments for aging to full cures.
I agree that the ‘white mirror’ scenario might be some time off (even 100+ or 1000+ years away), but remember that we only need to reach longevity escape velocity for everyone on Earth to make it to the ‘white mirror’ scenario, not reach the ‘white mirror’ scenario right away. For example, within the next 50 years, we might have drugs that keep us alive for another 100 years, meaning even if it takes 80 years to develop drugs that keep us alive for 1000 years, and then it takes 800 years for us to develop drugs that would bring us to the ‘white mirror’ scenario, we would still reach it. This is the beauty of longevity escape velocity—we only need drugs that keep us alive until better drugs arrive, to stay alive indefinitely and reach the ‘white mirror’ scenario.
I, and many others in the field, would disagree with you here for a simple reason: once we start getting drugs that work, and good evidence that they work—for example, a drug that prevents cancer—people will take them. People generally care about their health enough to take medicines that improve/protect their health—for example, vaccines, statins, cancer therapies and so on. Aubrey de Grey explains that a primary reason people remain in the pro-aging trance is because they are too scared to get their hopes up. However, this all changes as soon as you have drugs that work, even modestly.
If you look historically, there is a relevent parallel with infectious diseases such as tuberculosis 100 years ago, as David Wood explains in my interview with him. Back then, the population generally accepted the disease as ‘natural’, ‘normal’ and an ‘act of god’ (as they do with aging today) rather than fight it, primarily because they didn’t think there was a way to fight it. But as soon as Rober Koch created a vaccine for tuberculosis, people’s values shifted immediately and they began making use of these vaccines.
So, the goal isn’t necessarily to persuade the world to consider aging a problem. It’s to convince enough people with the capacity to speed up the research to become interested, so that the first generations of anti-aging therapies come into the world, and have strong evidence behind them, after which people will begin taking them.
Tractability:
I don’t think either of these results are strong evidence of recent progress. Calorie restriction has been known about for at least 85 years. The thymic rejuvenation result was a tiny trial with ten participants, and the basic results have been known since at least 1992.
Regarding calorie restriction, the key significance of this finding was that this is one of the first indications that a marker of biological aging (DNA methylation age) has been significantly modulated using an intervention. This is a big step up from lifespan studies using calorie restriction in mice, since as you noted, not all interventions in mice translate well to humans.
This is a reasonable concern to have, and one that many outside of the field (i.e. not attending the conferences, not having kept up to date with the literature) do have. I too shared this view when I was studying neuroscience, before I started becoming more involved in the field.
What makes it different is that anti-aging is targeting the root cause of the problem, rather than the symptoms of the problem. So although 86% of clinical trials fail, this is because the approach to most of these trials (sick-care, essentially) that attempt to treat chronic diseases such as cancer, heart disease, awithout treating the root cause (aging) is ineffectual. Let’s take Alzheimer’s disease for example. This is a neurodegenerative illness that emerges as a result of decades of damage accumulation associated with the hallmarks of aging. Now, attempting to cure Alzheimer’s without treating any of the underlying damage that continues to perpetuate the disease (such as senescent cells, mitochondrial dysfunction and other hallmarks of aging) is clearly ineffectual. How are you going to reverse the huge amount of molecular damage that occurs in the brain due to Alzheimer’s, if you are not addressing the root causes of this damage, such as senescent cells, which are continuing to secrete pro-inflammatory factors that are driving neurodegeneration? Hence, it’s really no surprise that over 100 clinical trials for Alzheimer’s have failed and the $5.6 billion spent on trying to treat Alzheimer’s since the approach is misguided. It’s a similar story for cancer, too. There is a multi-decade long process of damage accumulation that alters the microenvironment that predisposes to tumorogenesis. So again, simply attempting to kill the tumor without attenuating the underlying damage that predisposes to tumorogenesis is clearly an ineffective approach. By contrast, anti-aging is targeting the common causes of all of these age-related diseases (senescent cells, etc.), and the preliminary evidence in mice and humans suggest that this is not just theory—it works in practice to extend healthy lifespan.
If you are still skeptical, considering watching this summary of the state of the field in 2020 by Bill Falloon from RAADfest 2020 and all of these lectures from ARDD 2020 and see if you still think that meaningfully slowing aging is not likely in the near future.
If the number of companies working on rejuvenation biotechnology did not accurately represent the amount of total effort in the field, then what was the point of bringing it up in the introduction?
To demonstrate to readers that anti-aging is a real thing, and a legitimate field of biomedical research that they can support, rather than a whimsical sci-fi fantasy. That said, the field needs more support.
I don’t doubt Aubrey de Grey’s expertise or his intentions. But I’ve heard him say this line too, and I’ve never heard him give any strong arguments for it. Why isn’t the number $10 billion or $1 trillion? If you think about comparably large technological projects in the past, $500 million is a paltry sum; yet, I don’t see a good reason to believe that this field is different than all the others. Moreover, there is a well-known bias that people within a field are more optimistic about their work than people outside of it.
He is forecasting, so there’s going to be some uncertainty. I don’t know what evidence he could really draw on, since this figure is based on his impression on the current state of the entire field. But it’s probably something like, his estimation of the marginal increase in progress towards achieving negligible senescence associated with increased funding, based on the marginal increase in progress associated with SENS’ existing funding. The progress the SENS-funded projects have made is significant, and if you extrapolate that out to the best of one’s abilities, you probably get something like the $250-500 million figure. Remember that this is not the total amount needed to make meaningful progress on aging, which indeed is probably in the order of many billions or tens of billions. But, the field fortunately is well placed to take advantage of huge leverage opportunities, since big pharma are watching closely to see how the field develops (I can dig up some reviews about this) as are other stakeholders. Once sufficient de-risking has been done, which is what that initial $250-500 million is needed for, bigger players are likely to enter the game and the field will take off. The public will also start taking note, since the $250-500 million is very likely to be enough to fund research that yields legitimate first-generation anti-aging therapies, enough to pique the public’s interest. Ultimately, given the biggest bottleneck is funding, and every few million to make a new discovery or promising geroprotective compound results in tens of millions flowing in to finance the longevity biotech company spin-outs of these findings, that $250-500 million for SENS really looks more like $10 billion+ for the field as a whole. To clarify though, this is probably hard for those outside the field who are not familiar with longevity biotech financing to conceptualize, and I plan to write a separate post about this explaining it in more detail.
This is only true so long as the drug can be distributed widely almost instantaneously. By comparison, it usually takes vaccines several decades to be widely distributed. I also find it very unlikely that any currently researched treatment will add 10 years of healthy life discontinuously. Again, progress tends to happen gradually.
If you don’t think that some combination of multi-omics-aging-biomarker-optimised combination of senolytics, mTOR inhibitors, gene therapies, nanotech, parabiosis, epigenetic reprogramming, exercise protocols, diet, 3D-printed organs—all of which are technologies available today—could extend life by 10 years, I’d be curious to know why. Even David Sinclair in his book Lifespan and interview explains that metformin+exercise+not smoking+intermittent fasting alone adds 14 years of healthy life.
I’d also highlight that we have fine-grained empirical data about clinical trial success rates, though not for geroscience-based therapies. The overall success rate for a therapeutic can range from 3.4% (cancer drugs) to 33.4% (vaccines), with an average including oncology of 13.8% and an average excluding oncology of 20.9%. Some of the most promising drug candidates, like rapamycin, have already passed clinical trials for other indications, so we know they’re safe. The work now is to show they can be safe enough at lower doses to justify giving them to healthy people.
I appreciate the detailed and thoughtful reply. :)
I agree that anti-aging is neglected in EA compared to other short-term, human focused cause areas. The reason is likely because the people who would be most receptive to anti-aging move to other fields. As Pablo Stafforini said,
I wrote a post about how anti-aging might be competitive with longtermist charities here.
Again, this is nice, and I think it’s good evidence that we could achieve modest success in the coming decades. But in the post you painted a different picture. Specifically, you said,
If humans make continuous progress, then eventually we’ll get here. I have no issue with that prediction. But my objection concerned the pace and tractability of research. And it seems like there’s going to be a ton of work going from modest treatments for aging to full cures.
One possible response is that the pace of research will soon speed up dramatically. Aubrey de Grey has argued along these lines on several occasions. In his opinion, there will be a point at which humanity wakes up from its pro-aging trance. From this perspective, the primary value of research in the present is to advance the timeline when humanity wakes up and gets started on anti-aging for real.
Unfortunately, I see no strong evidence for this theory. People’s minds tend to change gradually in response to gradual technological change. The researchers who said this year that “I’ll wait until you have robust mouse rejuvenation” will just say “I’ll wait until you have results in humans” when you have results in mice. Humans aren’t going to just suddenly realize that their whole ethical system is flawed; that rarely ever happens.
More likely, we will see gradual progress over several decades. I’m unsure whether the overall project (ie. longevity escape velocity) will succeed within my own lifetime, but I’m very skeptical that it will happen within eg. 20 years.
I don’t think either of these results are strong evidence of recent progress. Calorie restriction has been known about for at least 85 years. The thymic rejuvenation result was a tiny trial with ten participants, and the basic results have been known since at least 1992.
The recent progress in epigenetic clocks is promising, and I do think that’s been one of the biggest developments in the field. But it’s important to see the bigger picture. When I open up old Alcor Magazine archives, or old longevity books from the 1980s and 1990s, I find pretty much same arguments that I hear today for why a longevity revolution is near. People tend to focus on a few small laboratory successes without considering whether the rate of laboratory successes have gone up, or whether it’s common to quickly go from laboratory success to clinical success.
Given that 86 percent of clinical trails eventually fail, and the marginal returns to new drug R&D has gone down exponentially over time, I want to know what specifically should make us optimistic about anti-aging, that’s different from previous failed predictions.
If the number of companies working on rejuvenation biotechnology did not accurately represent the amount of total effort in the field, then what was the point of bringing it up in the introduction?
Interestingly, I get the opposite impression. But maybe we talk to different EAs.
I don’t doubt Aubrey de Grey’s expertise or his intentions. But I’ve heard him say this line too, and I’ve never heard him give any strong arguments for it. Why isn’t the number $10 billion or $1 trillion? If you think about comparably large technological projects in the past, $500 million is a paltry sum; yet, I don’t see a good reason to believe that this field is different than all the others. Moreover, there is a well-known bias that people within a field are more optimistic about their work than people outside of it.
This is only true so long as the drug can be distributed widely almost instantaneously. By comparison, it usually takes vaccines several decades to be widely distributed. I also find it very unlikely that any currently researched treatment will add 10 years of healthy life discontinuously. Again, progress tends to happen gradually.
I agree with Pablo’s reasoning as to why anti-aging has not taken off in the EA community.
I agree that the ‘white mirror’ scenario might be some time off (even 100+ or 1000+ years away), but remember that we only need to reach longevity escape velocity for everyone on Earth to make it to the ‘white mirror’ scenario, not reach the ‘white mirror’ scenario right away. For example, within the next 50 years, we might have drugs that keep us alive for another 100 years, meaning even if it takes 80 years to develop drugs that keep us alive for 1000 years, and then it takes 800 years for us to develop drugs that would bring us to the ‘white mirror’ scenario, we would still reach it. This is the beauty of longevity escape velocity—we only need drugs that keep us alive until better drugs arrive, to stay alive indefinitely and reach the ‘white mirror’ scenario.
I, and many others in the field, would disagree with you here for a simple reason: once we start getting drugs that work, and good evidence that they work—for example, a drug that prevents cancer—people will take them. People generally care about their health enough to take medicines that improve/protect their health—for example, vaccines, statins, cancer therapies and so on. Aubrey de Grey explains that a primary reason people remain in the pro-aging trance is because they are too scared to get their hopes up. However, this all changes as soon as you have drugs that work, even modestly.
If you look historically, there is a relevent parallel with infectious diseases such as tuberculosis 100 years ago, as David Wood explains in my interview with him. Back then, the population generally accepted the disease as ‘natural’, ‘normal’ and an ‘act of god’ (as they do with aging today) rather than fight it, primarily because they didn’t think there was a way to fight it. But as soon as Rober Koch created a vaccine for tuberculosis, people’s values shifted immediately and they began making use of these vaccines.
So, the goal isn’t necessarily to persuade the world to consider aging a problem. It’s to convince enough people with the capacity to speed up the research to become interested, so that the first generations of anti-aging therapies come into the world, and have strong evidence behind them, after which people will begin taking them.
Tractability:
Regarding calorie restriction, the key significance of this finding was that this is one of the first indications that a marker of biological aging (DNA methylation age) has been significantly modulated using an intervention. This is a big step up from lifespan studies using calorie restriction in mice, since as you noted, not all interventions in mice translate well to humans.
This is a reasonable concern to have, and one that many outside of the field (i.e. not attending the conferences, not having kept up to date with the literature) do have. I too shared this view when I was studying neuroscience, before I started becoming more involved in the field.
What makes it different is that anti-aging is targeting the root cause of the problem, rather than the symptoms of the problem. So although 86% of clinical trials fail, this is because the approach to most of these trials (sick-care, essentially) that attempt to treat chronic diseases such as cancer, heart disease, awithout treating the root cause (aging) is ineffectual. Let’s take Alzheimer’s disease for example. This is a neurodegenerative illness that emerges as a result of decades of damage accumulation associated with the hallmarks of aging. Now, attempting to cure Alzheimer’s without treating any of the underlying damage that continues to perpetuate the disease (such as senescent cells, mitochondrial dysfunction and other hallmarks of aging) is clearly ineffectual. How are you going to reverse the huge amount of molecular damage that occurs in the brain due to Alzheimer’s, if you are not addressing the root causes of this damage, such as senescent cells, which are continuing to secrete pro-inflammatory factors that are driving neurodegeneration? Hence, it’s really no surprise that over 100 clinical trials for Alzheimer’s have failed and the $5.6 billion spent on trying to treat Alzheimer’s since the approach is misguided. It’s a similar story for cancer, too. There is a multi-decade long process of damage accumulation that alters the microenvironment that predisposes to tumorogenesis. So again, simply attempting to kill the tumor without attenuating the underlying damage that predisposes to tumorogenesis is clearly an ineffective approach. By contrast, anti-aging is targeting the common causes of all of these age-related diseases (senescent cells, etc.), and the preliminary evidence in mice and humans suggest that this is not just theory—it works in practice to extend healthy lifespan.
A few other comments about tractability:
There is a huge range of therapeutic approaches that have a reasonable chance of slowing or reversing aging in the future besides those mentioned in the article, including nanotechnology (companies like Alzeca Biosciences and Bikanta), gene therapy to treat the cause of multiple diseases at once, 3D-printed organs, and research is now being augmented by AI platforms for anti-aging drug discovery. Importantly, the same could not be said as recently as 5 years ago, when these approaches had not been developed.
If you are still skeptical, considering watching this summary of the state of the field in 2020 by Bill Falloon from RAADfest 2020 and all of these lectures from ARDD 2020 and see if you still think that meaningfully slowing aging is not likely in the near future.
To demonstrate to readers that anti-aging is a real thing, and a legitimate field of biomedical research that they can support, rather than a whimsical sci-fi fantasy. That said, the field needs more support.
He is forecasting, so there’s going to be some uncertainty. I don’t know what evidence he could really draw on, since this figure is based on his impression on the current state of the entire field. But it’s probably something like, his estimation of the marginal increase in progress towards achieving negligible senescence associated with increased funding, based on the marginal increase in progress associated with SENS’ existing funding. The progress the SENS-funded projects have made is significant, and if you extrapolate that out to the best of one’s abilities, you probably get something like the $250-500 million figure. Remember that this is not the total amount needed to make meaningful progress on aging, which indeed is probably in the order of many billions or tens of billions. But, the field fortunately is well placed to take advantage of huge leverage opportunities, since big pharma are watching closely to see how the field develops (I can dig up some reviews about this) as are other stakeholders. Once sufficient de-risking has been done, which is what that initial $250-500 million is needed for, bigger players are likely to enter the game and the field will take off. The public will also start taking note, since the $250-500 million is very likely to be enough to fund research that yields legitimate first-generation anti-aging therapies, enough to pique the public’s interest. Ultimately, given the biggest bottleneck is funding, and every few million to make a new discovery or promising geroprotective compound results in tens of millions flowing in to finance the longevity biotech company spin-outs of these findings, that $250-500 million for SENS really looks more like $10 billion+ for the field as a whole. To clarify though, this is probably hard for those outside the field who are not familiar with longevity biotech financing to conceptualize, and I plan to write a separate post about this explaining it in more detail.
If you don’t think that some combination of multi-omics-aging-biomarker-optimised combination of senolytics, mTOR inhibitors, gene therapies, nanotech, parabiosis, epigenetic reprogramming, exercise protocols, diet, 3D-printed organs—all of which are technologies available today—could extend life by 10 years, I’d be curious to know why. Even David Sinclair in his book Lifespan and interview explains that metformin+exercise+not smoking+intermittent fasting alone adds 14 years of healthy life.
I’d also highlight that we have fine-grained empirical data about clinical trial success rates, though not for geroscience-based therapies. The overall success rate for a therapeutic can range from 3.4% (cancer drugs) to 33.4% (vaccines), with an average including oncology of 13.8% and an average excluding oncology of 20.9%. Some of the most promising drug candidates, like rapamycin, have already passed clinical trials for other indications, so we know they’re safe. The work now is to show they can be safe enough at lower doses to justify giving them to healthy people.