To this day there is a lack of systematic research to evaluate a cause area with immense potential: aging research. This is the first of a series of posts in which I'll try to begin research to address this gap. The points made in this post are about how to evaluate impact using the concept of Longevity Escape Velocity. Bringing the date of Longevity Escape velocity closer by one year would save 36,500,000 lives of 1000 QALYs, using a conservative estimate. Other sources of impact that arise from the same concept include: increasing the probability of Longevity Escape Velocity, making Longevity Escape Velocity spread faster, and making a new future portion of the population reach Longevity Escape Velocity by increasing its life expectancy. Aging research could also positively impact the cost-effectiveness of other interventions by increasing the probability that Longevity Escape Velocity will be attained in the recipients' lifetimes. I will also discuss why the probability of Longevity Escape Velocity is substantial and why QALYs should be the measure of impact, and I'll give mathematical proofs that the adoption speed of the technologies that arise from research doesn't impact cost-effectiveness analyses.
I think one important approach to research in Effective Altruism is to try to lay theoretical foundations and put together tools for helping to evaluate a specific cause area that can be generalised to any intervention inside that cause area. Such work is often not possible because of lack of time and expertise, making it preferable, sometimes, to scout specific promising interventions or refine existing research.
One cause area that absolutely needs this kind of more systematic groundwork is aging research. The current EA research about aging is lacking in number and in what I think are crucial considerations, even though informal discussion with members of the community reveals that many people regard it as potentially promising. The expertise required to make such an analysis possible is rare to find. It requires people with a strong quantitative background who are also interested not only in biology but in the biology of aging in particular, and they must be accustomed to predicting the future of scientific research and making cost-effectiveness evaluations. I observed that the Effective Altruism community seems to have plenty of people with a background in philosophy, economics, social sciences or computer science, but people with a strong background in biology, or at least a strong interest in it, are scarce. This makes it even harder to find people willing to do the work of evaluating the cause area of aging research.
For these reasons, and since I'm very familiar with the topic and I think I have important things to say about it, I am willing to try to lay as much groundwork as possible, at least until I think I'm needed.
My long-term hope is that the groundwork I will lay will be good enough for a more formal discussion about this topic within Effective Altruism, both for evaluating specific interventions inside this cause area and for evaluating the cause area as a whole. I will write about what I think are original points and put together all the existing tools that could help both Effective Altruism organisations and organisations within the cause area of aging to make better decisions.
I have chosen to split the analysis into multiple posts so that I can receive and incorporate feedback during the process and thereby modify my work and its planning along the way. Organising the work in this way will also make the whole thing easier to read.
I'm doing this alone and in my free time, between university and other activities, so the posts will probably come out a few weeks or even months apart.
Although I hope that the bottom line of my arguments is strong, there will probably be many mistakes and many corrections to make. I encourage you to comment, give feedback and to contribute new ideas, especially if you have a consideration about something that I didn't address that would substantially impact the result of a potential cost-effectiveness analysis. Along the way I will probably need to collaborate with other people and coauthor some posts, since my knowledge probably has gaps and needs to be complemented. Nonetheless I will try to learn what I currently don't know along the way.
This is the first of a series of posts in which I'll explore different ways of reasoning about the potential cost-effectiveness of aging research. Each post will focus on one or more considerations. In the last post I would like to wrap everything up with a comprehensive framework useful for evaluating the cost-effectiveness of any given avenue of scientific research into the aging processes and how to treat their various facets. The points made will also provide an idea of the potential of the cause area as a whole.
An initial major focus will be on the scope of the problem and on moral considerations that could affect it. Neglectedness and tractability will be given space in later posts, in which I will try to lay out useful methods and heuristics to evaluate them in this cause area.
After this work, I would like to discover the best funding opportunities within this area and compare my conclusions with other past efforts within Effective Altruism that have been made to evaluate aging research.
Points made in this first post:
The next posts in the series will probably be about:
Longevity Escape Velocity (LEV) is the minimum rate of medical progress such that individual life expectancy is raised by at least one year per year if medical interventions are used. This does not refer to life expectancy at birth; it refers to life expectancy calculated from a person's statistical risk of dying at any given time. This is equivalent to saying that a person's expected future lifetime remains constant despite the passing years.
It's possible, given sufficient ongoing improvement of medicine and its democratisation, that nearly everyone on the planet, at a certain date in the future, will benefit from therapies that allow Longevity Escape Velocity to be attained, at least until aging is eradicated completely. Then, other factors will influence risk of death, and expected future lifetime could start falling again each passing year if risk of death flattens or doesn’t continue to fall fast enough.
How likely that Longevity Escape Velocity is to become a reality in the future depends on a number of factors, which will be explored later in this post.
If a given intervention "saves a life", this usually means that it averts 30 to 80 Disability-Adjusted Life Years (DALYs). In order to evaluate the impact of aging research, one could be tempted to try to estimate how many end-of-life DALYs that a possible intervention resulting from the research could save and adjust the number using the probability of success of the research.
This is the line of reasoning that OpenPhilanthropy's medium investigation on aging uses, although without making any explicitly quantitative argument. This is part of the impact, and it has to be factored in, but it doesn't consider where the largest impact of aging research is: making the date of Longevity Escape Velocity come closer. This would have the effect of saving many lives from death due to age-related decline and disease, but here, "a life" means, more or less, 1000 Quality-Adjusted Life Years (QALYs). This figure is derived as follows:
In actuarial science, the expected future lifetime of an individual at age x is denoted with . It can be seen as the expected value of the random variable , also called "Curtate Future Lifetime", which is defined as , where maps to the amount of additional time that an individual of age is projected to live. For our purposes, we can use the discrete random variable instead of directly . Thus, with being the probability of surviving between age and age :
If is the probability of dying between year and year , then:
When the whole population benefits from LEV, the risk of death will fall for everyone. By definition, it will fall at a rate such that the expected future lifetime of any given individual will remain constant until aging gets eradicated completely. So, in order to make the most conservative estimate about life expectancy after LEV, we need to find the minimum rate of decrease of p(x) such that this condition holds. The answer to this doesn't seem easy, so I'll find this lower bound in another post.
For now, I'll use a constant risk of death to calculate the life expectancy of individuals after aging is eradicated completely and risk of death has presumably stopped falling. While this method doesn't yield a lower bound, since it leaves out from the calculation the risk of death when it's decreasing, it can be made conservative using a relatively high risk of death. I'll use , which is more or less the current risk of death of someone between 20 and 30 years old. It is conservative because it doesn't account for future improvements in medicine and general safety outside of aging research. I also don't expect the lower bound to be much smaller. Therefore,
Since we are talking about life expectancy in a world without aging, 1000 years of life expectancy should amount more or less to 1000 QALYs.
Any given aging research project, if successful, could have the effect of making the date at which most people will reach Longevity Escape Velocity come closer by a certain amount of time. We can estimate the expected QALYs gained because of such an effect. We have established that the average lifespan of a person who reached LEV will be around 1000 years, mostly without disability, and somewhat less if we use a lower bound. The number of QALYs saved are then calculated by multiplying 1000 by the number of people who would otherwise have died of aging if LEV wasn't moved closer. Currently, around 100,000 people per day (36,500,000 people per year) die due to age-related decline and diseases, although this figure will be larger when LEV arrives due to population growth.
So, in order to calculate an almost lower bound for how many expected QALYs that a certain research project would save by making LEV come closer, you simply multiply these values:
This is true for a crude estimate, without accounting for moral weights and potential discount rates.
It is important to stress the fact that none of these variables depend on how soon LEV will arrive, so we can totally ignore this kind of discussion, even if it is a highly debated topic outside the setting of cost-effectiveness evaluations.
The first two variables have been already discussed. Then, we need to examine the third one, which depends on many factors, such as:
If we had the minimum rate of decrease of risk of death such that LEV would happen, then the probability of LEV happening is the probability that the risk of death would fall at that rate or faster, and so the probability largely depends on that rate and on how fast medical research will be.
For now, we can reason about the problem by dividing the situations in which LEV will not happen in at least two scenarios:
The scenarios in which LEV will happen, instead, are the ones in which the risk of death falls fast enough, which means that new therapies would be developed sufficiently close together. This would be brought about through steady progress in medicine or relatively large jumps in life expectancy that enable previous recipients of therapies to extend their lives by another large amount of time. We can imagine how such scenarios could unfold:
Given these scenarios, can we have a preliminary idea, without knowing how fast the risk of death needs to fall, of how likely LEV is? There are, at least, probably some relevant points to make regarding the current best guesses about aging and the present state of research.
It's difficult to predict major future roadblocks, but at least it seems that the "very slow research" scenario is proving less and less likely. This doesn't mean that we already have effective therapies against aging, or that the pace of science is optimal. But how research is distributed and the theories about what aging is make believable the possibility of therapies being developed closer together, thereby enabling a high-enough rate of decrease of overall risk of death.
The current best guess about how to tackle aging rests on a milestone paper from 2013: The Hallmarks of Aging. The paper has citations in the thousands and counting, and researchers are using it as a framework to orient and justify their own research. It proposes various categories of dysfunction. Every category, or almost every category, should be addressed periodically in order to maintain a youthful state of health. Reversing one hallmark would mean restoring an internal state of the body that is typical of a youthful body. It could also prove true that it will not be necessary to address every hallmark, due to the possible cause-effect relationships between each of them.
What does this say about how close together therapies will come? It says a lot: a paper like The Hallmarks of Aging means that the field already has an idea of what combination of foreseeable therapies will bring major gains in health and, in turn, life expectancy. This is because this theoretical categorisation constitutes what needs to be addressed.
It also implies that it enables thinking about rejuvenation, not only "slowing down" aging. This is because the dysfunctions described are exactly what is "wrong" with an old body, and not how those dysfunctions arise, so getting rid of those kind of dysfunctions means rejuvenation.
It's a "downstream" view of aging that decomposes the problem and leaves out what is unnecessary to know in order to intervene, increasing the tractability of the problem. We don't need to know how the Hallmarks arise in order to develop therapies that address them. One added benefit is that the hallmarks influence each other in negative feedback loops; reversing one slows down the progress of many others.
Theoretically, interventions aiming at reversing all of the hallmarks of aging could be developed in parallel, and, in fact, they currently are (although not optimally so). Interventions to ameliorate each one of the Hallmarks, at least in specific parts of the body, are underway. You can follow the progress of each research targeting each hallmark by using the Rejuvenation Roadmap made by the Life Extension Advocacy Foundation. This map tracks the progress of research projects that ameliorate each hallmark and provides links with explanations of each project; it also contains citations to the relevant papers.
As you can see, there are some hallmarks, such as mitochondrial dysfunction and loss of proteostasis, which are in the very early stages of research: the furthest they have reached, so far, is the preclinical stage. Research on how to ameliorate mitochondrial dysfunction, in particular, is in such an early stage of research that it is only pursued by nonprofits and academia, but it needs to be addressed in the wider scheme of therapies that will be needed in order to address all of the dysfunction arising from aging.
There are other hallmarks, such as cellular senescence and stem cell exhaustion, which are in fairly advanced stages of research (phase 1 and phase 2 trials), and research on them is pursued by well-funded, for-profit companies, such as Unity Biotechnology.
The fact that all of these lines of research are pursued in parallel is important. It means that at an unspecified time in the future, near or far, lines of research could come together in a relatively short period of time. The fact that right now, many interventions are being researched on specific diseases (e.g. Unity Biotechnology's trial is for arthritis) does not negate the previous point: treatments that are being researched using the Hallmarks framework, even though they are being tested for specific conditions, are relevant for therapies that treat a wide range of diseases. Parallel development makes it more likely that therapies will come in waves, with each therapy being released shortly after another.
There are also other approaches in aging research, such as targeting aging in a more upstream fashion, with less ambitious interventions that target metabolic pathways. One example is metformin, although I don't think that, right now, science is advanced enough for research on specific medical interventions using this approach to substantially make the date of LEV come closer or substantially impact its probability. These kinds of research projects, nonetheless, could have the effect of buying some time for an additional slice of the population to reach LEV. This brings us to another way of accounting impact in this cause area.
Another factor potentially greatly influencing impact is the life expectancy increase resulting from research projects or health interventions. If the project is not likely to be funded in the future or subsumed by other research, the recipients of the intervention who would have died near LEV get saved. I think the health interventions or projects for which this factor is relevant are very few or maybe even non-existent. This consideration influenced the impact measure I used in my previous analysis on the TAME trial, but in retrospect I think I overestimated the probability that the health benefit of metformin will not be subsumed by other research.
In order to account for this, the relevant factors to multiply are:
Due to the possibility of LEV, expected QALYs should be the measure of impact of aging research. Lives saved lose their original meaning, unless 1 life of 1000 QALYs is counted as multiple lives of 30-80QALYs. Exactly how many also depends on how moral weights are chosen. In my previous analysis about the cost-effectiveness of the TAME trial, I made the mistake of measuring impact in lives saved instead of directly in QALYs, without considering the fact that a life saved in that context amounted to 1000 or more QALYs and actually counted as multiple lives saved. In that analysis, I also didn't account for DALYs averted at the end of life and every other factor that influences impact, which I will discuss in future posts.
A concern sometimes comes up when I present LEV-based reasoning: how do we account for the fact that LEV will probably spread to the whole population over a large period of time (e.g. following the sigmoid technology adoption curve)? This consideration has no effect on the final estimate of cost-effectiveness, and making the date of LEV closer by any given period of time prevents exactly the number of deaths by aging occurring during that period of time, regardless of how LEV spreads. Let's first see a simple example where this holds and then prove it mathematically in the general case. I came up with two proofs, each one of which is sufficient alone.
These same arguments and proofs work for any other outcome of a given technology. How a certain technology (health-related or not) will spread doesn't influence the cost-effectiveness of financing the research leading to it. I may include the generalised version, which trivially follows from this one, in a separate post.
Keep in in mind that this does not mean that making LEV spread faster doesn’t impact CEAs. In fact, this is a potential impact factor that I will discuss. This result means that the impact of making the date of LEV come closer isn't influenced by how LEV spreads.
I will use deaths prevented in the example and in the proofs, but a generic measure of impact yields the same result. Using QALYs is not necessary in this case.
Example
Let's consider two specific scenarios as an example: in the first scenario, LEV spreads to the whole population instantly, and in the second, it spreads over four years.
First scenario: A particular piece of research makes LEV come closer by one year. Since LEV spreads instantly over the whole population, it's easy to see that the resulting deaths prevented are exactly the deaths by aging occurring during one year: more or less 100k.
Second scenario: A particular piece of research makes LEV come closer by one year, but LEV spreads over the world during a period of four years. In the first year, 1/4 of the population reaches LEV; in the second year, 1/2; in the third, 4/5; and in the fourth, 5/5. If we shift this gradual transition by one year, then in the first year, we prevent, on the margin (deaths that would have occurred if we didn't move the date), 1/4-0 = 1/4 of the deaths of aging occurring during that year. In the second year, we prevent 1/2-1/4 = 1/4 of the deaths by aging that occur during that year. In the third year, we prevent 4/5 - 1/2 = 3/10 of the deaths by aging occurring during that year. In the fourth year, we prevent 5/5 - 4/5 = 1/5 of the deaths by aging occurring during that year. So, in total, by shifting the date of LEV by one year, we prevented: 1/4 + 1/4 + 3/10 + 1/5 = 1. That is, we prevented the deaths by aging occurring during one year: more or less 100k.
As you can see, the number of deaths prevented in the two scenarios is the same: the number of deaths by aging occurring during one year. LEV is moved closer by one year in both scenarios, but it spreads differently.
Now, I'll prove, more generally, that making LEV closer by any given period of time prevents exactly the number of deaths by aging occurring during that period of time, regardless of how LEV spreads.
Proof 1:
the number of years needed for therapies to spread to the whole population.
the year in which the therapies leading to LEV begin spreading.
number of deaths caused by aging each year ( could be the number of deaths by aging occurring in any arbitrary unit of time; the proof remains the same).
expresses how many deaths from aging are prevented in a given year during the time that therapies are spreading. How exactly is defined depends on how the therapies spread (e.g. exponentially or linearly), but we know that and that .
If LEV spreads to the whole population all at once, then and . In this case if the date of LEV is moved closer by year, then the resulting new function , has as the only member of its domain, also mapping to . So the deaths prevented on the margin by making the date of LEV closer by one year are exactly .
We want to prove for all values of and that if the date of LEV is moved closer by one year but the therapies do not spread to the whole population all at once, the number of deaths prevented on the margin still amounts to .
Let be the function that expresses deaths by aging prevented each year after making LEV come closer by one year and the (already defined) function that expresses deaths by aging prevented each year without LEV being moved closer. Therefore has the following properties:
, this holds under the very solid assumption that making the date of LEV closer only shifts : it doesn't change how it is defined, but only subtracts to all the members of its domain.
Then, the deaths by aging prevented each year on the margin if we make LEV come closer by one year are:
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Note that the same exact proof works if the date of LEV is moved closer by more or less than one year: It is sufficient to let be the deaths by aging prevented in an arbitrary unit of time. Another proof, with f having a continuous domain, involves manipulating integrals. Here it is:
Proof 2:
Let be the function that associates time with deaths by aging prevented at that time. Then, the total number of deaths prevented in a given time interval is . The number of deaths averted on the margin if we make the date of LEV come closer by the time interval is:
Let's divide the interval in n smaller periods of time of length (the period of time LEV is moved closer by). Let's call those subintervals . Then the above integral can be rewritten as a sum of integrals over the smaller intervals.
But since it's true that:
Then, the terms of the sum simplify with each other and we have:
Notice that if happens one unit of time before LEV begins spreading and is the time at which LEV has reached the whole population, then and is exactly the number of deaths by aging that would have occurred in the time interval ; this is exactly the number of deaths by aging prevented if LEV was moved closer by and the therapies spread instantly. This proves that the number of deaths by aging prevented on the margin by moving the date of LEV closer by is always equal to the number of deaths by aging occurring during , regardless of how the therapies spread over the world.
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As anticipated, another potential source of impact to consider is if a certain project, for example an advocacy-related or policy change, can change how fast people get access to treatments. This would make LEV spread faster, and, in turn, save the people who otherwise wouldn’t reach it.
In order to evaluate this, we need to come up with an estimate of how the future adoption curve will look like. This could possibly be achieved by looking at the way that current health treatments spread, and then evaluate how many people, and, in turn, QALYs, get saved by a change in the curve resulting from the project.
This consideration will probably be given more space in a separate post investigating current adoption curves for health-related technologies and the impact of advocacy and inducing policy change in this area.
Another consideration that may be taken into account to evaluate impact is how much a given research project increases the probability of LEV. This doesn't mean increasing the probability of aging getting eradicated completely; it means increasing the probability of research being fast enough to ensure LEV and not a scenario in which research is so slow, or roadblocks so dire, that aging eventually gets eradicated but no one experiences LEV in the meantime.
This probably depends much on the project in question, but it is also possible that, in general, the impact of this consideration could be small, unless we assume a really inefficient research community, or we are analysing a specific research project that is highly neglected and has the potential effect of removing a major roadblock or unlocking further progress, thus speeding up the general pace of research and making the risk of death for future recipients of interventions fall faster. This could be true for research on new scientific tools or research done in a particularly original way that shows a new approach to problems that wasn't seen before.
In case this consideration has to be taken into account and we need to calculate how many QALYs that increasing this probability would save, we should come up with a distribution of probabilities (with the sum of the probabilities = 1 - the probability of LEV not happening) about how fast the risk of death would fall after LEV. Each outcome yields a different number of QALYs saved by LEV. Then, we should calculate the expected value in QALYs of the distribution with an increased total probability of LEV and the expected value in QALYs of the distribution without an increased total probability of LEV, then determine the difference between the two results.
It should be noted that another effect of aging research is to increase the chance for people saved by other interventions to reach LEV. If a life in Africa is saved thanks to insecticidal nets, then the expected QALYs saved will be more or less the person's expected remaining life plus his/her life expectancy after LEV in QALYs (more or less 1000 as we have seen) multiplied by the probability that person has to achieve LEV during the rest of his/her life.
The probability of an individual reaching LEV depends on:
The first depends on the recipients of the intervention, but even in the worst cases, it should be a pretty high number, considering that even in Africa, the lowest average life expectancy for children born in 2018 is 57 years. The second probability depends on how likely LEV is to appear in any given year. In order to determine this, a very thorough and detailed analysis is needed, and so I will probably tackle this problem in another post.
This is a crosspost from my post in the Effective Altruism Forum.