Why SENS makes sense

post by Emanuele_Ascani · 2020-02-22T16:28:27.576Z · score: 41 (28 votes) · EA · GW · 17 comments

Contents

  Summary
    Introduction
    SRF's approach to aging research
    Funding Methodology and focus
    Funding gap and counterfactual impact
    SRF's current projects
    The engine of an industry
      Oisín Biotechnologies and Ichor Therapeutics
      Covalent Biosciences
      Arigos and Human Bio
    Unfair dismissals
    SENS' scientific status
      The damage repair approach in the literature
      Scientists and citations
      Partner organizations
      Research Advisory Board
    Questions for Aubrey de Grey
    Suggest or criticize questions
None
17 comments

Summary

In this post, you'll find why I think SENS Research Foundation (SRF) is great to finance from an EA perspective along with the interview questions I want to ask its Chief Science Officer, Aubrey de Grey. You are welcome to contribute with your own questions in the comments or through a private message. Here is a brief summary of each section:

Introduction: Aging research looks extremely good as a cause-area from an EA perspective. Under a total utilitarian view, it is probably second or third after existential risk mitigation. There are many reasons why it makes sense to donate to many EA cause-areas, such as to reduce risk, if there are particularly effective specific interventions, or if some cause-areas are already well funded.

SRF's approach to aging research: SRF selects its research following the SENS general strategy, which divides aging into seven categories of damage, each having a corresponding line of research. This categorization is very similar to the one described in the landmark paper The Hallmarks of Aging, which represents the current scientific consensus. This sort of damage repair approach seems more effective and tractable than current geriatrics and biogerontology that are aimed at slowing down aging, as it enables LEV and many more QALYs. It makes rejuvenation possible instead of just slowing down aging as a best-case scenario, and it doesn't require an in-depth knowledge of our metabolism, which is extremely complicated and full of unknown-unknowns.

Funding methodology and focus: By watching the talks that Aubrey de Grey gives, we can see that the core tenets of EA, scope, tractability, and neglectedness, guide SRF's focus. After choosing the general strategy, the subcategories of research are chosen, prioritizing the most difficult projects that are neglected and need to catch up in order to have the greatest impact on the date of Longevity Escape Velocity, a metric that is being addressed head-on by Dr. de Grey's prioritization strategy and constitutes the major source of impact [EA · GW] of aging research.

Funding gap and counterfactual impact: SRF spending has been between three and five million dollars since 2012. Aubrey de Grey has stated in different interviews that SRF would need more than ten times this amount before experiencing significant diminishing returns. It's unlikely that someone will step in and close the gap any time soon, given the slow increase in funding. Dr. de Grey estimates that $2.50 would prevent one death from aging, granting 1000 QALYs (QALYs estimate mine [EA · GW]). This stance should be further analyzed in the interview.

Current SRF Projects: In this section, I summarize the current intramural and extramural projects financed by SRF: MitoSENS, Maximally Modifiable Mouse, A Small Molecule Approach to Removal of Toxic Oxysterols as a Treatment For Atherosclerosis, Glucosepane Crosslinks and Undoing Age-Related Tissue Damage, Target Prioritization of Tissue Crosslinking, Functional Neuron Replacement to Rejuvenate the Neocortex, Enhancing Innate Immune Surveillance of Senescent Cells, Identification and Targeting of Noncanonical Death Resistant Cells.

The engine of an industry: Past SRF research projects have been spun off in private companies, and this is the strategy that SRF is pursuing for bringing forward this research to the most costly phases. This multiplies the effect of a donation at the early stages of research because it enables private capital to pour in. SRF spin-offs include Underdog Pharmaceuticals, Oisin Biotechnologies, Ichor Therapeutics, Covalent Biosciences, Arigos, Human Bio, Revel Pharmaceuticals. I'll describe them in the full section and provide external sources of information.

Unfair Dismissals: SRF has recently been dismissed by Open Philanthropy for two poor reasons:

1. Open Philanthropy's list of selected topics and SRF's plan differ in focus.

2. Open Philanthropy, unlike SRF, doesn't claim that progress on the topics they identified would be sufficient to make aging negligible in humans.

The first reason conflates SRF's general strategy to what it is selecting to fund inside the general strategy. The second implies that SRF claims that its strategies, by themselves, will make aging negligible in humans. This is not true, and the real claim is that the strategy is probably complete to reverse the aging damages that become problematic during a human lifespan, but no further. Additional strategies will be required when this limit ceases to be, but having the initial strategies developed allows for people to live during the time required to develop the additional ones. This is the crux of Longevity Escape Velocity.

SENS scientific status: The SENS plan is twenty years old. When it was first proposed, it was met with skepticism, but over the years it has been widely accepted and re-proposed. Intramural and extramural research at SENS Research Foundation is performed by reputable and highly cited scientists. SRF has collaborated and continues to collaborate with many established universities and research institutions around the world. Its research advisory board comprises many world-leading scientists in biology and medicine.

Questions for Aubrey de Grey: You can find them at the end of the post without any additional commentary/discussion.

Suggest or criticize questions: I invite the reader to come up with questions, or criticize the questions I have proposed. Please use the comment section in the forum or private messages.

Introduction

For the past year, I've been working on a framework for helping evaluate the cost-effectiveness of aging research. The cause area as a whole is promising, especially because of its large potential impact and the combination of neglectedness and tractability of certain sub-areas. As I explained in previous posts, the majority of the impact comes from moving the date of Longevity Escape Velocity (LEV) closer. In my first post [EA · GW], as a crude estimate, I calculated that moving LEV closer by one year would save 36,500,000 lives of 1000 QALYS.

LEV is defined as 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 at least constant despite the passing years.

I think this fact alone makes aging research second or third in terms of cost-effectiveness after X-risk, which may vary with moral assumptions and degree of risk-aversion regarding philanthropy. Given an attentive analysis of the field, it's very probable that we can select highly cost-effective research to fund. The fact that this cause-area doesn't generally look like the best one doesn't necessarily mean that it's worthless to finance. Diversifying areas of philanthropic donations can reduce risk. It also makes sense to donate to a seemingly suboptimal cause-area when specific interventions in that cause-area are more cost-effective than available interventions in a cause-area that only superficially looks better. This includes cases in which the most cost-effective interventions in the top cause-areas are already being funded, or if there are particularly cost-effective interventions in the seemingly worse cause-area.

As my framework has approached its completion, I've been wanting to interview specific figures involved in charities in the field of aging research. In particular, two organizations always struck me as potentially very cost-effective: SENS Research Foundation and Life Extension Advocacy Foundation. The first will be the focus of this post.

SRF is a research organization founded in 2009 that does basic but translational research on treating different aspects of aging and finances other organizations and universities that it deems effective.

In the rest of this post, I'll explain why SENS seems particularly cost-effective, and I will offer some questions that I would like to ask SRF. I would like my next post to be an interview of Aubrey de Grey, hoping that he will have time to be interviewed for the audience of this forum.

SRF's approach to aging research

SRF selects each study to perform intramurally or finance extramurally in accordance with a general research roadmap: the development of seven solutions to the seven kinds of aging damage that Aubrey de Grey identified in the early 2000s. You can find a description of the SENS roadmap on this page of the foundation's website, or in Aubrey de Grey’s book, Ending Aging. It is also always briefly described in every talk that Aubrey de Grey gives (example).

The damages listed can be mapped with near-complete precision to the Hallmarks of Aging listed in the namesake paper from 2013, which is one of the most cited in the field and represents the current scientific consensus.

SRF holds that all of the damages together are probably a complete or near-complete description of what causes age-related diseases during a human lifespan, considering that the last discovery of new damage was in 1972.

Many of the solutions stated are generic, meaning that they consist of a large panel of different but similar therapies (in this category, there are cell loss, death-resistant cells, extracellular matrix stiffening, extracellular aggregates, and intracellular aggregates). In practice, each solution already has some existing examples in at least a proof of concept stage. See this roadmap for examples of existing therapies being developed for each hallmark. Some solutions are at really advanced stages of research, such as cell loss and death-resistant cells), others are still in early stages, such as mitochondrial mutations. SRF focuses on the most neglected.

In his talks, Dr. de Grey always stresses how the damage repair approach, which he also calls "the maintenance approach", has a big advantage over geriatrics and the kind of biogerontology aimed at targeting the metabolic processes that are causing this damage.

Current geriatrics targets symptoms and consists of treatments that offer very short-term improvements. They don't aim to repair the molecular and cellular damage that sits at the basis of deterioration itself, which will continue to accumulate.

What Dr. de Grey calls the "messing with metabolism" approach or "traditional biogerontology approach", instead, is aimed at slowing down aging, and it requires an in-depth knowledge of how metabolism works, which is extremely complicated and full of unknown-unknowns. Drugs and interventions in this latter category are things like caloric restriction or drugs that seem to affect multiple metabolic pathways related to aging, such as metformin.

The advantages of the repair approach, then, reside in:

Notice that this approach, and the theory behind it, is not in contrast with other theories of aging (Examples: antagonistic pleiotropy, information theory of aging, inflammaging). They just explain different causal levels of the process, upstream or downstream in respect of the hallmarks. Sometimes, they are just names used for referring to single aspects of aging already recognized as such in the hallmarks or among the SENS damages, such as the mitochondrial free radical theory of aging.

Funding Methodology and focus

Even very superficial research about this organization reveals something very interesting. If you watch one of Aubrey de Grey's many talks (a good example is this TED Talk from 2017), it's clear that his arguments follow the same lines of Effective Altruism's core tenets: tractability, neglectedness, and scope. The talks Aubrey de Grey gives to a public of non-experts are all very similar and revolve around a few arguments, including:

It's really weird to me how no one has recognized Aubrey de Grey's methodological alignment with EA, especially considering that he has been a known figure in Effective Altruism since when the movement was at its start.

At the beginning of this recent webinar, he explains that to identify priorities for SENS (usually inside the areas already selected by his higher-level strategy, as explained in his usual talks), he uses difficulty as a metric. He explains that in a divide-and-conquer strategy, the most difficult things need to "catch up" and so they are worthy to finance. Usually, they are also the most neglected, due to the fact that other researchers, constrained by peer review and the need to output research, tend to be biased in favor of working on low-hanging fruit.

Using difficulty as a metric is a good strategy if we view impact in terms of making LEV closer. Nearing the date in which the most difficult things are solved probably means having the highest impact possible on LEV's date because the most difficult things to solve would act as bottlenecks on life expectancy. As I explain in the first post in the framework [EA · GW], making LEV closer is by far the greatest impact factor of aging research.

So far, SRF seems to be the only research organization that is addressing this metric head-on; therefore, it has the highest probability of having the highest impact. This is certainly not surprising since Aubrey de Grey has been the biggest disseminator of the concept of LEV, which is central in his vision of how aging research will shape the future. Wikipedia's article on LEV states that it was first publicly proposed by David Gobel, co-founder of the Methuselah Foundation (the other co-founder was Aubrey de Grey), which is the older non-profit that ended up spinning off SRF. It's no wonder that one of the first promoters of the concept is the one actually optimizing for it.

In the light of what is important to consider when evaluating aging research, as outlined in my posts regarding the framework, SRF seems to be doing everything right:

Funding gap and counterfactual impact

In the last few years, SRF's annual spending has been 3-5 million dollars. This page contains the last annual report and public tax returns document.

You can find the previous organizational reports and public tax returns on this page on archive.org.

2009: Total revenue: $1,295,292. Total expenses: $804,040.

2010: Total revenue: $1,132,346. Total expenses: $1,145,124

2011: Total revenue: $1,506,925. Total expenses: $1,702,845

2012: Total revenue: $14,589,300. Total expenses: $2,985,680. $13M of revenue was from Aubrey de Grey's inheritance of $16.5M, which was donated almost entirely to SRF.

2013: Total revenue: $1,807,197. Total expenses: $4,549,400.

2014: Total revenue: $1,829,946. Total expenses: $5,065,181.

2015: Total revenue: $1,578,576. Total expenses $4,060,680.

2016: Total revenue: $2,701,563. Total expenses: $3,907,561.

2017: Total revenue: $7,871,530. Total expenses: $3,915,862. The revenue is higher in 2017 mostly thanks to crypto-currency donations ($4,672,532). In 2017, almost every cryptocurrency’s value was at an all-time high, with huge upward fluctuations in price. The major donations to SRF have been in BTC and ETH at the end of 2017, mostly thanks to Vitalik Buterin ($2.41M), founder of the Ethereum Foundation, and the Pineapple Fund ($2M). BTC's price at the end of 2017 was around 20 times the price it had at the beginning of that year. ETH's price, instead, saw a surge of 100 times from the beginning to the end of 2017. Source: coinmarketcap.com.

2018: Total Revenue: $2,436,573. Total expenses: $3,568,259.

As we can judge from the financial reports, the spending figure "3-5 million dollars" is not very descriptive of how much this organization is supported. The reality is somewhat bleaker. Only from 2012 to 2016 has such spending been allowed, only thanks to Aubrey de Grey's inheritance. Inheritance not counted, the revenue before 2016 has always been less than $2M. 2017 saw a particularly good year thanks to the cryptocurrency boom, although the $2.7M and $2.4M in total revenue during 2016 and 2018 seem to indicate that SRF's income is slowly improving.

Aubrey de Grey has said in many interviews that the organization would need around ten times or more of its current income before diminishing returns became too high. The figure is given in light of the fact that each kind of damage Aubrey de Grey defines needs a lot of different but similar therapies, pursued by different groups. For each therapy, SRF would develop the proof of concept in vitro or in animal models and leave clinical trials to spin-off private companies (see section "The engine of an industry"). In this recent interview from 2 December 2019, hosted on longevity.technology, Aubrey de Grey re-states SRF's funding gap:

Longevity.Technology: And you initially started out with a goal of raising $50 million?
Dr de Grey: Yes, and that remains the case. The amount of money we have in the foundation to fulfill this research is very much rate limiting. In other words, if we had 10 times more money, we wouldn’t go 10 times faster but would definitely go a couple of times faster and that would still save a hell of a lot of lives. So the question is, how much more money would we need in order to ensure it was not rate-limiting? And the kind of numbers that I have always given are in the range of $50 million to $100 million per year, in contrast to the kind of budget that we have historically had, which is in the mid-single-digit millions. We’re only talking about one order of magnitude more money, but that’s still a lot, and obviously we still don’t have it so the concept and the pitch is still the same.

In this interview dated 27 July 2018, hosted on lifespan.io, Aubrey de Grey answers how much SRF's research would speed up if they had a billion dollars, and how he thinks the speed-up would impact the date of Longevity Escape Velocity:

Yuri: If you had unlimited funding, how long do you think it would take for us to reach Longevity Escape Velocity or the technology necessary for it?
Aubrey de Grey: It’s actually pretty difficult to answer that question because the amount of funding is kind of self-fulfilling. Every increment of progress that we achieve makes the whole idea more credible, makes more people more interested, and makes it easier to bring in the money to make the next step. I think that, at the moment, unlimited funding could probably let us increase our rate of progress by a factor of three, but that does not mean that we will change the time to get to Longevity Escape Velocity by a factor of three, because when we get even a little bit closer to it, it will be easier to get money, and that factor of three will come down. I think that right now, if we got like a billion dollars in the bank, then, in the next year, we would probably do the same amount of work and make the same amount of progress that we would otherwise make in the next three years. In the year after that, only two years of progress, and in the year after that, only a year and a half, and so on. What that adds up to is that if I got a billion dollars today, we would probably bring forward the defeat of aging by about 10 years. And it’s a lot of lives, maybe 400 million lives.

If the last sentence is true, and 1 billion dollars given to SENS can save 400M lives, then that means that $2.50 would save one life of 1000 years, as calculated using the estimate in my first post [EA · GW]. Some details are missing, such as why he thinks SRF's research would speed up by 2-3 times with 10x more funding and why he thinks that LEV would be brought nearer by 10 years. I will ask these questions in the interview.

Aubrey de Grey partially answers the question of counterfactual impact: is the funding gap likely to be funded anytime soon? In the interview answer, he makes the case that more funding would attract even more funding by speeding up progress and raising the profile of the organization. If speeding up its research by a factor of three requires $100M and that reduces the counterfactual impact of the next year by one third (to 2x rate, as stated in the interview answer), then that means that to get an additional $100M/3 = $33M, it would require $100M. That means that $33M would be pretty difficult to get at the start while still not being sufficient to cover the whole funding gap. Starting from the current average annual budget of $3M-5M, to get to $100M, SENS would require around $95M in the first year, that would grant an additional $33M the year later, in which the funding gap would be reduced to $62M, and so on.

Aside from Dr. de Grey's claims, we can try to get an idea of how likely it is that someone will step up in the near future to close SRF's funding gap. After ten years in operation, the organization’s spending is still in the range of $3M-5M. The increase has been pretty slow, and it seems unlikely that someone will step any time soon to fill the whole gap. I've read multiple people in EA arguing that financing aging research seems palatable for a more egoistic kind of person, thus reducing the need for philanthropy coming from altruistic people. This stance has been proven wrong by reality, as after 10 years, SRF's funding is still less than one-tenth of what is required.

SRF's current projects

In the following bulleted list, I summarize the research that SRF is currently doing intramurally or financing extramurally. For each project, you'll find in brackets information regarding what kind of research it is, what SENS strand it corresponds to, and what hallmark of aging it addresses. It is also specified if the project is within a category that I identified as necessary and/or neglected in my previous post [EA · GW] about how to evaluate tractability and neglectedness of aging research. Quotes from the SRF website are in quotation marks.

As you can see, I ordered the projects thematically. The first two are both aiding the long-term objective of allotopic expression of mitochondrial genes, with the MMM project also having a wider application for delivering in vivo gene therapies. The following two studies promise to have an important impact on atherosclerosis (but hopefully on more age-related diseases) and are related to the same SENS strand. Immediately below the glucosepane study, there is its natural complement, "Target Prioritization of Tissue Crosslinking", which is aimed at gathering data to develop a strategy for prioritizing other types of crosslinks. Below, "Remediation of Aberrant Intracellular Tau" and "Functional Neuron Replacement to Rejuvenate the Neocortex" are both related to brain rejuvenation. "Enhancing Innate Immune Surveillance of Senescent Cells" is a collaboration with Judith Campisi, who is probably the most well-known figure in the senescent cells research space. The last project is still inside the "death-resistant cells" topic.

Most research projects allineate with what I identified [EA · GW] as necessary and neglected, and the last three fall into the areas that Open Philanthropy identified as probably impactful in its medium investigation.

The engine of an industry

The ones listed are only the current projects, but SRF has financed and undertaken many more in the past 10 years of its operation. You can find the past projects on its old website in the sections under the "Research" tab. Some of the projects gave life to companies and are now being brought forward by research in the private sector. That's why sometimes you can hear Aubrey de Grey talking about SRF as the "engine of an industry". When the basic research goes far enough, SRF tries to spin off a company. This makes sense since private capital is much more abundant than funds accruable through philanthropy. From an EA perspective, this is crucial information. It means that if through philanthropy we bring forward a project that wouldn't otherwise be brought forward and if the project ends up spinning out a private company (which is always the objective), the value of our donation is multiplied through all the private capital that it will have enabled.

Aubrey de Grey recently talked at EA Global 2019 about the explosion of the private sector in the area, and how SRF acts as an engine for the nascent aging industry. The part about this topic begins at minute 21:40 and finishes with the end of the video. In short, he makes the case that philanthropy might be now less important than in the past for aging research, due to all the private capital coming in. But he also says that for the most difficult projects, it is still necessary because the private sector is currently only financing the lower-hanging fruits. Philanthropy needs to fill the gaps, because in a divide-and-conquer strategy, "you can't hit only the low hanging fruits, you have got to hit all the components". I think the question asked at the end of the video is particularly interesting: "How much money do we need to defeat aging?". At first it could seem like a too difficult and broad question, but Aubrey de Grey's answer made perfect sense and succinctly got to the real point of the question, which is: "how much more philanthropic funding do we need to defeat aging?". The answer, in short, is this: "The amount of money you need to develop these technologies at the early stages is much less than what you need at the later stages, but obtaining money for the later stages, like clinical trials, is much easier because much of the de-risking has already happened. Since philanthropic money is only needed at the early stages, the answer to that question is a relatively tiny amount of money: 500 millions or even 250 millions over a period of 10 years, which is an order of magnitude of what SENS currently has, which is about 5 million dollars per year. 250-500 millions is still a pitifully small amount of money as compared to the kind that's spent in medical research generally." The figures are already cited in the "Funding gap and counterfactual impact" section.

If you think that SRF's plan is theoretically enough to bring forward all of the basic early-stage research necessary for the first comprehensive rejuvenation therapies, then you are probably satisfied with this answer. It's worth considering that there might be multiple complementary organizations working on research which falls into the SENS general strategy and that there is also the possibility that SENS could not work as expected or that Aubrey de Grey's estimate is wrong. Therefore, you might want to consider that figure as a reasonable lower bound, keeping in mind that this is just for having a chance of bringing aging under medical control through bringing the basic research far enough for the private sector to finish the job.

Aside from the recent Underdog Pharmaceuticals and Revel Pharmaceuticals, which I mentioned among the SENS projects, some of SRF's spin-off companies include Oisín Biotechnologies, Ichor Therapeutics, Covalent Biosciences, Arigos, and Human Bio. Oisín Biotechnologies and Ichor Therapeutics have the most information available.

Oisín Biotechnologies and Ichor Therapeutics

Oisín started as a company about senescent cells clearance, and Ichor started with the focus of removing vitamin A byproducts as a treatment for macular degeneration (here is an in-depth talk by the CEO about this program). If you use the search function on lifespan.io, you can find a lot of aggregated press about both, (link with "Oisin" inserted as the keyword, link for "Ichor" inserted as the keyword). You can find some interviews with the CEO of Ichor and at least two conference videos for each of the companies. In the last years, both companies expanded while pursuing their main focus.

Covalent Biosciences

You can find a description of what Covalent Biosciences does here and an in-depth conference talk here about its research on catalytic antibodies for amyloid diseases, the leading cause of death for supercentenarians. Its therapies also apply to Alzheimer's and many ailments related to amyloids. Its catabodies show high specificity and no dependence on inflammatory cells, therefore they shouldn't have side-effects, unlike regular antibodies. The speaker is a founder and scientist in Covalent, and if you look at his profile on Google Scholar, he is cited more than 10,000 times and has authored more than 600 papers since the 1980s. At the end of his talks, he stresses how his research is aligned with Aubrey de Grey's and the SENS general strategy to combating aging.

Arigos and Human Bio

Arigos and Human Bio have less online material. Arigos works on finding methods for organ preservation, and you can find a good description here, by the Founder of Repair Biotechnologies. We can also find some information in this long interview with Aubrey de Grey dated July 2018, in which he talks about Arigos’ new method of organ preservation (helium persufflation) as a massive breakthrough outdoing vitrification. It could be employed not only for the preservation of single organs but also for whole-body preservation.

In the same interview, we can also find information regarding the less visible Human Bio. They were the first SENS spin-off, funded by Jason Hope. From the Interview:

It [Human Bio] was initially created to do something very similar to what we’re doing with Ichor in macular degeneration. In that case, it was for atherosclerosis. The target was not this byproduct of vitamin A; instead, it was oxidized cholesterol, and they have kind of run into the sand a little bit on that. We’re trying to reactivate it right now, but they’ve got other interests as well. They’re working on senolytics, drugs that will kill senescent cells. They are potentially going to be quite a big player in a number of different areas at SENS. At the moment, they are a bit stealthy; they don’t need money, because they are funded by this wealthy guy. They are not going around telling everyone all that much about what they are doing, the way that most of these companies are.

Unfair dismissals

I can count at least three times in which non-profits operating under the principles of Effective Altruism have acknowledged SENS and then dismissed it without good reasons. Here is the most recent and probably the most relevant:

In Open Philanthropy's medium investigation on aging research from 2017, they compare their highlighted topics with SENS. This happens in footnote 14:

In a document titled “Strategies for Engineered Negligible Senescence,” Zealley and de Grey of the SENS Foundation outlined a plan for engineering people to age negligibly. The plan featured seven topics: cell loss (partially related to “stem cell exhaustion” above), cell death resistance (closely related to “senescent cells” above), cell overproliferation, intracellular junk, extracellular junk, tissue stiffening, and mitochondrial defects.* Two items on our lists are closely related and have similar high-level objectives, but the lists otherwise differ in focus. Another difference is that we do not claim that progress on the topics we identified might be sufficient to make aging negligible in humans.
* See section headings in the introduction of Zealley and de Grey 2013.

Open Philanthropy is dismissing SENS with two claims. I’ll answer them in order.

OP’s claim number one: Open Philanthropy's list of selected topics and the SENS' plan differ in focus.

What Open Philanthropy is saying here is equivalent to saying that their list and the list in The Hallmarks of Aging, which is the paper they are using for selecting their areas of focus, differ in focus. SENS is a general plan to address aging that is almost the same as the list in The Hallmarks of Aging, not necessarily a list of research to fund. The particulars of what to fund inside the list are dictated by reasoning about neglectedness and difficulty. If Open Philanthropy had said that what SRF is funding right now differs in focus with their list of selected topics, I would agree.

Open Philanthropy's list of highlighted topics is this: Preventing the accumulation of epigenetic errors associated with aging or restoring more youthful epigenetic states in cells, solving the problem of senescent cell accumulation, reversing stem cell exhaustion, and learning how to use induced pluripotent stem cells (IPSCs) to regenerate and/or replace tissues and organs damaged by aging and aging-related diseases.

Moreover, it identifies a list of topics also important to aging but that it doesn't cover because "they have focused on topics that seemed more basic": genomic instability, telomere attrition, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, altered intercellular communication, decline of the immune system, inflammation, neurodegeneration, the microbiome, and damage to individual cells (e.g. antioxidants and DNA repair).

The highlighted topics plus the additional ones constitute what appears in The Hallmarks of Aging paper, with some redundancy and additions. By looking at what SRF is currently funding, we can see that it is, in fact, funding things that are mostly in the list of topics which Open Philanthropy deems important but outside of its highlighted topics (focusing mostly on mitochondrial dysfunction and loss of proteostasis, although it has two projects on cellular senescence).

As I say in my previous post [EA · GW] about neglectedness and tractability, I think Open Philanthropy's way of proceeding in selecting topics may prove fruitful, and in fact, I tend to agree with what tit funded in practice (Steve Horvath, who was very much funding constrained, and the work of Irina Conboy on heterochronic parabiosis, which has also been financed by SRF in the past due to its neglectedness). What I think Open Philanthropy is lacking, though, is a bigger focus on neglectedness and difficulty in selecting a high-level list of topics, which is the strategy that SRF is adopting.

OP’s claim number two: Open Philanthropy, unlike SRF, doesn't claim that progress on the topics they identified would be sufficient to make aging negligible in humans.

It’s the "unlike SRF" part that is wrong here. Neither Open Philanthropy nor SRF claim that progress on all of the seven categories/nine hallmarks of aging will be enough to make aging negligible in humans.

What SRF claims is that solving all the seven categories will probably lead to lifespans longer than the current maximum. After that, what other forms of damages will appear is not known, but at that point, those additional damages may be cured (maybe through a SENS 2.0 panel of therapies) during the time "bought" by the first therapies and through their improvement. This stance is explained at length in Aubrey de Grey and Michael Rae’s book Ending Aging.

The name "SENS" (Strategies for Engineered Negligible Senescence") and the claim that the therapies are for "negligible senescence", doesn't contradict the previous claim. These strategies are, indeed, for achieving negligible senescence, but it's not implied that they will prove to be enough to achieve the goal alone.

Aubrey de Grey can often be heard making another claim that may prove confusing. He says: "Since no other damage has been discovered in decades, it is more and more probable that the SENS list is complete". "Complete" here means that it is the complete list of things that go wrong in a normal human lifespan. It's clear that we currently can't acquire direct data about what will go wrong after the current maximum human lifespan is exceeded.

SENS' scientific status

Aubrey de Grey devised the SENS approach in the early 2000s and, at first, some researchers ridiculed it. Things have changed gradually in the last 20 years, and I feel there is a need to clarify the current SENS status among the scientific community, especially because some people may not have followed SRF's progress and may have remained stuck on how it was perceived in the past.

The damage repair approach in the literature

I have already cited The Hallmarks of Aging multiple times in my posts, and it is the paper that constitutes the strongest evidence of the change of outlook I'm talking about. The theoretical approach is very much the same of SENS: to identify categories of what goes wrong. This enables a divide-and-conquer way of thinking about the problem. The high number of citations, is, in fact, also thanks to the fact that it is used by researchers to justify their own projects and to pin them to a bigger picture. The SENS strands together constitute the same bigger picture. This view of aging is now widely accepted.

Scientists and citations

Most cited scientists currently working on intramural projects at SRF:

Most cited scientists currently working on extramural projects financed by SRF:

Note that, although not working directly on any specific project, Aubrey de Grey is pretty well-cited too. According to ResearchGate, he has 4,370 citations, a lot of them probably due to the well-received contributions he made in 1999 and the early 2000s on the mitochondrial free radical theory of aging. He wrote some papers on the topic and the book that earned him a Ph.D. in biology from Cambridge.

Another interesting fact about de Grey: In 2018 he made progress on the Hadwiger–Nelson problem, a famous 65-years-old problem in graph theory. His paper prompted a Polymath Project to improve on the result. The project was first announced on Terence Tao’s Google+ and blog and then moved to Dustin Mixon’s. Here the fifteenth thread.

Partner organizations

Current: Buck Institute for Research on Aging, Albert Einstein College of Medicine, Yale University, Babraham Institute (partner of the University of Cambridge), and Stanford’s spin-off Applied StemCell. Past partners organizations include Rice University, University of Oxford, the Collaboration for the Advancement of Sustainable Medical Innovation (CASMI) hosted by the University College London (UCL), the University of Texas, the Wake Forest School of Medicine. Past project partner organizations include the Albert Einstein College of Medicine, Applied StemCell, Arizona State University, Brigham's and Women's Hospital, UPMC, Stanford University, the University of Arizona, the University of Arkansas for Medical Science, Berkeley, the University of Chicago, and the University of Denver.

Research Advisory Board

Many individuals listed on SRF's research advisory board are world-leading scientists. You can find many with world-firsts and important discoveries under their belts, directors of research institutes, and many with more than 50,000 citations reported on their Google Scholar profiles. Some of them are renowned outside their fields and among the general public. You may have heard of George Church or even Irina Conboy (who received grants from SRF and from Open Philanthropy), even if you don't have haven't a technical interest in biology.

Interesting note: Brian Kennedy, listed in that board, is the ex-CEO of the Buck Institute. In the early 2000s, he was one of the biggest detractors of SENS, but now you can find him talking at SRF conferences and doing public debates with Aubrey de Grey (on the same side). Moreover, as mentioned earlier, the Buck very often collaborates with SRF.

Questions for Aubrey de Grey

I came up with a lot of questions. I’m not sure if de Grey will be able to answer them all, but here they are:

In their medium investigation on aging research, Open Philanthropy concludes with some questions. Here are some similar questions, based on what I deem more important or difficult to evaluate:

Suggest or criticize questions

I invite the reader to come up with questions or criticize the questions I have proposed. Use the comment section in the forum or private messages.

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Crossposted to LessWrong [LW · GW]

17 comments

Comments sorted by top scores.

comment by Matthew_Barnett · 2020-02-22T17:26:08.982Z · score: 22 (13 votes) · EA(p) · GW(p)

(Comment cross-posted from Lesswrong)

Under a total utilitarian view, it is probably second or third after existential risk mitigation.
[...]
I can count at least three times in which non-profits operating under the principles of Effective Altruism have acknowledged SENS and then dismissed it without good reasons.

I once read a comment on the effective altruism subreddit that tried to explain why aging didn't get much attention in EA despite being so important, and I thought it was quite enlightening. Supporting anti-aging research requires being weird across some axes, but not others. You have to be against something that most people think is normal, natural and inevitable while at the same time being short-termist and human-focused.

People who are weird across all axes will generally support existential risk mitigation, or moral circle expansion, depending on their ethical perspective. If you're short termist but weird in other regards, then you generally will help factory farm animals or wild animals. If you are not weird across all axes, you will support global health interventions.

I want to note that I support anti-aging research, but I tend to take a different perspective than most EAs do. On a gut level, if something is going to kill me, my family, my friends, everyone I know, everyone on Earth if they don't get killed by something else first, and probably do so relatively soon and in a quite terrible way, I think it's worth investing in a way to defeat that. This gut-level reaction comes before any calm deliberation, but it still seems compelling to me.

My ethical perspective is not perfectly aligned with a long-termist utilitarian perspective, and being a moral anti-realist, I think it's OK to sometimes support moral causes that don't necessarily have a long-term impact. Using similar reasoning, I come to the conclusion that we should be nice to others and we should help our friends and those around us when possible, even when these things are not as valuable from a long-termist perspective.

comment by Pablo_Stafforini · 2020-02-22T21:01:46.434Z · score: 19 (10 votes) · EA(p) · GW(p)
I once read a comment on the effective altruism subreddit that tried to explain why aging didn't get much attention in EA despite being so important, and I thought it was quite enlightening.

For background, here's the comment I wrote:

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.
comment by aaronhamlin · 2020-02-22T17:38:30.350Z · score: 17 (12 votes) · EA(p) · GW(p)

As someone who started a nonprofit to speed up pharmaceutical drug development, this quote rings very true:

"The amount of money you need to develop these technologies at the early stages is much less than what you need at the later stages, but obtaining money for the later stages, like clinical trials, is much easier because much of the de-risking has already happened. Since philanthropic money is only needed at the early stages, the answer to that question is a relatively tiny amount of money: 500 millions or even 250 millions over a period of 10 years, which is an order of magnitude of what SENS currently has, which is about 5 million dollars per year. 250-500 millions is still a pitifully small amount of money as compared to the kind that's spent in medical research generally."

Disclaimer: The bulk of my recent personal giving ($1k) went to SENS.

comment by gavintaylor · 2020-03-09T21:57:05.721Z · score: 5 (2 votes) · EA(p) · GW(p)

Nice piece Emanuele, I felt that I actually got what LEV was and why we should aim to get there more after reading this post than I did after reading your previous ones. A general comment is that from what the Lifespan.io roadmap shows, it really seems like anti-aging research has progressed quite far (i.e. quite a few on going and some late-stage clinical trials) relative to the fields fringe nature and apparently limited funding.

In terms of questions, there is one thing that I think is fairly critical - how well do multiple interventions combine?

What SRF claims is that solving all the seven categories will probably lead to lifespans longer than the current maximum.

As I understand this, treatments for all of the categories are being developed in independently. Is anybody looking to see if they can all be used in parallel? Could there be interactions between treatments that prevent this? It seems that the expected value of the anti-aging research is only realised if it will, at some point, be possible to treat all the categories in parallel. Research into a treatment for one category that wouldn't be compatible with other treatments seems like it should receive much lower priority.

It seems like there could be ways to test this already. For instance, the roadmap shows many treatments are already at the pre-clinical in-vivo stage. If we start applying multiple therapies in-vivo, we can start to test how compatible they are. Do you know if that has been done?

Starting to test multiple therapies in-vivo could also provide some fundamental evidence about how the benefits of multiple therapies combine. At the moment the assumption seems to be that, say, individually treating mitochondrial mutations and extracellular aggregates, prolongs expected life by X and Y years, respectively, so treating them both in combination will prolong life by X + Y years, but both negative or positive returns on the combination could occur. To be honest, I have some general scepticism about anti-aging research because ageing is very widely conserved in the animal kingdom (there are only a few animals with negligible senescence). It could be that there is some evolutionary path way negligible senescent animals went down that is hard to cross-over to even if we treat all the categories, so I have a weak prior that senescent animals will get diminishing returns from multiple therapies.

Another point that I think is worth discussing is how the damage repair approach effects the metabolic processes causing the damage?

Dr. de Grey always stresses how the damage repair approach, which he also calls "the maintenance approach", has a big advantage over geriatrics and the kind of biogerontology aimed at targeting the metabolic processes that are causing this damage.

For instance, if we treat an 80 year olds telomere attrition, are we going to need to treat them again in the future? Are consecutive treatments going to need to occur at more regular intervals? I don't know much about how treatments effect the underlying metabolic processes (as noted, metabolism is very complicated), but it could be that these continue picking up pace even as the damage they cause is repaired. Knowing about this could also be important in assessing the value of LEV as a whole, particularly if treatments have dose dependent side-effects. For instance, it may be that we can treat ageing out to 200 or so, but then rate of damage is so high that treatment dose required is too strong to tolerate. This is probably an issue for SENS 2.0, but it also seems like an area where some in-vivo testing can provide some useful information. If nothing else, finding that regularity of therapy is expected to increases suggests that treatments with more tolerable side-effects might be preferred (where there is a choice).

This are both fairly technical issues compared to the other questions you proposed in the post, but I think they point towards some fairly crucial considerations about how the additivity and repeatability of therapies will effect the goal of LEV.

comment by Emanuele_Ascani · 2020-03-16T18:48:32.278Z · score: 2 (2 votes) · EA(p) · GW(p)

Thanks Gavin, there are some great questions in here.

I'm only able to answer two of them pretty conclusively:

For instance, if we treat an 80 year olds telomere attrition, are we going to need to treat them again in the future? Are consecutive treatments going to need to occur at more regular intervals?

The answer is simply: absolutely, yes.

If you condense the most crucial questions I will add them in the interview, and we will see what Aubrey de Grey has to say.

comment by gavintaylor · 2020-03-17T15:46:35.590Z · score: 2 (2 votes) · EA(p) · GW(p)

Sure, I think the key questions would be:

-Of the treatments currently being developed (in reference to the list on lifespan.io), is it likely that treatments for multiple hallmarks can be used in parallel?

--Are there currently any observed or expected interactions between different treatments?

--Has any effort been made to see if the effects of multiple treatment are additive, in terms of improved lifespan, in a pre-clinical study?

-What side effects have been observed for the treatments currently in clinical trials?


It's interesting to know that recurring and more frequent treatments are going to be needed. That point hasn't been obvious to me before, but it could be important to consider in relation to the economics of scaling up mass anti-aging treatment - it's not like a one of vaccination against a specific type of ageing damage, but still a 'condition' that requires ongoing, and perhaps increasing, care.

comment by Emanuele_Ascani · 2020-03-18T11:17:10.974Z · score: 2 (2 votes) · EA(p) · GW(p)

You are correct. I will also add a question about how much time he estimates will need to pass between one treatment and its repetition. This could be fairly calculable from the informations the scientific community already has (the rate of damage in the elderly). I will get back to you with another reply in case I come up with other questions in light of your comment and if I modify or add something to your questions.

comment by RomeoStevens · 2020-02-23T20:55:29.820Z · score: 3 (3 votes) · EA(p) · GW(p)

I think that much of the disconnect comes down to focusing on goals over methods. I think it is better to think of goals as orienting us in the problem-space, while most of the benefits accrue along the way. By the time you make it a substantial fraction of the way to a goal, you'll likely be in a much better position to realize the original goal was slightly off and adjust course. So 'eliminating all infectious disease' could easily be criticized as unrealistic for endless reasons, yet it is very useful for orienting us to be scope sensitive, think in terms of hits-based reasoning and so on. Similarly, even having an 'N problems of aging' list to argue about is because someone did the work of trying to figure out what it would take at a multi-year research level. If we want to talk about neglected areas of funding, I think a great place to start is neglect for funding promising methods or directions that might plausibly generate new methods with less focus on what the particular outcomes might be. Or, to sort of paraphrase Hanson and Bostrom a bit: new considerations generally trump fine tuning of existing considerations.

What could we measure that would make seemingly intractable problems trivial? Can we take moonshots at those? And I'm not talking about actually funding the moonshot once the opportunity has been identified. I'm talking about the seed research to identify plausibility, funding small numbers of people at the 1 year level to do deep dives in much weirder areas than in house researchers have been doing.

comment by Florin · 2020-02-25T07:03:12.015Z · score: 2 (2 votes) · EA(p) · GW(p)

I'd like to point out a few things.

1) The key reason why SENS makes the most sense as a way to cure aging is that—as with any physical system—structure determines function; by repairing damage that accumulates in the body's molecular and cellular structures, the normal, disease-free functioning of the body should also be restored.

2) A more detailed version of the SENS roadmap is available at SENS' original website.

3) You've miscategorized some of the SRF's projects.

4) SENS and Hallmarks aren't as similar as they first appear. Sometimes, there's no overlap between SENS and Hallmarks. And unlike SENS, Hallmarks advocates lots of messing with metabolism.

5) Human Bio never took off and now Repair Biotechnologies has replaced it.

6) SRF publications are available here.

comment by Emanuele_Ascani · 2020-02-25T11:26:28.104Z · score: 1 (1 votes) · EA(p) · GW(p)

3) If you point out what categories I got wrong and why, I can correct if needed.

4) It seems to me that the biggest point of difference is the genomic instability hallmark, which is not present in SENS because de Grey believes it acts more slowly and probably belongs to a "SENS 2" panel of therapies. The others either mostly overlap or they are closely causally related. Do you agree?

comment by Florin · 2020-02-26T22:54:16.196Z · score: 1 (1 votes) · EA(p) · GW(p)

Well, it's complicated. Hallmarks is missing crosslinks, intracellular junk like lipofuscin and lipids like 7KC, and damaged elastin. SENS is partly missing genomic instability at least in SENS 1.0 (as you've mentioned), but it does include mitochondrial mutations which Hallmarks considers to be one aspect of genomic instability and mentions cancer as a consequence of nuclear mutations which are another aspect of genomic instability. SENS is also missing epigenetic alterations but might consider them for SENS 2.0. SENS doesn't consider telomere attrition as a significant type of damage, and in fact, SENS advocates removing the ability of all cells to extend their telomeres as a strategy to prevent cancer. Besides the differences regarding aging damage, the most crucial difference between SENS and Hallmarks is that most of the interventions that Hallmarks mentions won't help out that much in reaching LEV.

Now, it should be even easier to figure out how to correct those miscategorizations.

comment by Emanuele_Ascani · 2020-02-27T09:23:12.525Z · score: 1 (1 votes) · EA(p) · GW(p)
SENS doesn't consider telomere attrition as a significant type of damage, and in fact, SENS advocates removing the ability of all cells to extend their telomeres as a strategy to prevent cancer.

I think SENS doesn't consider telomere attrition because the solution would be the same as the one for cell loss (and telomere attrition is a direct cause of cell loss). Also note that at SRF they consider the strategy against cancer less and less likely to be necessary (and I hope so, since it is the most far fetched and difficult).

Edit: categorization mistakes corrected :)

comment by Florin · 2020-02-27T21:31:40.945Z · score: 1 (1 votes) · EA(p) · GW(p)

Besides the cancer thing, SENS ignores telomere attrition, because it's still unclear if telomere attrition is a significant cause of aging. And the likelihood that WILT will be needed is still above 50%.

The miscategorizations have only been partially corrected. 7-KC isn't related to Hallmarks, and the crosslink projects should be classified as "extracellular crosslinks" or "extracellular matrix stiffening."

comment by Emanuele_Ascani · 2020-02-28T13:34:38.277Z · score: 1 (1 votes) · EA(p) · GW(p)

Yep, seems like for some reason I, err... aggregated extracellular matrix stiffening and extracellular aggregates together. Mistake corrected.

comment by Florin · 2020-02-28T20:11:24.900Z · score: 1 (1 votes) · EA(p) · GW(p)

The proteins that the proteostasis hallmark talks about refers to proteins like beta-amyloid and tau that misfold and subsequently form aggregates. Proteins that are crosslinked aren't misfolded but rather they become "glued" together by a chemical reaction and don't form aggregates. 7-KC isn't a protein and doesn't misfold; it's an oxidized lipid.

comment by Emanuele_Ascani · 2020-02-28T20:53:11.142Z · score: 1 (1 votes) · EA(p) · GW(p)

Edited my comment slightly before yours appeared. Wanted to specify the reasons more but resolved to delete them since I was going to modify the post anyway. The rationale was that 7-KC, even if not a protein, is still an aggregate that overwhelms lysosomes and actively causes their dysfunction (loss of function of lysosomes and other degradation mechanisms being accounted for in the loss of proteostasis paragraphs in the Hallmarks).

comment by Florin · 2020-02-28T23:43:35.805Z · score: 1 (1 votes) · EA(p) · GW(p)

If you still feel unsure about the 7-KC thing, the following reasons should put your doubts to rest:

1) Although 7-KC accumulates, it doesn't aggregate.

2) If Hallmarks really thought that lipid accumulation belonged to the proteostasis hallmark it would have said so.

3) Hallmarks completely ignores 7-KC as a causative factor of atherosclerosis and instead ties atherosclerosis to "uncontrolled cellular overgrowth or hyperactivity" which is nonSENSical.