Why SENS makes sense

post by emanuele ascani (emanuele-ascani) · 2020-02-22T16:28:42.025Z · LW · GW · 2 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
2 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. 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 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.

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:

• Its tractability: It doesn't require in-depth knowledge of the processes that cause damage, and we already have therapies tackling every kind of damage (at least in vitro, but many in clinical trials).
• Aging reversal, which is SENS' best-case scenario. The other approaches' best-case scenarios are the treatment of symptoms or slowing aging down. Each one of the mentioned best scenarios has high probability and should be treated as the default given current scientific knowledge: the very strong evidence in animal models, especially mice, and aging’s theoretical understanding. The possibility of aging reversal makes the SENS approach lead to expected gains in QALYs that are much higher than other strategies, and it is the only result that would enable longevity escape velocity.

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:

• Aging is the biggest problem that present humans face (it's currently responsible for 2/3 of all deaths). This is the scope of the problem.
• Why the research line he follows is tractable, as opposed to the approach of traditional biogerontology and geriatric medicine.
• His kind of research is neglected. In introductory talks, he usually doesn't discuss this point at length, but there's a long section at the end of his book, Ending Aging, explaining why he thinks that certain strands of research perceived as high risk tend to be neglected because of incentives regarding publishing papers and funding policies. He makes the point that philanthropy is the best (perhaps the only) way to solve this chronic neglectedness, which would greatly accelerate some of the most vital areas of aging research.

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:

• Focusing on LEV, thus maximizing impact.
• Focusing on tractability and neglectedness when choosing the general research strategy, and then preferring difficulty, which drives neglectedness, when choosing specific things to finance inside the general strategy. (Read my previous post [EA · GW] on how to evaluate neglectedness and tractability of aging research for more about this.)

Funding gap and counterfactual impact

In the last few years, SRF's annual spending has been 3-5 million dollars. This pagecontains 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 Leafscience.org, 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.

• MitoSENS: Intramural research aimed at solving mitochondrial dysfunction by expressing mitochondrial genes from the cell's nucleus, where they are much more protected than inside the mitochondrion. For now, the group has achieved stable nuclear expression of ATP8 and ATP6 encoding genes in cells from a human patient with a single point mutation in the overlap region between the two mitochondrial genes. ATP8 and ATP6 are two out of thirteen mitochondrial proteins. This solved the problems caused by the mutation, demonstrating that the approach works. MitoSENS is a hard and long term project that would probably solve this hallmark of aging entirely. It necessitates better delivery methods of gene therapies to be brought in mice and in humans, which are also being researched by SRF funded groups: see the Maximally Modifiable Mouse project described below. [SENS strand: mitochondrial dysfunction. Hallmark: genomic instability/mitochondrial dysfunction. Identified as necessary and neglected].
• Maximally Modifiable Mouse: Extramural research at Stanford gene therapy spinoff Applied StemCell (ASC). This project has the objective of overcoming the difficulty of in vivo gene therapies in mammals when integrase is used, which is a gene insertion system used by phages. "Bxb1 [the integrase] catalyzes precisely-targeted, one-way insertion of even very large genes into the host genome. Unfortunately, mammals lack the genetic “docking sites” that this integrase targets. SENS Research Foundation has been funding Stanford gene therapy spinoff Applied StemCell (ASC) to create a line of Maximally-Modifiable Mice (MMM). The MMM will have two of the needed docking sites engineered directly into their genomes, which will then be ready for the insertion of new therapeutic transgenes at any time during the lifespan." This will "enable the development of models of diseases of aging and the rapid testing and eventual human delivery of rejuvenation biotechnologies". SENS plans to use this technology "to both develop better models in which to test the allotopically-expressed mitochondrial genes that our in-house Mito team has been testing in cells, and to deliver those genes and actually test them in such mice." [Type of research: delivery methods. Identified as necessary and potentially neglected. SENS strand: mitochondrial dysfunction. Hallmark: genomic instability/mitochondrial dysfunction. Identified as necessary and neglected]
• A Small Molecule Approach to Removal of Toxic Oxysterols as a Treatment For Atherosclerosis (spun off into Underdog Pharmaceuticals in November 2019): Intramural research, led by Matthew O' Connor, to Identify and test molecules for selectively removing toxic forms of cholesterol from early foam cells as a therapy for reversing atherosclerosis."Atherosclerotic lesions form when immune cells called macrophages take in 7-ketocholesterol (7-KC) and other damaged cholesterol byproducts in an effort to protect the arterial wall from their toxicity, only to ultimately fall prey to that same toxicity themselves. These macrophages – now dysfunctional “foam cells” – become immobilized in the arterial wall and spew off inflammatory molecules that in turn promote advanced atherosclerosis, heart attack, and stroke." A patent application for a lead compound and others to be derived from it has been submitted. "The team is now working to refine their original assay with the expectation that it will more accurately reflect the desired activity on toxic and native cholesterol, and also on an entirely different chemical approach to improved molecules derived from the original family. We are also working with a potential contract laboratory to test the absorption, circulation to tissues, and disposal of our lead candidate, and to perform toxicity assays". [SENS strand: intracellular waste products. Identified as necessary and neglected].
• Glucosepane Crosslinks and Undoing Age-Related Tissue Damage: Extramural research at Yale University, with David Spiegel as principal investigator. A seed round has been completed to fund a spin-off company from this project: Revel Pharmaceuticals. Glucosepane is thought to be the most abundant form of Advanced Glycation End-product (AGE) crosslink. AGEs are responsible for tissue stiffening, and cleaving glucosepane would restore elasticity to blood vessels and prevent the effects of their age-related stiffening. The Yale group has been financed by SRF for many years, and their first milestone was achieved in 2015: the first complete synthesis of glucosepane (here is the paper published in Science). In 2018, they were able to scale up their method to produce glucosepane in quantities useful for industrial production and synthesize three variants of glucosepane that may occur in vivo. They are now working on two more such variants. "They have also used their synthetic glucosepane to develop glucosepane-targeting antibodies capable of labeling glucosepane in aging tissues, which they are now working up into a monoclonal antibody for mass production that will be compatible with human metabolism and will allow researchers to track the effects of potential glucosepane-cleaving drugs. Finally, and most excitingly, they have now identified a lead candidate glucosepane-cleaving biocatalyst, and completed the evaluation of seven significant variants and their AGE-breaking mechanism. Today, work continues on synthesizing pentosinane (another common AGE crosslink) and additionally on the AGE-related compounds iso-imidazole and 2-aminoimidazole." [SENS Strand: extracellular matrix stiffening. Identified as necessary and neglected]
• Target Prioritization of Tissue Crosslinking: Extramural research at the Babraham Institute, partner of the University of Cambridge. "It’s not obvious that the sheer number of crosslinks of a given kind is a good measure of how high a priority it is for rejuvenation biotechnology: some crosslinks may have a disproportionate effect on tissue elasticity depending on where they occur in the protein strand, how tightly they bind, and how much they interfere with the body’s ability to break down and renew the tissue. [...] SRF is funding a systematic study of this question in the tissues of “normally”-aging, nondiabetic mice [...] Drilling down into these issues will be critical to identifying the next targets as glucosepane crosslink-breakers enter into animal testing." [Type of research: basic/understanding to aid translational research. SENS strand: extracellular matrix stiffening. Identified as necessary and neglected]
• Remediation of Aberrant Intracellular Tau: Extramural research at the Buck Institute. "Aging brains accumulate aggregates composed of aberrant forms of the protein tau, both inside and outside of neurons [...] Dr. Andersen’s team is being funded by SRF to test the idea that this tau accumulation may result from age-related dysfunction of the cellular "recycling centers” (lysosomes) due to the buildup of other kinds of intracellular aggregates, such as beta-amyloid, the other major damaged protein characteristic of the AD brain. [...] Neurons of patients with AD and other neurodegenerative aging diseases are often full of autophagosomes (APGs), the vesicles that form around targets for autophagy and in which they are dragged to the lysosome for degradation. This buildup is thought to result from a failure of lysosomal function, as the already-overburdened organelle refuses to take up any more cargo. The Andersen lab has developed lines of human and rat neuronal cells that produce APGs with molecular tags that allow them to track the production and disappearance of APGs in neurons. They can use these tags to screen for compounds that increase the successful trafficking of APGs and their cargo to the lysosome. Compounds that pass this preliminary test will then be evaluated in neurons treated with small, soluble beta-amyloid aggregates, to see if these compounds will prevent or reverse the formation of insoluble aggregates of both beta-amyloid and tau." [SENS Strand: intracellular/extracellular waste products. Hallmark: loss of proteostasis. Identified as necessary and neglected]
• Functional Neuron Replacement to Rejuvenate the Neocortex: Extramural research in the Albert Einstein College of Medicine, with Dr. Jean Hébert as principal investigator, to test a method for replacement of neurons in the neocortex to achieve its rejuvenation. "Of all the challenges in cell therapy, replacement of neurons in the neocortex is both the most important (the brain being the seat of consciousness and identity) and perhaps the most formidable." [Type of research: delivery methods. SENS strand/hallmark: stem cell exhaustion. Identified as necessary.]
• Enhancing Innate Immune Surveillance of Senescent Cells: An intramural and extramural collaboration project with Dr. Judith Campisi's lab at the Buck Institute seeking to answer the question of why senescent cells accumulate with age and what might we do to enhance immune surveillance to eliminate them. "When normal cells lose their ability to replicate, they become senescent cells. Over time, senescent cells accumulate in aging tissues, spewing off a cocktail of inflammatory and growth factors, as well as enzymes that break down surrounding tissue (the “senescence-associated secretory phenotype” (SASP)). The charge sheet against senescent cells has now expanded into a remarkable litany of the diseases of aging." [Type of research: basic understanding and translational. SENS strand: death-resistant cells. Hallmark: cellular senescence. Identified as necessary.]
• Identification and Targeting of Noncanonical Death Resistant Cells: An Intramural research project aimed at testing the hypothesis that "secondary senescent cells are different from primary senescent cells and would therefore need a different set of senolytics to eradicate. In addition, the project will study the role of the different SASP components involved in the spreading of senescence, and test the hypothesis that intervening in SASP signaling could be therapeutically viable." What are SASP: "Throughout the aging process senescent cells accumulate and secrete a characteristic set of proteins, called a senescence-associated secretory phenotype (SASP). Although SASPs act as tumor suppressors and recruit immune cells to repair damage, they also mediate the deleterious effects of senescence to cause different pathologies, such as cancer, neurodegenerative diseases and diabetes. Furthermore, SASPs induce senescence in the surrounding cells (secondary senescence), which aggravates the effect." [Type of research: basic understanding and translational. SENS strand: death-resistant cells. Hallmark: cellular senescence. Identified as necessary.]

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 hallmark. 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 leafscience.org, 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:

• Alexandra Stolzing. Google Scholar citations: 4,693. She became the new vice president of research when Matthew O' Connor co-founded Underdog Pharmaceuticals, which spun off from the project he led at SRF.
• Amit Sharma. Google Scholar citations: 1,084. Projects: principal investigator in the intramural research project regarding enhancing innate immune surveillance of senescent cells.

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

• Judith Campisi. Citations: 64,262. Project: Enhancing Innate Immune Surveillance of Senescent Cells Institution: Buck Institute for Research on Aging. More on her here.
• Julie Andersen. Citations: 12,159. Project: Remediation of Aberrant Intracellular Tau. institution: Buck Institute for Research on Aging.
• Jean M. Hebert. Citations: 4,456. Project: Functional Neuron Replacement to Rejuvenate the Neocortex. Institution: Albert Einstein College of Medicine.
• David Spiegel. Citations: 1,278. Project: Glucosepane Crosslinks and Undoing Age-Related Tissue Damage. Institution: Yale University.

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:

• How do you choose the staff to hire for intramural research projects?
• How do you choose what intramural research to do or extramural research to finance?
• To what extent does your funding overlap with (i.e., fund the same organizations as) government funding? Private-sector funding?
• How do SRF projects differ from what is currently done at NIA?
• What portion of your organization's expenses are devoted to funding research as opposed to other activities? What are the other activities?
• How important do you think the education programs are compared to research? Have they brought any noticeable benefit (good researchers that you hired, researchers who founded companies, made discoveries…)?
• What is your biggest achievement obtained with intramural research? What is the best project you financed extramurally? What makes these the greatest?
• What are the biggest research contributions that SRF spin-off companies have made?
• In many interviews, you stated what you would use at least ten times your current spending. How would you use it, and what research projects would you finance? Would you put all of it in research, or would you also scale up education and advocacy?
• How likely do you think it is that someone will close your funding gap in 2 years? 5 years? 10 years? Why?
• Have you been overconfident/underconfident about the pace of the research you funded in the past? Have you been overconfident/underconfident about how much funding you would have received? If the answer is "yes" to both, were these failed predictions dependent on each other?
• In many past interviews (examples here and here), you state that with around ten times your current spending, you would go 2-3 times faster. What is the reasoning behind this prediction?
• In one interview with LEAF, you state that 1 billion donated to SENS would bring longevity escape velocity nearer by 10 years and save approximately 400M lives. This means that one (more than 1000 years long) life would be saved with $2.50. What are the details of the reasoning that made you arrive at the "10 years" figure?
• One thing that would bring down the impact of aging research, in terms of how many years it brings LEV closer by, is if better technologies (enabling a much faster pace of research) come along and reduce the use of our "foresight" in prioritizing the most difficult projects. How likely is this to happen?
• Is it possible that solving one aging damage would completely solve another one? How likely is this? If yes, how does this impact your reasoning on what to finance?
• How likely is it that the SENS approach, before coming to fruition, will be rendered useless by a single general solution that has nothing to do with SENS? Is this kind of thing even on the horizon?
• How high do you think the probability of LEV happening at all is? How much is this probability improved by SRF?
• How much do you think that SRF's education, advocacy, and even research are improving the pace at which LEV will spread through the world population once it will be accessible?
• It seems to me that aging research might boost the effectiveness of many other altruistic interventions. For example: if you prevent a kid from dying from malaria, you might have enabled him to reach LEV. When do you think this effect is going to come into play? This certainly depends on how far we are from LEV.
• Other measures of impact for aging research are: end of life DALYs averted, impact on life satisfaction and "the longevity dividend": economic and societal benefits of improved healthspan. How much do you think SENS research is influencing these more "short term" measures?
• When discussing the impact of aging research, the focus is usually on humans, and animals are almost always overlooked. How large do you think would be the impact of SENS research on non-human animals (example: pets)?
• Are there any research projects that you had to shut down due to a lack of funding? Would you restart them if you could?
• What would things look like if those projects had been actually put forward?
• What would things look like if you have had all the money you needed from the beginning?
• Do you have reports that provide your organization's track record of producing concrete output from your research - for example, analysis of patents, publications, or citations that came from your research?

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:

• What are the most neglected areas in aging research?
• What are the most promising unfunded projects in the field?
• How likely is it that general-application tools and basic research areas that might not be thought of as part of “aging research” (analogous to epigenetics, stem cells, neuroscience, and drug delivery) will be bottlenecks to accomplishing the core objectives of translational aging research?
• What tools and/or research directions under these headings are most neglected relative to their promise, for the purpose of addressing these bottlenecks?
• Would interventions focused on these more basic/general themes have greater or smaller effects on the time by which such objectives might be achieved?

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.

-----------------------------------------------------------------

Crossposted from the EA Forum [EA · GW]

2 comments

Comments sorted by top scores.