Why SENS makes sense

by Emanuele_Ascani30 min read22nd Feb 202051 comments

42

Life ExtensionAnti-aging research
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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 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). 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, 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:

  • 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, 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 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 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. 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 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 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 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 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:

  • 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.

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Crossposted to LessWrong

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(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.

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.

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.

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.

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.

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.

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.

Looking for the transaction on the Ethereum blockchain associated with Vitalik's $2.4M SENS donation (if there is one). Can anyone link to it?

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.

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.

This is a great overview post of SENS, and I've read a lot

FWIW, both SENS and Hallmarks neglect the mentioning of A LOT of other kinds of damage but which are mentioned in Jan Vijg's book (eg genetic mosaicism, improper stoichiometric ratio of synthesized proteins, histone loss, proteins and DNA not being localized in places they should be localized, accumulation of extracellular metabolites that get trapped in the cell and don't get extruded out). SENS has many of the right high-level initial ideas regarding how to repair damage (it helps train people WHAT to look for regarding damage), but there are many more types of damage than what people have originally mapped (eg protein carbamylation, aspartic acid racemization, changes in membrane unsaturation index).

There's far too little discussion on bowhead whales - the warm-blooded organism that can live 200+ years. We know that living for 200+ years is organically possible in a warm-blooded organism, so we should figure out why. Some of the researchers who are most bullish on our ability to achieve LEV within 100 years come from the field of ecology/comparative metabolomics (eg Steve Austad, Michael Rose of UCI), precisely because they've seen the intense variation in longevity seen in different organisms [and this provides us with much more diverse insight than ].

 SOME researchers have considered CRISPR'ing bowhead whale ERCC1/DNA repair genes into human tissue. 

There can be more discussion of novel techniques in bioengineering that haven't received as much coverage (eg exosomes - which can be used to transport waste material into the cell and out of the cell), immunotherapies (cells can export SOME "junk" to be degraded/processed by immune cells like macrophages), T-cell transfer of telomeres (and presumably other things)

There should be more discussion on improving the general "efficiency" of biomedical science research (eg increased automation), many which will make "boring" bioscience research occur faster (and also, ideally, not have most of their details get lost). Aging demands different/unconventional techniques in research dissemination where one's precious research is interoperable with the research of everyone else and where intermediary work you do isn't lost (eg there is A LOT of data that's lost even with the publication of a journal article). FWIW, since aging is so different from other areas of biomedicine (and ideally should also be funded differently from all the other areas), it should respond to different incentive structures that aren't seen in other biomedical fields. Also, from the POV of many people (esp billionaires and their family), it is in their rational self-interest to donate a significant fraction of their funds into fulfilling Pascal's Wager - putting in millions of your dollars into tractable biomedical research per year is the only way to plausibly improve your "life satisfaction" once you realize that they have far more money than they have time available, and there are a huge number of understudied areas that deserve more basic research. I know juvenescence recently did a poll showing how many "rich people" would be willing to invest, say, 10% of their net income per year into living an extra 10-20 years if they were convinced that the extra money would help (this is kind of tantamount to Jim Mellon's thesis). 

[longevity research is also one of the only feasible ways of getting many billionaires, especially the ones who are more self-interested, to donate more of their money to any cause]

They also don't discuss the most obvious solution - gradual replacement (or transplantation) of all aged organs with new lab-grown or artificially produced organs. Growing new organs is a tractable problem that may be solved within a few decades - if this happens - the only thing left is repairing damage to the brain/head, and methods of neuronal replacement (eg what Jean Hebert discusses in his latest book), as already practiced in Parkinson's patients, could be the most promising. It may also be possible that a human might be able to experience at least a few more decades if given a proper body transplant (eg reductions in GFR, or gradual kidney failure, that reduce the rate of "waste clearance", causing waste accumulation to further accelerate.)

You should follow Jose Luis Ricon btw - he thinks that the issue is an engineering challenge and is solveable, and he is even collaborating with Adam Marblestone on that front. 

FWIW, both SENS and Hallmarks neglect the mentioning of A LOT of other kinds of damage but which are mentioned in Jan Vijg's book (eg genetic mosaicism, improper stoichiometric ratio of synthesized proteins, histone loss, proteins and DNA not being localized in places they should be localized, accumulation of extracellular metabolites that get trapped in the cell and don't get extruded out). SENS has many of the right high-level initial ideas regarding how to repair damage (it helps train people WHAT to look for regarding damage), but there are many more types of damage than what people have originally mapped (eg protein carbamylation, aspartic acid racemization, changes in membrane unsaturation index).

One has have to be careful about distinguishing between categories of damage and specific damage and whether what seems to be damage is associated with pathology or not. For instance, genetic mosaicism would belong in SENS' "mutations in the nucleus" damage category. But there's still some controversy about whether genetic mosaicism really leads to any age-related disease or condition, and that's why SENS doesn't target that particular form of damage yet. DNA damage in the nucleus can cause cancer and cell senescence and is targeted by OncoSENS and ApoptoSENS respectively. Bad stuff that accumulates inside cells would fall under SENS' "intracellular aggregates" damage category, but if the stuff is inert or accumulates too slowly, it can be safely ignored. Protein carbamylation may accumulate too slowly to matter (since it's excreted to some extent), but this isn't well established. Aspartate racemisation was also thought to accumulate too slowly to matter, but recent evidence suggests that it might need to be a SENS target. I doubt membrane unsaturation should be a target, but I'll look into it.

It's unfortunate that a comprehensive and continually-updated list of specific SENS damage targets doesn't exist anywhere. For instance, SENS doesn't refer to asparagine isomerisation or medin amyloid accumulation as damage targets, but they are. I've wanted to create such a list for awhile, but I don't know if I'll find the time to make one.

There's far too little discussion on bowhead whales - the warm-blooded organism that can live 200+ years. We know that living for 200+ years is organically possible in a warm-blooded organism, so we should figure out why. Some of the researchers who are most bullish on our ability to achieve LEV within 100 years come from the field of ecology/comparative metabolomics (eg Steve Austad, Michael Rose of UCI), precisely because they've seen the intense variation in longevity seen in different organisms.

SOME researchers have considered CRISPR'ing bowhead whale ERCC1/DNA repair genes into human tissue.

There's probably not that much that can be learned from ageless animals and that can also be applied to humans. Whales are huge and have slower metabolism than humans; that's probably why they live so long. So, slowing metabolism in humans won't work.

There can be more discussion of novel techniques in bioengineering that haven't received as much coverage (eg exosomes - which can be used to transport waste material into the cell and out of the cell), immunotherapies (cells can export SOME "junk" to be degraded/processed by immune cells like macrophages)

As long as those novel techniques don't mess with metabolism, SENS could certainly make use of them. For instance, immunotherapy might be repurposed to eliminate senescent cells. However, I suspect that exosomes probably can't be made to target specific junk or transport the junk where it can be safely eliminated.

There should be more discussion on improving the general "efficiency" of biomedical science research (eg increased automation), many which will make "boring" bioscience research occur faster (and also, ideally, not have most of their details get lost). Aging demands different/unconventional techniques in research dissemination where one's precious research is interoperable with the research of everyone else and where intermediary work you do isn't lost (eg there is A LOT of data that's lost even with the publication of a journal article). FWIW, since aging is so different from other areas of biomedicine (and ideally should also be funded differently from all the other areas), it should respond to different incentive structures that aren't seen in other biomedical fields.

Efficiency is outside the scope of SENS, but I agree that it makes sense to try to find ways of significantly speeding up more efficacious biomedical research by increasing outside-the-box thinking. And that's why I sort of re-invented the idea of creating a DARPA-like agency for medicine to do just that, a few years ago. Something similar was proposed two decades ago by Lou Weisbach and Richard Boxer and was unsuccessfully championed by politicians such as Joe Lieberman. The 21st Century Cures Act and the NIH also fund high-risk, high-reward biomedical research, but the specific criteria for selecting which research projects get funded is kind of vague.

Also, from the POV of many people (esp billionaires and their family), it is in their rational self-interest to donate a significant fraction of their funds into fulfilling Pascal's Wager - putting in millions of your dollars into tractable biomedical research per year is the only way to plausibly improve your "life satisfaction" once you realize that they have far more money than they have time available, and there are a huge number of understudied areas that deserve more basic research. I know juvenescence recently did a poll showing how many "rich people" would be willing to invest, say, 10% of their net income per year into living an extra 10-20 years if they were convinced that the extra money would help (this is kind of tantamount to Jim Mellon's thesis).

Except for a few high-networth individuals like the Google bros (Calico), Larry Ellison (Ellison Medical Foundation), Jeff Bezos (Unity), and a few others, most HNWIs aren't convinced that any amount of money would help or that it's even a good idea (Bill Gates, Elon Musk).

They also don't discuss the most obvious solution - gradual replacement (or transplantation) of all aged organs with new lab-grown or artificially produced organs. Growing new organs is a tractable problem that may be solved within a few decades - if this happens - the only thing left is repairing damage to the brain/head, and methods of neuronal replacement (eg what Jean Hebert discusses in his latest book), as already practiced in Parkinson's patients, could be the most promising. It may also be possible that a human might be able to experience at least a few more decades if given a proper body transplant (eg reductions in GFR, or gradual kidney failure, that reduce the rate of "waste clearance", causing waste accumulation to further accelerate.)

[also, the faster we can develop/grow replacement organs, the less suffering people get from chronic diseases = the slower rates at which they age]. I'm really surprised Aubrey de Gray hasn't discussed this yet given its tractability.

Gradual neuronal replacement, by itself, would take too long to repair the brain; you'd still need SENS to repair the brain, and if you use SENS on the brain, you might as well use SENS on the rest of the body and avoid organ replacement altogether.

You should follow Jose Luis Ricon btw - he thinks that the issue is an engineering challenge and is solveable, and he is even collaborating with Adam Marblestone on that front.

While digital technology like mind uploading (if that's what you're referring to) should be pursued, biomedical methods to achieve immortality like SENS have a higher likelihood of succeeding, because it may turn out that consciousness is not substrate independent, and mind uploading is probably harder to achieve than SENS.

The question of substrate independence can be sidestepped by an approach that's a hybrid of tissue engineering, digital technology, and nanotech: grow a new body without a brain, copy the old brain's connectome, and nanotech the old brain's connectome inside the new body's skull (or grow it outside and insert it later). Unfortunately, this is probably a lot harder to achieve than even mind uploading.

#ALLTIMEIMPORTANTTHREADS #IMPORTANTTHREADS #INFLECTIONPOINTS #ALLTIMEMOSTIMPORTANTPOSTS #YOUWILLREGRETNOTINCORPORATINGMOREOFTHIS #ALLTIMEFAVORITEANSWERSOFAKC

But there's still some controversy about whether genetic mosaicism really leads to any age-related disease or condition, and that's why SENS doesn't target that particular form of damage yet. DNA damage in the nucleus can cause cancer and cell senescence and is targeted by OncoSENS and ApoptoSENS respectively

 

https://www.nature.com/articles/s42255-020-00304-4

Genetic mosaicism, in itself, isn't necessarily sensed by the cell as damage. It can be DNA damage that has been corrected, albeit corrected to a form different than the form it was originally in). 

https://www.google.com/books/edition/Aging_of_the_Genome/BIQSDAAAQBAJ?hl=en&gbpv=1&dq=jan+vijg+aging+of+the+genome+mosaicism&pg=PA201&printsec=frontcover

If a significant part of the adverse effects associated with aging is the consequence of random alterations in the information content of the genome, corrective intervention would be impossible, or at the very least subject to enormous complications. In contrast to chemical or cellular damage, which share the basic features suitable for therapeutic targeting, random genome alteration creates (epi)genetically different cells, a situation that cannot be easily reversed. In the absence of turnover from an immutable template, altered genomes can also not be liquidated as in protein repair. Hence, every individual cell would now be genetically different and would need individual ‘treatment’ to correct its mutation load. In principle, such correction would be very similar to current attempts at gene therapy: through the use of vectors transferring the correct piece of DNA sequence into the sick cell to replace the mutated fragment. Editing genes to correct defects has made great strides, but it is unlikely that we will ever be able to correct the collection of random mutations in our genome that result from natural wear and tear. Indeed, it is entirely reasonable to assume that stochastic alterations in the information content of the genome are essentially irreversible. If this proves to be the main underlying cause of aging SENS would have a problem because its strategy ignores the need to correct genomic errors as a potential source of cellular malfunction.

I would guess, that genetic mosaicism leads to a lack of intercellular coordination that manifests in reduced biological resilience/frailty (which can be measured by factors such as heart rate variability, neuroplasticity/learning speed, wound recovery rate, reductions in grip strength/general weakness, or dynamic morbidity index - you need all the cell proteins to be positioned+posttranslationally modified at the right positions and amounts in order to correctly sense/signal, actuate and vary heart rate contractions). Cancer and cell senescence are much easier to detect/sense than other forms of age-related damage, but even if we removed ALL the leading causes of death (NONE of which C elegans die from), you still have the loss of biological resilience that causes ppl's respiratory capacity/FEV1/heart rate variability/grip strength to decrease with age that ultimately lead to weakness and death, like pharyngeal weakness found in  C elegans (we know impaired proteaostasis plays a major/primary part of that in C elegans).

Except for a few high-networth individuals like the Google bros (Calico), Larry Ellison (Ellison Medical Foundation), Jeff Bezos (Unity), and a few others, most HNWIs aren't convinced that any amount of money would help or that it's even a good idea (Bill Gates, Elon Musk).

Peter Nygard is another example (I KNOW he was talking to church lab people on this). You're only listing the most prominent individuals you know of (I know life extension is more popular among rich bay area people than is popularly discussed). I know that Ray Dalio was convinceable (his son often talked to Aubrey de Gray to work on biomedical initiatives right before his tragic car accident), and people in the area often talk to eccentric billionaires (Laura Deming mentioned this in one of her slides). Jim Mellon is another example and he talks about it in his presentation. Right now, most of them don't view it as a tractable problem, but [from what I read of a survey he distributed] it does appear that a significant fraction would be willing to spend a significant portion of their income [like at least 10%] for 10+ more years of healthy life (and we could devise a program where, for instance, money used for prolonging healthspan could also have a provision providing funding for basic SENS-ish research)

[you also forgot to mention Peter Diamandis and his gang].

They don't have to be convinced about immortality to really care about living longer for healthier. Leroy Hood (of Arivale) is now 82 and he definitely cares about being effective for longer [with personal health analytics - see https://www.genengnews.com/commentary/leroy-hood-reflections-on-a-legendary-career/ ], though I'm not sure if he is convinced by the potential of SENS. SENS got a bad rap early on [and a lot of older people have high skepticism of SENS precisely because its proponents made unfulfillable promises for much of their lifetimes, so they have a naturally skepticism base rate, one which younger people might not have, and one that convincing progress in the field might reverse, except that this convincing progress may still be dependent on general speedup of biotechnological tools that still might not fully manifest for another 10 years].

[with the super-successful people, the value prop SHOULD be easy - you WANT them to remain FUCKING AWESOME for another 10-20 years, which EVEN MATTERS for the deathists among them -  given how rare people like Musk and Bezos and Gates are, spending 30% of their net worth to stay healthy enough to be awesome for another 10-20 years [which obvs demands some level of anti-aging intervention/regenerative medicine] IS worth it [and may be SINGULARLY important for the future trajectory of humanity - esp b/c politics/western democracy has degenerated to the point where people are more likely to trust certain big business leaders than any other group of people, AND they have more ability/agility to shape its long-term trajectory than anyone else at the moment, even the  dictators that the deathists often worry about [1], whether or not they want to live forever, because you really can't replicate someone like Gates/Musk/Bezos/whatever]. 

[1] All the EAs worried about dictators living forever present it in theoretical terms rather than actually make a LIST of all the dictators that they ARE concerned about living forever, even though this IS a determinable problem because there aren't many. The only dictators who really matter for the long-future are the ones who control countries that are large enough to have outsized impact to matter, which constrains the list to leaders of large non-democracies, of which there are very few to begin with [just Putin or Xi or whoever their successors even are, and it's unclear if Putin/Xi even want to live forever or have the mental agility to tap into these resources - plus as we've seen with NK's Kim, their regimes are such that oppressiveness continues after the dictator's death, though this may cause Cuba to ultimately open up].  Certainly, there are more tech/business titans who care than there are dictators, and none of them individually has the power to do substantial amounts of damage to the world that I'm concerned about [esp since it's clear that oil companies are on their way down due to natural market forces]. There are so few dictators who seem to have the neuroplasticity to express the desire to even live forever (other than Qi Shi Huang Di, who lived so long ago)

===

All the points raised by SENS are a bare minimum overview of the challenges, and most of the suggested interventions only act on one small component of all forms of SENS (there are so many possible reactions where that different proteins/lipids/nucleotides/ribosomes/metabolites can get tangled with each other and form all sorts of weird reactions with each other. Just clearing glucosepane crosslinks isn't going to help with the numerous other crosslinks that form between proteins [ESPECIALLY structural ones like histones and lamin and cytoskeletal filaments]/DNA/ribosomes/nucleic acids/random metabolites - some which appears in the form of liposomes, and some which doesn't appear in the form).  

Incidentally, Denis Odinokov (WHO YOU TOTALLY SHOULD FRIEND ON FACEBOOK) posted about the potential effects of low levels of snake venom.

While digital technology like mind uploading (if that's what you're referring to) should be pursued, biomedical methods to achieve immortality like SENS have a higher likelihood of succeeding, because it may turn out that consciousness is not substrate independent, and mind uploading is probably harder to achieve than SENS.\

I'm definitely not referring to mind uploading or digital technologies here.

Gradual neuronal replacement, by itself, would take too long to repair the brain; you'd still need SENS to repair the brain, and if you use SENS on the brain, you might as well use SENS on the rest of the body and avoid organ replacement altogether.

If you read Jean Hebert (and also ppl in the Gage lab at Salk - ESP Dylan Reid), you'll see that people have already been starting to do gradual neuronal replacement on Parkinson's patients. We don't know if these are advanced enough to work yet [though Hebert seems optimistic], but if they can [and be guided in the right directions], then it might be able to do it. Given the sheer number of challenges that come with ALL forms of SENS, I'm not optimistic enough about SENS to be confident in its ability to reverse all the relevant aspects of damage in our lifetimes (because solving one issue means there will only be ANOTHER rate-determining step of aging). Increasing autophagy rates certainly seems to be one of the most robust ways to reduce the basal rate of aging, but errors do happen during autophagy and this eventually results in clogged lysosomes (or autophagosomes) that cause accumulation of lipofuscin/ceroids (and lipofuscin is not just one chemical modification - it is the accumulation of many chemical motifications [of which michael adducts/amordori rearrangements/inappropriately excessive alkylation or methylation are SOME but not all exhaustive cases], many which are difficult to recognize by any specific enzyme). 

I've wanted to create such a list for awhile, but I don't know if I'll find the time to make one.

We can collaborate. I know other people have made lists too, but none of them are organized in any database. Hell, I'm obsessed with aging beyond everything else and I want to spend my entire life working on it, but I often feel discouraged for various reasons (even though a basic list, in itself, can be helpful to everyone AND we have to do everything we can to make sure that people who contribute in any way they can don't get discouraged in making these lists - we have to make it collaborative in a way that doesn't discourage systematizers from making it). I have a wider "breadth" of knowledge than most (+taste + linguistic dexterity) and I'm not sure how many people would be able to make the ideal lists [I know John Furber made a HUGE list but he hasn't gotten deep into the chemical modifications involved]

[FWIW, I also know people in the area well enough to know that most of them are emotionally stunted on some level - especially the ones who blog and hang out in aging communities. YES, they are SO much more friendly and accessible than people in MOST other communities and I AM GRATEFUL to them for it, but they are still on the whole, emotionally stunted. 

And them being emotionally stunted is a big reason why they're not taken more seriously by other people and ALSO why they aren't able to win much public favor to their side even though if they get what they want, WE WOULD ALL EASILY BE BETTER OFF]. OH and if they WERE less emotionally stunted, they would be better able to emotionally support and validate others who simply DO A LOT to simply develop the narrative of the area better [hell, most people in aging are insufficiently attuned to the needs of training people from non-formalized backgrounds (eg they dont have enough curiosity about SENG], which also makes them emotionally stunted]. Hell, the very OP of this thread, Emanuele_Ascani, is socially isolated (growing up in Italy) and could use more emotional support/guidance, but I'm not sure if anyone I know in the ENTIRE field of aging has the emotional flexibility to advise Emanuele_Ascani on what his best options are next, even though he clearly has talent and taste and ability to make analytical outlines.

 I mean, they're all psychologically okay, but giving this sense of emotional support to people who have "weird backgrounds" but who still CAN shape thinking in a good way CAN do A LOT to increase the supply of people who want to do it, because something as "weird" as aging is going to take people with "weird/messy" [including BUT NOT RESTRIcTED TO autistic and ADHD] backgrounds to contribute to the dialogue and they probably need a lot more emotional support b/c they are often more easily discouraged and traumatized by mainstream socialization so ANYTHING that makes them feel UNSHAMED of it helps) [[2]]

"One reason they become the entrepreneurs they become is because they can't or don't or won't fit into the structures and routines of corporate life," she wrote. "They are dyslexic, they are autistic, they have ADD, they are square pegs in round holes, they piss people off, get into arguments, rock the boat, laugh in the face of paperwork."

even Laura Deming doesn't come off as visibly weird to people [that's why the mainstream is more willing to accept her now] but she was unschooled which made her unable to fit into the standard career track which caused her to drop out of MIT for a thiel fellowship, and yet here we are 10 years later and we STILL can find so few people who are like her? [though she seems to be getting Joanne Peng to now follow in her footsteps since Joanne is now a Thiel Fellow who declined Princeton to work directly with Laura AND she is getting the scientific background/training to help reshape the narrative for the future generation AND direct her own research program] - but still - there CAN be more people like this [ever notice how the most enlightened people are SUPER-interested in getting personal development RIGHT - like - they're the people who actually ASK you about your childhoods - I know Laura often does that to people and I know Nick Cammarata often mentions this on his twitter - DOING SCIENCE RIGHT AND FIXING AGING IS ALSO TANTAMOUNT TO NOT FUCKING UP CHILDHOOD DEVELOPMENT THE WAY SCHOOL DOES].

[also, the VERY ORIGINAL POSTER of this thread, Emanuele_Ascani [even though he is clearly very smart and talented+conscientiousness], comes from a "weird/unique" background that stems from being isolated in Italy and hasn't gotten the encouragement he has really needed, in part b/c people tend to be only used to helping those who "fit" within their original frameworks of who they can help]. He wants to work on the aging problem, and yet doesn't quite know how he can contribute, and if I sent his profile to aging researchers who I currently know (as is), most of them would be confused as to how they could help.

==

FWIW, there has to be A LOT done to make this research more accessible to people with "weird" backgrounds - A LOT of us in the field have "weird" backgrounds b/c we come from all sorts of different backgrounds (Hell, fightaging.org, josh mittledorf, and myself ALL were into astronomy before aging) before realizing that aging really is the ONLY thing that matters to the point that we really should just throw all other priorities away in order to focus on the area precisely because it's the only thing that matters. But the traditional way people in the area are trained certainly doesn't help encourage people with "weird backgrounds" to go into the area [especially because grad school tends to cause depression/trauma in ~50% of people who do end up going through the process - Ben Kuhn says it's worse to public health than STDs]. I know Jose Ricon and Laura Deming also have somewhat "weird backgrounds" too [Laura Deming even admitted on her blog that she was literally crying in undergrad every day before she dropped out - it was hinted that it was because the education system in undergrad really is incredibly dull - she also mentioned in an interview in palladium that she had to take several years to "unlearn" the damage that comes from all her training from biochemistry lab volunteering]. It took her a few years to be taken seriously by the biotech establishment despite her lack of a PhD (even though she had the support of the thiel fellowship AND people in the bay area who really wanted to believe in her), and ultimately she seemed to realize that her best efforts are done doing VC/strategy work (AND in SHAPING THE NARRATIVE) rather than pure research or technical work [of course we DO need people involved in these areas TOO]. 

[FWIW Laura Deming mentioned on twitter that she still recommends people major in math/CS/physics if anything, but she didn't mention that she was a physics major at MIT and that was probably what led her to "cry every day after class" when she was in school probably because the "education was so dull" as her father admitted somewhere - the thiel fellowship literally was the lifeline that saved her]. We DO need more math/physics/CS people in aging FOR SURE [it is MOST lacking in people who have hardcore physics/biophysics talent, and google search results for biophysics are utterly lacking and this is also why we don't have a systematized list of interventions for solving aging]

We have to recognize that there are SO SO SO many ways to make a difference/impact in aging that don't depend on traditional forms of PhD-based socialization (remember that Freeman Dyson called the entire PhD system an abomination - and note how ash jogalekar of curiouswavefunction often mentions how cargo cult science has made science incredibly dull [look at how journal articles are so dull now, and compare/contrast it with the playful unpublished scientific notebooks that scientists used to publish BEFORE science became so cargo cult in the 1950s - even Laura Deming often mentions that she LOVES reading isaac newton's and darwin's old notebooks]. And no one rewards those who read Newton or Darwin notebooks - they certainly don't help you with getting a 5 on an AP test or getting into a top college or grad school [at least in the ways people think that they help). 

And the thing I often notice with talking to people in established fields is that they often DO lack imagination of what's possible, and they seem to lack a certain kind of narrative imagination, and This is all the gist of Thomas Kuhn's Structure of Scientific Revolutions. Even Riva Melissa-Tez loves Feyerband, who comes as close to scientific/epistemiological anarchism as you can come to in anyone. The thing is, you have to be taken seriously in a way that inspires more people to want to be more like you in inspirational direction, and preferably in a way that makes you more accessible and humanizeable. The author of fightaging.org, for instance, is amazing in his level of monomaniacal devotion to the area, but his blog becomes a scalar quantity in output, rather than a qualitative vector (or tensor)-like quality in output. It is singularly important, but it is not going to (in itself) result in the radical change in transformational thinking that we NEED to fix the problem, especially because most people who read the blog don't even know who reason is, to the point that people don't feel inspired by reasons. Similarly, while Aubrey is doing important work in propagating the science, there are many scientists who don't take him seriously, to the point that some people I know think that he damages the field and its credibility (he also attracts a lot of pseuds). 

I think they seem more willing to give Laura Deming benefit of the doubt because she doesn't trigger their "low signal to noise" ratio detectors the way that Aubrey does, though even then, she is very sphinx-like in her thinking, which makes it very hard for her to scale up to the point that others would feel inspired by her. There are SO SO SO SO SO SO many people in the field of aging that many of them seem to turn into "replicas" of each other (you know, like how some people say that rationalists all seem to turn into replicas of each other, or Will Manidis mention on Twitter how hiring agencies on Twitter also seem to regard MIT students as replicas of each other). We need more people with relatively high S/N ratios who AREN'T replicas of each other and who can transform our thinking of aging into a form that literally FEELS (on a S1 LEVEL) tractable to everyone, b/c right now, so FEW people S1 feel that is a tractable thing to do (even all the current interventions suggested by SENS cover a small percent of ALL aging related damages even though we can probably INCREASE the number of possible interventions if we write out ALL the forms of aging damage + all the forms that biotech HAS been advancing) in a format that's MORE accessible/readable than yet another annoying journal article PDF because we are ALL force-fed more PDFs than we can deal with AND the amount of sensory contrast in PDFs [with each other] is SO low that they all blend in with each other in our sensory field, causing ALL of them to become indistinguishable with each other {AND basically lead to increases in knowledge that DON'T scale with the number of hours we put into understanding it all - that's why more INFORMAL STYLES and less "conforming to journal articles OR behavioral motifs" is NECESSARY in solving the issue because most people, ESPECIALLY including the hardcore academics who just end up posting MORE on their blogs, are basically forgettable - oh yeah one person I know simply said that most rationalists end up pattern-matching as people who just end up posting on blogs and doing nothing else }

BTW, ppl hate reading the formalisms/and rules of journal articles. Like what one of my scientist-trained friends has said here:

I don't need to sift through yet another bullshit article on aging

or for that matter, I don't want to fuckign read another bullshit journal article on anything but fucking god that's all I seem to find these days

[as you can notice, my post here is weirdly formatted, because FUCK FORMATTING. it only turns EVERYTHING into one homogeneous entity, and the less we have consistent formatting, the more distinct/memorable everything is]. ofc LIFE IS TOO SHORT FOR FUCKING FORMATTING [OR FORMALISMS - oh yeah DON'T YOU EVER NOTICE HOW THE "cool people" love michael faraday], and in the long run someone else (or AI) can format it for you if needed. FORCING FORMALISMS ON EVERYONE REDUCES CREATIVITY AND TURNS EVERYONE INTO CARBON COPIES OF EACH OTHER.

GIVEN THAT ANY OF CONTINUATION OF THE STATUS QUO (OR ANYTHING AT CURRENT RATES OF PROGRESS) GUARANTEES DEATH, WE HAVE TO BE OPEN TO THINGS THAT ARE RADICALLY DIFFERENT, AND YOU KNOW, SOME OF THOSE THINGS FEEL RADICALLY DIFFERENT AND ACTUALLY FUN AND NOT A WASTE OF LIFE LIKE PUBLISHING YET ANOHTER JOURNAL ARTICLE OR GETTING INTO ACADEMIA. [now hardcore biology research is not consistently fun and you have to instil a sense of discipline in people who really DO it [ and they DO produce valuable work, just not the radical paradigm-changing kind of work that qualitatively convinces people that a qualitative change to where they focus their output MATTERS], but it can be MUCH less dull than it is practiced right now - AS FREEMAN DYSON/LAURA/GAURAV ALL RECOGNIZE - oh btw gaurav LOVES the essay Why Modern Scientists are so Dull ], AND the training process for being taken seriously ALSO can be significantly less dull [Gaurav has mentioned how he often had conflicts with upper level supervisors and also didn't do well in HS because SO much of HS was pointless and how it had to take him various shenanigans to get into a PhD program - also notice how the MIT Media Lab at least tacitly encourages certain kinds of "disobedience" and takes pride in accepting some students who DON'T have a bachelor's degree]

There are people in biomedicine who DO have weird backgrounds and we SHOULD encourage more people who have weird backgrounds to go into it [it's easier when it doesn't require as many resources - access to resources is the thing that makes it easier for mathematicians to have weird backgrounds [or who don't have a huge amount of money] than it is for biologists]. 

I also think making experimentation MORE accessible [eg see dhash and keoni gandall] would make it easier for people to go in the area without as much wetlab experience [there is a lot in biomedical research that is drudgery that does discourage a lot of people who value their time from doing more wetlab research and if we have better biomedical automation it would make wetlab research take A LOT LESS out of people who do go in the area]. I know people in the broad institute, for instance, and while they are INCREDIBLY technically competent (and SO well-versed in all the new seq techniques - I also know it attracts some of the analytically most talented ppl in the nation, it takes SO much out of them that it seems that they lose sight of what the rest of the world is like - and this is what A LOT of biomedical experimentation does to people, and might perhaps be the reason why someone like Laura ISN'T doing wetlab biomedical research anymore)

FOR THE RECORD, there are SO SO SO many ways for people to contribute to the area even if they're cognitively "weird" or don't have a scientific background [because contributing to the field takes SO many multimodal talents that go beyond simple scientific expertise even though scientific progress STILL is the most important thing]. OTOH, people know that the field has lots of quacks and that the area doesn't have a high S/N ratio. 

There are A NUMBER of people on twitter who have mapped out ways that people have done drastic biotech interventions  (esp in the early days where we did things like head transplants or ) - we should do that more

Ok I distilled A LOT here and tbf I could distil more and am not doing it because I haven't had the type of emotional encouragement I wish I could always have had (even if the emotional encouragement can only come from outsiders/newer people because hey - anyone with a "weird background" often only gets that kind of emotional encouragement from outsiders, rather than insiders who are often only prepared to give these kinds of emotional encouragement to people who fit within their predefined notions of what works [though I KNOW FREEMAN DYSON might have been an exception - OFC he also OFTEN identified as a permanent outsider]). SARAH CONSTANTIN also DID NOT have that kind of emotional encouragement, and she STARTED longevity research institute, but sadly, it didn't go further, and I believe [after talking to her/knowing her] that her lack of emotional encouragement [esp earlier in life and grad school] definitely was a factor that prevented her from going further with it. 

[[2]] [also the bloggers on aging and the calorie-restricters on crsociety don't seem to be super-neuroplastic when it comes to adopting new frameworks of thinking - fightaging.org has pretty much stayed the same person/within the same framework for the last 10 years]. This is why if you want to access the best thinking, you want to look at other fields/frameworks and not stay within the aging-framework [notice how Laura Deming mentions on Twitter how she talks to scientists in OTHER fields rather than aging itself b/c that is where the insight is AND where you get access to other frameworks - she asks herself what NOT to read rather than what to read AND advises people to not pay too much attention to what's going on in current aging research [she recently said she took a liking to autophagy research] - this is the trap that the bloggers who blog about aging also fall into

Here's a thread I recently posted on fbook btw: https://www.facebook.com/simfish/posts/3741222205930450

I would guess, that genetic mosaicism leads to a lack of intercellular coordination that manifests in reduced biological resilience/frailty....

As I mentioned before, it's just a guess at this point whether or not genetic mosaicism is actually a problem that has to be dealt with right now, and that's why SENS isn't focused on it. If it becomes a problem hundreds of years from now as mutations accumulate, it'll probably be an easy bridge to cross.

They don't have to be convinced about immortality to really care about living longer for healthier....

Yeah, but the problem remains: they don't think SENS is likely to succeed at significantly improving health or don't have the expertise to evaluate it and the experts that they ask about it, tell them to just support non-SENS biomedical research instead.

...this convincing progress may still be dependent on general speedup of biotechnological tools that still might not fully manifest for another 10 years].

Actually, the most important limiting factor is the funding of the right research. There's just no way around that regardless of how good tools become.

If you read Jean Hebert (and also ppl in the Gage lab at Salk - ESP Dylan Reid), you'll see that people have already been starting to do gradual neuronal replacement on Parkinson's patients....

But we're talking about the entire brain here, not just the part that causes PD. If 1 cubic mm of brain tissue could be replaced every day, it would take about 3,561 years to replace all of it (the brain's volume is about 1,300,000 cubic mm).

...solving one issue means there will only be ANOTHER rate-determining step of aging....

Right, so we'll just have to whack ALL of the moles that matter in a normal lifespan, and monitor old-but-rejuvenated primates and people to see if and when any new moles (like genetic mosaicism) popup later.

We can collaborate....

If you have have a good understanding of SENS, you (and anyone else reading this) could search for active SENS-focused research projects in medical research databases and notify the SENS Research Foundation about them. This can help the SRF prioritize what research it funds and collaborate with projects funded by other organizations. This strategy is low-cost, high-impact, and I know it works well.

...(even all the current interventions suggested by SENS cover a small percent of ALL aging related damages....

If you know of any damage that's not covered by SENS, let me know.

Also, it turns out that membrane unsaturation doesn't need to be targeted.

...we can probably INCREASE the number of possible interventions if we write out ALL the forms of aging damage + all the forms that biotech HAS been advancing) in a format that's MORE accessible/readable than yet another annoying journal article PDF because we are ALL force-fed more PDFs than we can deal with AND the amount of sensory contrast in PDFs [with each other] is SO low that they all blend in with each other in our sensory field, causing ALL of them to become indistinguishable with each other....

There are lists that track progress in the development of interventions (like LEAF's Rejuvenation Roadmap), but unfortunately, they're not comprehensive or SENS-focused. Along with that comprehensive damage list, I also wanted to create a comprehensive SENS project/intervention/company list, but the time thing got in the way.

...if you want to access the best thinking, you want to look at other fields/frameworks and not stay within the aging-framework....

I don't see how a "better" framework than the repair-the-damage-without-messing-with-metabolism kind can exist. If anything will work at curing aging, it has to be damage repair almost by definition; it's the whole structure-determines-function thing I mentioned earlier.

Actually, the most important limiting factor is the funding of the right research. There's just no way around that regardless of how good tools become.

Lol, everyone in the SENS program tells people"GIVE US MORE MONEY AND MAGICAL THINGS WILL HAPPEN", but like, this seems to make other people feel like they can't contribute to changing the mission of SENS, given that it seems to delegate all control to whoever controls SENS. I know SENS creates mission reports and such, but so far they still haven't been great at convincing most HNWIs that SENS has made any real progress in the last 10-15 years. Funding may be necessary for progress and the chance to make a dent is probably worth it, but it's still not convincing enough for most people. 

There are far more ways to make an impact on aging than just donating more to SENS, and like, most of the anti-aging money seems to be flowing into ventures other than SENS (though expanding the number of possible routes people can take to slow aging rate is always helpful, even if it means doing silly N=1 things like injecting stem cells into one's own body)

Is Balaji sufficiently convinced enough to donate a good fraction of his networth into SENS in the same way that Vitalik is convinced?

But we're talking about the entire brain here, not just the part that causes PD. If 1 cubic mm of brain tissue could be replaced every day, it would take about 3,561 years to replace all of it (the brain's volume is about 1,300,000 cubic mm).

You created a good example.. Regeneration/rejuvenation should ideally be guided by natural progenitor cells that don't require surgical precision. I agree we should still emphasize SENS-ish issues of removing protein aggregates (both intracellular and extracellular) in the brain. 

https://www.ted.com/talks/jocelyne_bloch_the_brain_may_be_able_to_repair_itself_with_help/transcript?utm_content=2021-1-18&utm_source=facebook.com&utm_medium=social&utm_campaign=social&fbclid=IwAR1IwHG5Wyp7KN6CKi0_IpeYPxPJ7B70kMBD8KNvkAlfpIxQfuBoLJng_OE

I don't see how a "better" framework than the repair-the-damage-without-messing-with-metabolism kind can exist. If anything will work at curing aging, it has to be damage repair almost by definition; it's the whole structure-determines-function thing I mentioned earlier.

I mentioned bowhead whales earlier, and while it may be true that they have slower metabolism, their longevities are still relevant in the same way that the longevities of birds (esp kakapo, sulfur-crested cockatoos, hyacinth macaws, and andean condors) are relevant - the birds are most relevant b/c they have faster metabolisms than humans (we know at least that they're better at quenching mitochondrial ROS). We've already done A LOT to investigate the uniquely peculiar biology of naked mole rats to figure out how they are so resistant to cancer and oxidative stress (and they ARE important) [and we have papers on how their SIRT6 is different], but they ultimately age faster than humans especially b/c they still have much shorter lifespans than people and accumulate aggregated proteins at faster rates.

Many animals that have more saturated cellular membranes (high SFA to MUFA/PUFA ratio) are also more resistant to ROS and have higher longevities (though I saw a paper saying that higher levels of MUFAs are helpful)

[and with bowhead whales, it's still important for us to know WHAT their native DNA damage and endogenous antioxidant levels are]

I don't think we should entirely discount messing with metabolism either - hibernation induced by hydrogen sulfide might be an alternative to cryonics (aging rates do slow down during hibernation, and NASA is certainly studying induced hibernation responses in people)

Also, it turns out that membrane unsaturation doesn't need to be targeted.

Membrane unsaturation was a weak example, I was more looking at the example of damage to cell membranes (both in their proteins and in the molecules that compose cellular membranes). Cell membranes often "stiffen" over time.

If you know of any damage that's not covered by SENS, let me know.

Sure, what's your email?

Protein traffic jams (https://www.sciencemag.org/news/2019/01/halt-brain-diseases-drugs-take-aim-protein-traffic-jams-kill-neurons ) isn't mentioned by SENS and can occur even w/o protein aggregates or lipofuscin (though these def crowd out the cell and help) - it's the same as basic protein damage to extremely long-lived proteins like nuclear pore complexes.

Bejarano E, Murray J, Wang X, Pampliega, O, Yin D, Patel B, Yuste A, Wolkoff A, Cuervo AM. Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging. Aging Cell doi: 10.1111/acel.12777, 2018

What of mitochondrial transfer (https://twitter.com/Mito_News/status/1255968938648887297 + https://twitter.com/attilacsordas/status/1016775313152528386 ) as an alternative to mitoSENS? It certainly seems more feasible.

Does a model like https://twitter.com/z_chiang/status/1350933491274412032 count under SENS? I know people like George Church and David Sinclair are excited about IPSCs and epigenetic/genetic reprogramming, but having read SENS first, I've always been skeptical of the ability of reprogramming to clear out existing forms of cellular damage (it's possible that it still might clear out some of the damage through inducing a more youthful transcriptome - eg one with lower inflammatory proteins and higher autophagy proteins)

SENS also has missed out on changes in glycosylation in cells (eg see

).

What about introducing deuterated PUFAs into the cell? [this may have especially high impact]

SENS also seems to concentrate its funding among a small number of labs/PIs, but what about a higher number of labs/PIs (who might be more high-risk)? Even people who do gene (or iPSC) therapy on themselves (or inject themselves with stem cells) produce valuable data that collectively have a non-zero chance of making a significant difference. 

As we increase the number of tools (eg alphafold 2 advances count as another tool too), the number of possible avenues only increases (eg I know someone else who is working on trying to use RNA-based viruses to induce cells to produce the protein variants expressed by centenarians). This approach isn't as "basic research" and may get sufficient funding on its own through self-experimenters (in the same way that people who inject stem cells into themselves are also self-experimenters, and they certainly are willing to pay a lot of $ for it)

bowhead whales

birds

naked mole rats

more saturated cellular membranes...more resistant to ROS

deuterated PUFAs

protein variants expressed by centenarians

This is all messing-with-metabolism. How are you going to slow metabolism in humans? Supposedly, hyaluronic acid is what keeps naked mole rats from developing cancer. Do you think it would be a good idea to start injecting people with that stuff? Also, none of those animals avoid aging. Centenarians still age and die. More saturated cellular membranes and deuterated PUFAs might be more resistant to ROS, but that will only slow aging at best, not reverse it. There's just no reason to think that MWM could ever cure aging.

Protein traffic jams

isn't mentioned by SENS and can occur even w/o protein aggregates or lipofuscin

Actually, they occur due to TDP-43 and FUS aggregates gumming up the nuclear transport system. The SENS solution is to get rid of this aggregate junk, of course. These specific aggregates aren't mentioned by SENS, but they fit within the SENS damage category of "intracellular aggregates."

mitochondrial transfer

as an alternative to mitoSENS

Yeah, but what happens to the mutant mitos?

And in any case, this can be considered a different approach to MitoSENS, not an alternative. Yet another approach is the Shift effect. MitoSENS isn't wedded to the notion of copying non-mutated mito genes into the nucleus.

IPSCs and epigenetic/genetic reprogramming

iPSCs are useful for stuff like WILT and to replace cells that aren't so easily replaced in organs like the brain.

Transient reprogramming is also potentially useful, but more research is needed to determine whether or not it could lead to cancer.

glycosylation

This seems more like age-related changes in glucose and hormone levels that should return to normal once the relevant damage is repaired, rather than something for SENS to target directly, but I'll need to double check.

Yes, damage to long-lived NPCs can be causative given that mislocalized nucleocytoplasmic transport can be causative in reduced autophagy with age. From Autophagy in aging and longevity

immpaired nucleocytoplasmic transport and loss of nuclear integrity may derail autophagy
The proper nucleocytoplasmic transport of autophagy-inducing TFs such as TFEB by RanGTP-dependent importins and exportins and the retention of such factors in the nucleus are important processes in proper autophagic regulation. In fact, nuclear pore complexes (NPCs), which form nucleocy-toplasmic transport channels through the nuclear envelope, deteriorate with age and cause age-dependent nuclear pore leakiness in post-mitotic cells such as neurons (D’Angelo et al. 2009). The efficiency of TFEB nuclear retention may thus decrease with age, consequentially playing an important role in the age-dependent decline of autophagic activity. In the same vein, findings have highlighted the importance 

Recent evidence has additionally provided further support of the importance of nucleocyto-plasmic transport in health and disease by demonstrating that pathologically-affected proteins in NDs can disrupt this process by subcellularly mislocalizing proteins and RNA (reviewed in Fahrenkrog and Harel 2018). Mislocalized proteins included NPC components and nucleocytoplasmic transporters themselves which were aberrantly partitioned to the cytoplasm, and thus inhibited from performing their functions at the nucleus by phase separated stress granules

Phase separation is important too... (an this only became a research fad 2 years ago)

This sounds like (or is) the TDP-43 and FUS aggregates gumming up the nuclear transport system that was mentioned earlier.

SENS also doesn't mention cytoskeletal aging (eg https://www.molbiolcell.org/doi/10.1091/mbc.E18-06-0362 ). It's important because cytoskeletal proteins are among the most abundant proteins and are not easily replaceable or degradeable, given that they're often long-lived and you can't cut them in half without disrupting the rest of the cell [1]. You might call it a "more general version" of damage to elastin.

[1] this is also true for the most general case including structural proteins like lamin - aberrant transcripts of lamin also accumulate during aging, just not fast enough to be causative.

You might as well map out causes of aging in the most abundant proteins in https://www.proteomaps.net/index.html, with special importance placed to the extremely long-lived proteins or the ones that aren't easily replaced or degraded.

Spliceosomes are super-relevant too  given how they are upstream of everything else (William Mair has shown that dysregulation in these accelerates aging, and correcting the defects can up lifespan)

You can argue that "ER + aging", "golgi + aging", or any "cell process/component + aging" is going to cause some downstream effects on aging, and to fix everything, you have to "fix" the ER, fix the spliceosomes, fix the cytoskeleton, fix the golgi, fix the NPCs, fix the histones, whatever.

Spliceosomes are super-relevant too  given how they are upstream of everything else (William Mair has shown that dysregulation in these accelerates aging, and correcting the defects can up lifespan)

You can argue that "ER + aging", "golgi + aging", or any "cell process/component + aging" is going to cause some downstream effects on aging, and to fix everything, you have to "fix" the ER, fix the spliceosomes, fix the cytoskeleton, fix the golgi, fix the NPCs, fix the histones, whatever.

Yes, this can get tricky. Do you have to directly fix everything that goes wrong? If not, how do you know what damage to directly fix?

The stuff that needs to be directly targeted in the cell (ideally, before cellular structures are damaged too much) is damaged or aggregated lipids and proteins and mutations in the mitochondria. This is the primary damage that generates secondary damage to cellular structures (like cytoskeletons and nuclear transport systems). Mutations in the nucleus aren't targeted directly but are dealt with by WILT (or whatever could cure all cancer forever) and senescent cell killing via senolytics or whatever could get rid of them. So, fixing this primary damage should prevent most of the secondary damage from ever occurring, and if lots of secondary damage has already occured (like in older people), the repair of the primary damage may allow the self-repair machinery of the cell that still works to repair itself and the rest of this secondary damage.

cytoskeletal aging

Do you have evidence that this may be a cause of normal human aging rather than of progeria and aging in worms?

map out causes of aging

The SRF is always on the lookout for new categories and kinds of damage.

dysregulation

This is the structure = function thing again. Fix the structure and function should return to normal by definition.

Do you have evidence that this may be a cause of normal human aging rather than of progeria and aging in worms?

 

https://www.sciencedirect.com/science/article/abs/pii/S1566312408600528

The cytoskeleton is how the neuron is able to transport mitochondria, proteins, lysosomes,  and other organelles where they're supposed to be. Disruptions in axonal transport that happen due to cytoskeletal damage prevent the neuron from being able to transport cargo to the right places, especially to synapses). Dendritic size (and "stubs") often shrink wrt age in part due to decreased maintenance.

and yes => the cytoskeleton IS how the neuron transports lysosomes to where they are needed, particularly in neurons. See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201012/

Although the regulation of lysosome dynamics is important in most cells, it is particularly crucial in neurons because of their extreme asymmetry and the length of axons and dendrites. Indeed, variations or mutations in components of the lysosome-positioning machinery cause various psychiatric and neurological disorders

The process of CDA involves targeting autophagosomes to lysosomes, which requires a certain kind of spatial localization that can only happen when the proper spatial cues still exist [and anything affecting autophagy is extremely central to aging reduction/"reversal"]

Cytoskeleton dysfunction is probably a secondary kind of damage (like stroke damage) rather than damage that SENS needs to repair directly: consequence rather than cause. It's associated with the accumulation of tau and other kinds of junk that cause neurodegenerative disease and with excessive oxidation and lower energy levels (both probably caused by mutant mitos). SENS already covers that stuff.

However, I've never heard of these Hirano body aggregates before, so I'll take a look at that.

Cytoskeleton damage can be upstream/causal if it affects lysosomal positioning (just as anything that affects autophagy reaching the sites it needs to reach can be upstream/causal). It also affects cellular stiffness, which then affects whether molecules reach the places they should be reaching.

Lipofuscin can also be a secondary kind of damage too, and it doesn't seem to adversely affect the cell too much until its concentration reaches a critical level. 

Much of SENS was developed before the massive bioscience advances in understanding over the last 15 years - we can do better to adopt to what these new bioscience advances may imply, and there is a strong possibility that it's much more complicated than you think it is and that damage to every single critical of the cell is somehow causally involved. I know scientists who criticize SENS on account of it underestimating the sheer complexity of the cell [and its attitude of not needing to know everything to fix damage] - while it is probably true that you don't need to know everything to fix damage (especially if you look into low-hanging fruit like developmental biology/regeneration/stem cells/replacement organs), what SENS does right now is not sufficient 

Abrupt cellular phase changes (see https://shiftbioscience.com/ and also Tony Wyss-Corey) that happen through life may be more impt than previously thought. I don't doubt that more investment in SENS would have a high chance of producing something desireable, but there's a high chance that the most consequential interventions may come through other routes.

Cytoskeleton damage can be upstream/causal

Too much tau junk → too much cytoskeleton damage

Lipofuscin

Too much lipofuscin/A2E → AMD

what SENS does right now is not sufficient

That's LEV's job (SENS 2, 3, etc.).

If you still think that there's any potential primary damage targets that SENS doesn't specifically mention, please let me know.

Too much tau junk → too much cytoskeleton damage

That's not the only thing that causes cytoskeleton damage.

Ultimately one path forward is: how do you create the data-set/papers that can be used by a new version of GPT-3 to suggest potential interventions for aging. That's why ALL of the creative new technologies people use to treat genetic diseases or cancer (along with nanotechnology - yes UPenn people are already creating nanobots) can help, even if not originally designed for aging.

The point is that if the amount of tau/other junk could be kept low enough (by periodically removing it), then the accumulation of too much cytoskeleton damage should be avoided.

It's not just tau/junk that contributes to cytoskeleton damage - the cytoskeleton is made of proteins that are easily oxidizeable in the same way that nuclear pore complexes are, and damage to NPCs don't have tau as their primary culprit.

Mutant mitochondria.

More than anything, the main limitation of SENS is that it doesn't even plan for future interventions that are guided by AI/ML. Many of the smartest people I know (esp the computer scientists), for better or worse, think that a cure for aging will most likely come through AI, but they aren't able to describe/specify how this happens - they'll just magically think it will be. And most people in SENS don't even plan on how to make the kinds of experimental design that will make it easier for experiments to produce vast amounts of machine-readable output that make it much easier to apply future AI/ML algorithms for ranking+testing potential therapeutics/interventions [they still only publish in journals, which produce far less data than what would be optimally useful for training "AI"]. Unless both sides have a remote idea of how make aging bioscience datasets be used to successfully "train" interventions (especially those that go beyond single molecules), this dream will never happen. 

[living datasets would be nice too]

Theoretically it may be possible to evolve enzymes that can reverse most of the most common inappropriate oxidative modifications to proteins, or ones that can recognize, isolate, and clear lipofuscin deposits (though b/c they are so disorganized and hetereogeneous in size +chemical modifications, this is a difficult problem)

To start out with, funding studies to use new in-situ techniques like https://www.10xgenomics.com/spatial-transcriptomics/ can make everything in the future more machine-readable.

AI/ML

Again, better tools are nice-to-have, not must-haves.

enzymes that can reverse most of the most common inappropriate oxidative modifications

It's way easier just to clear them out...

enzymes...that can recognize, isolate, and clear lipofuscin deposits

...like this. But it's already part of the (SENS) plan.

It's way easier just to clear them out...

Um no, it's much easier to fix oxidative modifications before they all irreversibly clump together into weird aggregates that become inaccessible to most enzymes. See figure at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536880/bin/gr1.jpg . Early intervention >> late intervention. "The reduction of lipofuscin/ceroid formation by pharmacologically decreasing oxidative stress may represent a more promising approach to the problem. "

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536880/

Again, better tools are nice-to-have, not must-haves.

The scope of the aging problem is so vast that we need all possible routes to discover all of the interventions (including ALL the > 200+ oxidative modifications that happen to proteins), and we may never get at all of the interventions without better tools. They might theoretically not be must-haves, but better be at the safe side and use all techniques.

From Allen Brain Institute and Janelia and other institutes, we're seeing significant advances in our ability to image the cell and to get high throughput "-omic" data from cells, without needing too much human intervention [ever notice how Ed Boyden and Adam Marblestone are all into making better tools, even though they don't directly do bioscience research the way other biomedical researchers do it?]. Better tools help reduce the intense labor and time costs involved in figuring out the mechanism of an intervention. They also need to be paired with better post-PDF-publication platforms as the data they generate is not easily made available via PDFs. They're also the only way we can get to developing nanotechnology that can also play a role in identifying and removing damage.

it's much easier to fix oxidative modifications

How are you going to be able to fix every single modification? That seems physically impossible. At best, you're only going to slow down the rate of aggregate formation, but aggregates will still accumulate and kill you.

200+ oxidative modifications

How many of those actually matter? I'd expect that most get degraded, and the rest float around doing bad stuff or form aggregates.

The scope of the aging problem is so vast

use all techniques

This would only matter a lot if you want to disentangle what metabolism is doing (which is vast) and try to get it to do the impossible: prevent every single lipid and protein from going bad. I doubt even an AI god could make that happen, nevermind mere mortals equipped with what amount to fancy expert systems.

Better tools help reduce the intense labor and time costs

Better funding is better than better tools. If SENS got $100 million per year starting in 2004 or even as late as 2010, we'd already have immortality in the bag or know that SENS couldn't deliver the goods and moved on to something else.

This would only matter a lot if you want to disentangle what metabolism is doing (which is vast) and try to get it to do the impossible: prevent every single lipid and protein from going bad. I doubt even an AI god could make that happen, nevermind mere mortals equipped with what amount to fancy expert systems.

Preventing every single lipid and protein from going bad is precisely a problem that "AI" could help solve - one could envision artificially designed enzymes that can get into the cell and specifically modify every unnecessary oxidative modification.

Better funding is better than better tools. If SENS got $100 million per year starting in 2004 or even as late as 2010, we'd already have immortality in the bag or know that SENS couldn't deliver the goods and moved on to something else.

This is a bold claim that presumes that you and others know "all the right things to do" (rather than are adaptive) + underestimate the pure complexity of biology and very few people would believe you/SENS, and the tendency of SENS foundation people to make such claims are a reason why many doubt its credibility (some of the doubt is clearly unjustified, and stems from the uncharitable motivations of skeptics, but SENS people could at least be better at qualifying their claims).

I don't see how it would ever be physically possible to prevent every single lipid and protein from becoming oxidized or otherwise damaged in certain ways. And how will your enzymes prevent every single lipid and protein from ever forming aggregates? This seems only slightly less impossible.

Aubrey doesn't talk about immortality that much anymore and says that it's all about health, but that doesn't seem to have made much of a difference.

As for other forms of damage, it does seem that SENS focuses on repairing damage when it has already accumulated, rather than investigations into targeted interventions that can significantly slow this damage. Eg with proteasomes. The quote below is quite powerful~~

Fortunately much of the accumulated damage can be removed and the damaged proteins can be degraded and replaced by non-damaged ones. In fact, a mild degree of modification or damage to a protein makes it a better candidate for degradation by the 20S Proteasome or other proteases [33, 39, 41, 51]. However, if a protein becomes too heavily modified it becomes a very poor candidate for degradation [33, 39, 40]. Thus, while many mildly oxidized proteins are readily degradable, at least some of the age-associated (or time-associated) accumulation of damaged proteins is due to proteins which are so highly modified that they are difficult or impossible to degrade. It has been argued that it is the buildup of these non-degradable damaged proteins that causes age-related effects, however, the accumulation of oxidized proteins in cells is exponential rather than linear over time, indicating that the rise in protein oxidation is not just a product of a buildup of indigestible proteins, but a potentially reversible change in cell function [52].

The accumulation of oxidized or otherwise damaged proteins in cells during aging could be a product either of a rise in damaging conditions or a fall in the rate of removal of damaged proteins. it has been observed that over age there is a rise in mitochondrial generation of oxidants [53]. In addition, it has been shown that there is a decline in protein turnover. This decline in protein turnover is, at least in part, the product of a sharp decrease in 20S Proteasome function over age (which has been shown in a range of different tissues) [54-59]. In addition to a decline in 20S Proteasome function there is also a drop in 20S Proteasome levels over in aging which also reduces protein turnover [60-62]. The decline in 20S Proteasome function is partly the product of an increase in modification or damage to the 20S Proteasome over the course of age [54, 59-61]. For instance, it has been seen that 20S Proteasome isolated from old rats is 50% less proteolytically active than 20S Proteasome isolated from young rats [63]. As a result, not only is there a decrease in the amount of 20S Proteasome present during the aging process but there is also a decrease in the ability of the remaining 20S Proteasome to degrade the accumulating damaged proteins, thus resulting in an overall accumulation of damaged cellular proteins with age. As a result, older rats are less able to remove damaged proteins from their cells and tissues than are younger rats, which goes some way to explain the difference in the levels of protein damage found in the two animals.

Slowing the rate at which damage accumulates is generally a bad idea, because damage will continue to accumulate until it kills you. Instead, SENS proposes to periodically repair that damage in order to keep it below the threshold at which it would cause pathology. However, there are a few exceptions to periodic-repair rule such as when dealing with mitochondrial mutations and WILT.

Oxidation damage inside cells is caused by mutant mitochondria, and the SENS solution is to insert copies of non-mutant mito genes into the nucleus. This should prevent the cell's degradation machinery from being overwhelmed by having to process too much oxidized protein junk. Declines in cellular function are partly caused by mutant mitos, and this may also explain why 20S Proteasome function can also decline.

more on mosaicism - https://twitter.com/jpsenescence/status/1084560766735450113

 

João Pedro Magalhães

The large number of mutations with age recent studies are finding in some human tissues showcase how difficult it will be to significantly intervene in aging because we can't easily get rid of mutant cells and replace them by pristine cells.

https://www.nature.com/articles/d41586-018-07737-8 is very deep too - actually it hints that many older cells are dominated by pro-growth/pro-survival mutations that don't complete all the necessary conditions for cancer (but it just shows how cancer is the adaptive response of A LOT of other responses that are pro-growth/survival in ordinary cells that USUALLY don't result in cancer...)

There's no compelling evidence that these kinds of mutations cause bad stuff to happen in a normal lifespan.

Also haven't you heard of the use of lasers to disrupt/destroy amyloid plaque? (which could presunmably also be useful for protein aggregates?)

Yeah, lasers might help at getting rid of certain kinds of junk. As you mentioned, lasers might be useful at getting rid of beta-amyloid plaque (unfortunately, plaque is probably not the right target since amyloid oligomers are likely to be a lot more important in the development of Alzheimer's). LumiThera is developing a laser system to get rid of drusen which is one of kinds of junk that causes AMD. Longecity funded an unsuccessful attempt at using lasers to eliminate lipofuscin; apparently, the organisms used in the experiment lacked lipofuscin.

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?

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.

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 :)

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."

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%.

Isn't early detection of cancer (and intervention) more feasible? 

Can you think of any other intervention that has a good theoretical chance to eliminate all cancer? 

Besides WILT, the only other intervention I can think of that might provide a complete cancer cure are the leukocytes used in Cui's cancer-proof mice experiments, but it's not known whether all types of cancer can be eliminated by these immune cells. Fortunately, LIfT BioSciences is planning to start a clinical trial in 2022 using this approach.

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

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.

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).

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.