Why SENS makes sense

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 23 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 choles­terolfrom 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.

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

Cross­posted to LessWrong