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 thatmuch 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.
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
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).
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
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.
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.
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
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)
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)
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.
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 (the smaller spines shrink/die off more).
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.
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.
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.
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)
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. ”
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.
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.
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...)
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.
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 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.
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.
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.
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).
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.
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
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
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).
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.
I’m definitely not referring to mind uploading or digital technologies here.
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).
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]]
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:
[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
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.
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.
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.
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).
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.
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.
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.
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.
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.
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?
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 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)
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.
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)
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.
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.”
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 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.
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
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.
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.
Do you have evidence that this may be a cause of normal human aging rather than of progeria and aging in worms?
The SRF is always on the lookout for new categories and kinds of damage.
This is the structure = function thing again. Fix the structure and function should return to normal by definition.
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 (the smaller spines shrink/die off more).
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/
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.
Too much tau junk → too much cytoskeleton damage
Too much lipofuscin/A2E → AMD
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.
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.
Again, better tools are nice-to-have, not must-haves.
It’s way easier just to clear them out...
...like this. But it’s already part of the (SENS) plan.
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/
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.
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.
How many of those actually matter? I’d expect that most get degraded, and the rest float around doing bad stuff or form aggregates.
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 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.
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.
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~~
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
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.