#ALLTIMEIMPORTANTTHREADS #IMPORTANTTHREADS #INFLECTIONPOINTS #ALLTIMEMOSTIMPORTANTPOSTS #YOUWILLREGRETNOTINCORPORATINGMOREOFTHIS #ALLTIMEFAVORITEANSWERSOFAKC
But there’s still some controversy about whether genetic mosaicism really leads to any age-related disease or condition, and that’s why SENS doesn’t target that particular form of damage yet. DNA damage in the nucleus can cause cancer and cell senescence and is targeted by OncoSENS and ApoptoSENS respectively
https://www.nature.com/articles/s42255-020-00304-4
Genetic mosaicism, in itself, isn’t necessarily sensed by the cell as damage. It can be DNA damage that has been corrected, albeit corrected to a form different than the form it was originally in).
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)
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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.
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FWIW, there has to be A LOT done to make this research more accessible to people with “weird” backgrounds—A LOT of us in the field have “weird” backgrounds b/c we come from all sorts of different backgrounds (Hell, fightaging.org, josh mittledorf, and myself ALL were into astronomy before aging) before realizing that aging really is the ONLY thing that matters to the point that we really should just throw all other priorities away in order to focus on the area precisely because it’s the only thing that matters. But the traditional way people in the area are trained certainly doesn’t help encourage people with “weird backgrounds” to go into the area [especially because grad school tends to cause depression/trauma in ~50% of people who do end up going through the process—Ben Kuhn says it’s worse to public health than STDs]. I know Jose Ricon and Laura Deming also have somewhat “weird backgrounds” too [Laura Deming even admitted on her blog that she was literally crying in undergrad every day before she dropped out—it was hinted that it was because the education system in undergrad really is incredibly dull—she also mentioned in an interview in palladium that she had to take several years to “unlearn” the damage that comes from all her training from biochemistry lab volunteering]. It took her a few years to be taken seriously by the biotech establishment despite her lack of a PhD (even though she had the support of the thiel fellowship AND people in the bay area who really wanted to believe in her), and ultimately she seemed to realize that her best efforts are done doing VC/strategy work (AND in SHAPING THE NARRATIVE) rather than pure research or technical work [of course we DO need people involved in these areas TOO].
[FWIW Laura Deming mentioned on twitter that she still recommends people major in math/CS/physics if anything, but she didn’t mention that she was a physics major at MIT and that was probably what led her to “cry every day after class” when she was in school probably because the “education was so dull” as her father admitted somewhere—the thiel fellowship literally was the lifeline that saved her]. We DO need more math/physics/CS people in aging FOR SURE [it is MOST lacking in people who have hardcore physics/biophysics talent, and google search results for biophysics are utterly lacking and this is also why we don’t have a systematized list of interventions for solving aging]
We have to recognize that there are SO SO SO many ways to make a difference/impact in aging that don’t depend on traditional forms of PhD-based socialization (remember that Freeman Dyson called the entire PhD system an abomination—and note how ash jogalekar of curiouswavefunction often mentions how cargo cult science has made science incredibly dull [look at how journal articles are so dull now, and compare/contrast it with the playful unpublished scientific notebooks that scientists used to publish BEFORE science became so cargo cult in the 1950s—even Laura Deming often mentions that she LOVES reading isaac newton’s and darwin’s old notebooks]. And no one rewards those who read Newton or Darwin notebooks—they certainly don’t help you with getting a 5 on an AP test or getting into a top college or grad school [at least in the ways people think that they help).
And the thing I often notice with talking to people in established fields is that they often DO lack imagination of what’s possible, and they seem to lack a certain kind of narrative imagination, and This is all the gist of Thomas Kuhn’s Structure of Scientific Revolutions. Even Riva Melissa-Tez loves Feyerband, who comes as close to scientific/epistemiological anarchism as you can come to in anyone. The thing is, you have to be taken seriously in a way that inspires more people to want to be more like you in inspirational direction, and preferably in a way that makes you more accessible and humanizeable. The author of fightaging.org, for instance, is amazing in his level of monomaniacal devotion to the area, but his blog becomes a scalar quantity in output, rather than a qualitative vector (or tensor)-like quality in output. It is singularly important, but it is not going to (in itself) result in the radical change in transformational thinking that we NEED to fix the problem, especially because most people who read the blog don’t even know who reason is, to the point that people don’t feel inspired by reasons. Similarly, while Aubrey is doing important work in propagating the science, there are many scientists who don’t take him seriously, to the point that some people I know think that he damages the field and its credibility (he also attracts a lot of pseuds).
I think they seem more willing to give Laura Deming benefit of the doubt because she doesn’t trigger their “low signal to noise” ratio detectors the way that Aubrey does, though even then, she is very sphinx-like in her thinking, which makes it very hard for her to scale up to the point that others would feel inspired by her. There are SO SO SO SO SO SO many people in the field of aging that many of them seem to turn into “replicas” of each other (you know, like how some people say that rationalists all seem to turn into replicas of each other, or Will Manidis mention on Twitter how hiring agencies on Twitter also seem to regard MIT students as replicas of each other). We need more people with relatively high S/N ratios who AREN’T replicas of each other and who can transform our thinking of aging into a form that literally FEELS (on a S1 LEVEL) tractable to everyone, b/c right now, so FEW people S1 feel that is a tractable thing to do (even all the current interventions suggested by SENS cover a small percent of ALL aging related damages even though we can probably INCREASE the number of possible interventions if we write out ALL the forms of aging damage + all the forms that biotech HAS been advancing) in a format that’s MORE accessible/readable than yet another annoying journal article PDF because we are ALL force-fed more PDFs than we can deal with AND the amount of sensory contrast in PDFs [with each other] is SO low that they all blend in with each other in our sensory field, causing ALL of them to become indistinguishable with each other {AND basically lead to increases in knowledge that DON’T scale with the number of hours we put into understanding it all—that’s why more INFORMAL STYLES and less “conforming to journal articles OR behavioral motifs” is NECESSARY in solving the issue because most people, ESPECIALLY including the hardcore academics who just end up posting MORE on their blogs, are basically forgettable—oh yeah one person I know simply said that most rationalists end up pattern-matching as people who just end up posting on blogs and doing nothing else }
BTW, ppl hate reading the formalisms/and rules of journal articles. Like what one of my scientist-trained friends has said here:
I don’t need to sift through yet another bullshit article on aging
or for that matter, I don’t want to fuckign read another bullshit journal article on anything but fucking god that’s all I seem to find these days
[as you can notice, my post here is weirdly formatted, because FUCK FORMATTING. it only turns EVERYTHING into one homogeneous entity, and the less we have consistent formatting, the more distinct/memorable everything is]. ofc LIFE IS TOO SHORT FOR FUCKING FORMATTING [OR FORMALISMS—oh yeah DON’T YOU EVER NOTICE HOW THE “cool people” love michael faraday], and in the long run someone else (or AI) can format it for you if needed. FORCING FORMALISMS ON EVERYONE REDUCES CREATIVITY AND TURNS EVERYONE INTO CARBON COPIES OF EACH OTHER.
GIVEN THAT ANY OF CONTINUATION OF THE STATUS QUO (OR ANYTHING AT CURRENT RATES OF PROGRESS) GUARANTEES DEATH, WE HAVE TO BE OPEN TO THINGS THAT ARE RADICALLY DIFFERENT, AND YOU KNOW, SOME OF THOSE THINGS FEEL RADICALLY DIFFERENT AND ACTUALLY FUN AND NOT A WASTE OF LIFE LIKE PUBLISHING YET ANOHTER JOURNAL ARTICLE OR GETTING INTO ACADEMIA. [now hardcore biology research is not consistently fun and you have to instil a sense of discipline in people who really DO it [ and they DO produce valuable work, just not the radical paradigm-changing kind of work that qualitatively convinces people that a qualitative change to where they focus their output MATTERS], but it can be MUCH less dull than it is practiced right now—AS FREEMAN DYSON/LAURA/GAURAV ALL RECOGNIZE—oh btw gaurav LOVES the essay Why Modern Scientists are so Dull ], AND the training process for being taken seriously ALSO can be significantly less dull [Gaurav has mentioned how he often had conflicts with upper level supervisors and also didn’t do well in HS because SO much of HS was pointless and how it had to take him various shenanigans to get into a PhD program—also notice how the MIT Media Lab at least tacitly encourages certain kinds of “disobedience” and takes pride in accepting some students who DON’T have a bachelor’s degree]
There are people in biomedicine who DO have weird backgrounds and we SHOULD encourage more people who have weird backgrounds to go into it [it’s easier when it doesn’t require as many resources—access to resources is the thing that makes it easier for mathematicians to have weird backgrounds [or who don’t have a huge amount of money] than it is for biologists].
I also think making experimentation MORE accessible [eg see dhash and keoni gandall] would make it easier for people to go in the area without as much wetlab experience [there is a lot in biomedical research that is drudgery that does discourage a lot of people who value their time from doing more wetlab research and if we have better biomedical automation it would make wetlab research take A LOT LESS out of people who do go in the area]. I know people in the broad institute, for instance, and while they are INCREDIBLY technically competent (and SO well-versed in all the new seq techniques—I also know it attracts some of the analytically most talented ppl in the nation, it takes SO much out of them that it seems that they lose sight of what the rest of the world is like—and this is what A LOT of biomedical experimentation does to people, and might perhaps be the reason why someone like Laura ISN’T doing wetlab biomedical research anymore)
FOR THE RECORD, there are SO SO SO many ways for people to contribute to the area even if they’re cognitively “weird” or don’t have a scientific background [because contributing to the field takes SO many multimodal talents that go beyond simple scientific expertise even though scientific progress STILL is the most important thing]. OTOH, people know that the field has lots of quacks and that the area doesn’t have a high S/N ratio.
There are A NUMBER of people on twitter who have mapped out ways that people have done drastic biotech interventions (esp in the early days where we did things like head transplants or ) - we should do that more
Ok I distilled A LOT here and tbf I could distil more and am not doing it because I haven’t had the type of emotional encouragement I wish I could always have had (even if the emotional encouragement can only come from outsiders/newer people because hey—anyone with a “weird background” often only gets that kind of emotional encouragement from outsiders, rather than insiders who are often only prepared to give these kinds of emotional encouragement to people who fit within their predefined notions of what works [though I KNOW FREEMAN DYSON might have been an exception—OFC he also OFTEN identified as a permanent outsider]). SARAH CONSTANTIN also DID NOT have that kind of emotional encouragement, and she STARTED longevity research institute, but sadly, it didn’t go further, and I believe [after talking to her/knowing her] that her lack of emotional encouragement [esp earlier in life and grad school] definitely was a factor that prevented her from going further with it.
[[2]] [also the bloggers on aging and the calorie-restricters on crsociety don’t seem to be super-neuroplastic when it comes to adopting new frameworks of thinking—fightaging.org has pretty much stayed the same person/within the same framework for the last 10 years]. This is why if you want to access the best thinking, you want to look at other fields/frameworks and not stay within the aging-framework [notice how Laura Deming mentions on Twitter how she talks to scientists in OTHER fields rather than aging itself b/c that is where the insight is AND where you get access to other frameworks—she asks herself what NOT to read rather than what to read AND advises people to not pay too much attention to what’s going on in current aging research [she recently said she took a liking to autophagy research] - this is the trap that the bloggers who blog about aging also fall into
Here’s a thread I recently posted on fbook btw: https://www.facebook.com/simfish/posts/3741222205930450
Also haven’t you heard of the use of lasers to disrupt/destroy amyloid plaque? (which could presunmably also be useful for protein aggregates?)