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Comment by InquilineKea on Why SENS makes sense · 2021-01-27T07:20:11.854Z · EA · GW

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

 

João Pedro Magalhães

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

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

Comment by InquilineKea on Why SENS makes sense · 2021-01-22T06:36:49.432Z · EA · GW

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.

Comment by InquilineKea on Effects of anti-aging research on the long-term future · 2021-01-21T09:52:21.026Z · EA · GW

On moral progress - I think it's highly plausible that future generations will not be okay with people dying due to natural causes in the same way that they're not okay with people dying from cancer or infectious diseases.

Comment by InquilineKea on Why SENS makes sense · 2021-01-21T08:58:05.123Z · EA · GW

Too much tau junk → too much cytoskeleton damage

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

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

Comment by InquilineKea on Why SENS makes sense · 2021-01-20T06:50:04.239Z · EA · GW

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.

Comment by InquilineKea on Why SENS makes sense · 2021-01-20T06:41:55.142Z · EA · GW

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).

Comment by InquilineKea on Why SENS makes sense · 2021-01-19T09:31:16.207Z · EA · GW

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)

Comment by InquilineKea on Why SENS makes sense · 2021-01-19T07:51:39.964Z · EA · GW

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

 

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

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

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

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

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

Comment by InquilineKea on Why SENS makes sense · 2021-01-19T07:03:17.764Z · EA · GW

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

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

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

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

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

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

Comment by InquilineKea on A new study looks at how scientific fields have formed · 2021-01-19T01:44:23.467Z · EA · GW

Isn't there a difference between creating entirely new frameworks, and just adopting frameworks to different species in parallel?

For instance, it seems that adopting frameworks to different species in parallel often ends up happening over time (as we've seen people gradually adopt cognitive ethology from chimpanzees and captive dolphins into wild dolphins, elephants, african grey parrots, kea [where academic labs do exist to study them], capuchin monkeys, and new Caledonian Crows). It seems that some species of animals are intensively studied, and the vast majority of others not so much (like, WHERE are the Irene Pepperbergs on storks and pelicans or Andean Condors or deer?).

One thing I've often noticed is how little attention is spent on studying individual orders of protists and very small animals (especially nematodes that aren't C. elegans or most species of invertebrates), which should presumably have even more genetic diversity than what we see in charismatic megafauna.I know there is a conference specifically for tardigrades, but it hasn't gotten much attention..

As for cognitive ethology - people like Louis Herman, Joyce Poole (of elephants), Andrea Marshall (of manta rays) all seemed to get funding through independent research institutes. It seems that sometimes they get support from sources that overlap with sources that support zoos? 

John Marzluff def gets a lot of academic support  for studying crows (and before that, prairie dogs)

Comment by InquilineKea on Why SENS makes sense · 2021-01-19T00:26:01.813Z · EA · GW

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.

Comment by InquilineKea on Why SENS makes sense · 2021-01-18T17:05:17.832Z · EA · GW

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.

Comment by InquilineKea on Why SENS makes sense · 2021-01-18T11:18:37.154Z · EA · GW

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.

Comment by InquilineKea on Why SENS makes sense · 2021-01-18T09:04:38.153Z · EA · GW

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sure, what's your email?

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

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

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

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

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

).

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

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

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

Comment by InquilineKea on Effects of anti-aging research on the long-term future · 2021-01-18T08:20:18.364Z · EA · GW

No aging enables autocrats to stay in power indefinitely, as it is often the uncertainty of their death that leads to the failure of their regimes. Given that billions worldwide currently live under autocratic or authoritarian governments, this is a very real concern.

Among the largest nations that are most relevant to the world (or have a disproportionate ability to shape what happens to the world relative to their ability to be shaped by other countries), it only applies for China and Russia, and it's unclear whether Xi or Putin strongly care about immortality (and even if it did, it would be unlikely to arrive quickly enough to save them). Given that the next 100 years might be the most important years ever in human history, this makes this supposition more bounded on what might happen in the next 100 years, and there aren't that many dictators in that position. It's also unlikely that China would become less autocratic/flexible even after Xi dies (the CCP will just have other ways to maintain its power - probably in a way similar to how North Korea barely changed after Kim Jung Il died. When an autocrat's closest associates also die off over time, it can cause a weakening of the strong beliefs held by some of the previous generation, which might facilitate regime change.

I think this concern has a potential for strong negative downside on the tails, but it's unclear if it is a strong negative downside in the median case (given that we know who the most relevant dictators are here, and there aren't many). Given the increasing power disparity between China and the West, what happens in China then becomes uniquely important, so this concern may be more targeted around whether or not China's ability to change is affected by whether or not the death of Xi's successor (and everyone in Xi's generation of the CCP) would significantly increase the chances of China transitioning away from the strongest downsides of autocracy or authoritarian governments (I believe China transitioning away from authoritarianism is unlikely no matter what, though the death of its autocrats over the next 100 yearsmight increase China's chances of ultimately transitioning away from the most negative effects of authoritarian governments, such as censorship of thoughtcrimes). Conditioning everything into the far future could also time-localize (or impose an upper bound on) much of the "suffering" that comes from the mission of "transforming the identities of unreceptive people into Han Chinese" [eg people in Hong Kong now will most likely suffer in the present, but future people born in Hong Kong probably won't "suffer" as much from not having something tangible "taken away" from them], though what China is doing now (wrt stifling  dialogue) is certainly not making China's future more robust.

It's also possible that AI may ultimately improve social dialogue to the point that it may help the CCP get what it wants without feeling threatened if it relaxes some of its more draconian measures such as censorship. I'm not sure if prolonging the lives of China's authoritarians is guaranteed to be a strong negatives - it certainly has issues such as being insufficiently insensitive over what it's doing to Xinjiang/Tibet/Hong Kong (and possibly eventually Taiwan), but these issues are mostly in the now and will be unaffected by life extension in the future. What China is doing to increase its influence/power elsewhere will be done irrespective of who is in power, and it probably doesn't have a strong desire to "take over" other countries in the way that Hitler or Stalin did (ultimately, it is more constrained by what other countries can do to it more than it is constrained by the potential deaths of its dictators, unless it had an unusually powerful/effective/ruthless dictator, which I'm not sure if has). 

It may ultimately come down to anti-aging technology ultimately come at just the right time to save us from the worst of authoritarianism (given that we no longer have Stalin or Mao). 

2021 edit: Though who knows, democracies can easily turn into authoritarian regimes, and all it takes is a single terrorist or bioterrorist attack that forces universal surveillance...

Comment by InquilineKea on Effects of anti-aging research on the long-term future · 2021-01-18T08:09:49.269Z · EA · GW

As I wrote here, I think this could be due (in part) to biases accumulated by being in a field (and being alive) longer, not necessarily (just) brain aging. I'd guess that more neuroplasticity or neurogenesis is better than less, but I don't think it's the whole problem. You'd need people to lose strong connections, to "forget" more often.

George Church is over 60 and I've heard some people refer to him as a "child", given that he seems to not strongly identify with strongly held beliefs or connections (he's also not especially attached to a certain identity). I talked to him - he cares more about regeneration/rejuvenation - or maintaining the continuity of consciousness and the basic gist of his personality/mode of being than about maintaining specific memories (regeneration/rejuvenation research may ultimately come down to replacing old parts of your brain or identity with new untrained tissue - this is where developmental biology/SCRB becomes especially relevant). In fact, he's unironically bullish about anti-aging therapies coming in his lifetime 

Comment by InquilineKea on Why SENS makes sense · 2021-01-18T00:21:41.200Z · EA · GW

Besides the cancer thing, SENS ignores telomere attrition, because it's still unclear if telomere attrition is a significant cause of aging. And the likelihood that WILT will be needed is still above 50%.

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

Comment by InquilineKea on Why SENS makes sense · 2021-01-17T16:35:18.918Z · EA · GW

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

Comment by InquilineKea on Why SENS makes sense · 2021-01-17T11:47:54.703Z · EA · GW

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

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

 

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

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

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

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

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

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

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

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

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

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

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

===

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

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

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

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

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

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

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

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

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

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

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

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

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

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

==

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Comment by InquilineKea on Why SENS makes sense · 2021-01-15T09:16:17.523Z · EA · GW

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

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

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

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

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

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

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

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

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

Comment by InquilineKea on Why I'm focusing on invertebrate sentience · 2021-01-15T00:21:06.130Z · EA · GW

Shouldn't we weigh neurons by level of graph/central complexity? (eg neurons by how "central" they are to the system). Many neurons simply don't factor into evaluations of hedons (even motor and sensory neurons)

Comment by InquilineKea on Features Relevant to Invertebrate Sentience, Part 3 · 2021-01-14T13:51:37.672Z · EA · GW

Play behavior is in general not found in birds, with the exception of the highly intelligent corvid family

 

You forgot kea and cockatoo parrots. https://www.abc.net.au/news/2020-12-26/birds-that-play-are-smarter-finds-gisela-kaplan-research/12990902

Also, possibly emu (https://www.buzzfeed.com/annamenta/you-go-emu-you-play-fetch), which have among the largest brains in the bird world.

Comment by InquilineKea on Impact of aging research besides LEV · 2021-01-14T12:41:49.744Z · EA · GW

A lot of hallmarks (eg genetic mosaicism or improper stoichiometry or proteins not doing what they're "supposed to do") are systems effects rather than effects that can be analyzed reductionistically. Fedichev and Gladyshev have lots of papers that hint in that direction

Comment by InquilineKea on Do Long-Lived Scientists Hold Back Their Disciplines? · 2021-01-14T12:06:50.114Z · EA · GW

While old generation dying is one way of getting scientific and intellectual change to be enacted, there are longer-term trends towards reduced gatekeeping that may reduce the cost of training (eg when people prove that they're scientifically competent WITHOUT having to go through the entire wasteful process of K12 + PhD), then this could inhibit the gatekeeper socialization effects of the old generation that prevent the new generation from feeling free to express itself w/o permission (programming, at the very least, is much less hierarchical because people don't need to depend on the validation of an adviser/famous person to get their ideas out as much or gain access to resources critical to experimentation- it just has to work). Similarly, reductions in the cost of doing biological experiments could also inhibit this effect. 

There are power dynamics associated with scientific training and scientific publishing (not to mention that the training seems to help scientists get through publishing - blind review be damned)- and there are SOME  trends towards funding people who do work without needing access to gatekeepers (look at trends in funding from Emergent Ventures, or the Patrick Collision network). I've also noticed that people are growing

Comment by InquilineKea on Differences in the Intensity of Valenced Experience across Species · 2021-01-14T09:48:15.791Z · EA · GW

There also can be a significant difference between mere physical pain and actual suffering that leads to PTSD. It may be true mammals/birds can get traumatized, but few animals really reach the PTSD-levels of intense suffering (or lived resentment) that an elephant can experience after the death of all of its family members, or that an orca feels after its baby dies and it holds its young in its snout for days

[fwiw, elephants seem to be one of the only animals that becomes aware of persecution at a population-level - crows might be another example - these are animals that can distinguish between groups of people who endanger them and groups of people who are safe]

Similarly, larger parrots (as distinct from the smaller parrots, which also aren't seen as "behaviorally complex" as african greys or cockatoos) self-mutilate themselves when left alone by themselves w/o stimulation- cockatoos have even been called "velcro birds" due to their tendency to stick to the person they bond the most with. This could be evidence for a kind of suffering that less behaviorally complex birds don't have [though we really don't know what it is to have most birds as pets - anecdotally, I heard that crows/ravens might have similar tendencies]

Fwiw, I have a friend (from qualia computing institute) who wagered that "putting a sperm whale on MDMA" might be the most intense qualia that any animal can experience. 

Many animals seem to lack the ability to deliberately redirect their attention and focus away from valenced experiences, and this inability may increase the intensity of the experiences. James Yeates speculates that “animals more able to divide attention would experience pain of lower intensity (because the attention is divided)” (Yeates 2012: 29). Sahar Akhtar concurs, writing, “The facts, if they are facts, that many animals do not have many substitutes for focusing on their pain and cannot will themselves to focus on other things, cannot form expectations about the ending of pain, think about other times without pain, or consider more complex interests for which pain may be a necessary means, provide us with reasons for thinking that the overall pain experience caused by a given measure of pain might sometimes be worse for animals than it is for us” (Akhtar 2011: 509).

Although Yeates and Akhtar appear to base their reasoning on a priori considerations, there is at least modest empirical evidence to support their position. Cognitive inhibition is the ability to disregard stimuli that are irrelevant to the task at hand. Recent research suggests that, in humans, “a higher level of cognitive inhibition is associated with lower experimental pain sensitivity” (Bjekić et al. 2018: 580). Hence, it appears that humans that are better able to consciously redirect their focus also suffer characteristically less intense pains.[^66]

THIS quote is interesting - it reminds me of animals that are unable to disengage attention from their loss once they lose their mate (some self-mutilate to the point of unintentional suicide), and it also reminds me of parrots that are unable to disengage their attention from the person they're most attached to when away (eg it was so discomfiting for one raven that it held the person's finger in its mouth for a LONG time when away).

eg (from https://theconversation.com/laughs-cries-and-deception-birds-emotional-lives-are-just-as-complicated-as-ours-69471 )

Birds may feel for others (have empathy) and even console them, may have a sense of justice, may show deep affection for their partner and grieve for their loss. I witnessed the mate of a fatally injured tawny frogmouth not moving from the spot next to its dead partner for three days, and then dying on the fourth.

Comment by InquilineKea on Effects of anti-aging research on the long-term future · 2021-01-14T09:32:16.677Z · EA · GW

There are some scientists who roamed around and never really crystallized (famous examples being Freeman Dyson and Francis Crick)

Comment by InquilineKea on Effects of anti-aging research on the long-term future · 2021-01-14T09:28:11.689Z · EA · GW

While old generation dying is one way of getting scientific and intellectual change to be enacted, there are longer-term trends towards reduced gatekeeping that may reduce the cost of training (eg when people prove that they're scientifically competent WITHOUT having to go through the entire wasteful process of K12 + PhD), then this could inhibit the gatekeeper socialization effects of the old generation that prevent the new generation from feeling free to express itself w/o permission (programming, at the very least, is much less hierarchical because people don't need to depend on the validation of an adviser/famous person to get their ideas out as much or gain access to resources critical to experimentation- it just has to work). Similarly, reductions in the cost of doing biological experiments could also inhibit this effect. 

There are power dynamics associated with scientific training and scientific publishing (not to mention that the training seems to help scientists get through publishing - blind review be damned)- and there are SOME  trends towards funding people who do work without needing access to gatekeepers (look at trends in funding from Emergent Ventures, or the Patrick Collision network). I've also noticed that people are growing

Comment by InquilineKea on Cost-Effectiveness of Air Purifiers against Pollution · 2020-08-01T13:38:43.674Z · EA · GW

https://smartairfilters.com/en/blog/is-air-pollution-affecting-your-productivity-in-the-office/

Comment by InquilineKea on Ask MIRI Anything (AMA) · 2016-10-11T21:13:56.559Z · EA · GW

What makes for an ideal MIRI researcher? How would that differ from being an ideal person who works for DeepMind, or who does research as an academic? Do MIRI employees have special knowledge of the world that most AI researchers (e.g. Hinton, Schmidhuber) don't have? What about the other way around? Is it possible for a MIRI researcher to produce relevant work even if they don't fully understand all approaches to AI?

How does MIRI aim to cover all possible AI systems (those based on symbolic AI, connectionist AI, deep learning, and other AI systems/paradigms?)

Comment by InquilineKea on The morality of having a meat-eating pet · 2016-06-23T01:14:55.102Z · EA · GW

How about... just feeding the pet a vegetarian diet?

Dogs can thrive on such a diet - see http://www.cnn.com/2011/LIVING/03/10/vegan.dog.diet/ for examples. One of the longest living dogs was even mostly a vegetarian (http://www.monicasegal.com/wordpress/?p=431 ).

Cats would be harder (as they need supplemental taurine), but some evidence already shows that cats fed a vegetarian diet aren't deficient in taurine (http://www.petmd.com/blogs/nutritionnuggets/cat/jcoates/2014/jan/can-cats-thrive-on-vegetarian-diet-31187 ).

There aren't many papers on this - this can be an area where further research/investigation is warranted (I wonder if they ask about diet on the Dog Aging Project, for example?)