All of Florin's Comments + Replies

Concrete Biosecurity Projects (some of which could be big)

Unless you have a reason to think otherwise, those methods of transmission (except for aerosol transmission) don't seem capable of spreading a contagion rapidly enough to end civilization. This has been discussed in other comments.

Concrete Biosecurity Projects (some of which could be big)

Why do you think fomite transmission is still worth considering?

2Davidmanheim6mo
I think you're once again focusing far too narrowly - foodborne illness, waterborne disease, intermediate animal hosts and parasites, vector borne diseases, fomites, and sexual transmission are all mechanisms that currently spread disease, and it seems very strange to say that we should only ever look at aerosol transmission. Yes, it's the most worrying, but it's not enough on its own to address all threats.
Concrete Biosecurity Projects (some of which could be big)

Yeah, there were two groups that studied how rhinovirus is transmitted. One group was from the University of Virginia and found evidence of only fomite transmission. The study you cited is theirs. The other group was from the University of Wisconsin and found evidence for only airborne transmission. The Wisconsin group "...argued that the high rate of transmission via the hands in the Virginia experiments might be attributable to intensive contact with fresh wet secretions produced by volunteers who essentially blew their nose into their hand."

3Linch7mo
Oh this is really interesting, thanks!
Concrete Biosecurity Projects (some of which could be big)

cause maybe thousands of deaths.


Don't you mean millions of deaths?

I'm confused about the distinction between fomite and droplet transmission. 

From what I've read, fomite transmission must involve surface touching, whereas droplet transmission must involve droplets, which are expelled by coughing or sneezing, directly landing (like a bullet) in your mouth, nose, or eyes without any extra contact or touching.

These methods of transmission seem so implausible (how many people actually sneeze or cough directly in someone's face?) to be major causes of spre... (read more)

Concrete Biosecurity Projects (some of which could be big)

it's certainly not impossible for non-respiratory pathogens to achieve rapid global spread.

 

I can't think of a plausible, non-science fictional way in which this would not be impossible.

If you can but prefer not the mention it publically due to infohazard concerns, please send me a PM.

Concrete Biosecurity Projects (some of which could be big)

In the context of this discussion (the post is about GCBRs), it should have been clear what I meant by that term.

Also, it can be claimed that a lot of things are "pandemics" like TB and antibiotic-resistant bacteria, but what is usually meant by the term is rapid, global spread (within weeks to a few months at most) of a deadly pathogen.

It wasn't obvious to me, and apparently also not to others, that your statements about "pandemics" were not meant to apply to pandemics in general.

In general, when you realise you have been communicating unclearly, it's a bad idea to blame the people you confused.

Concrete Biosecurity Projects (some of which could be big)

rhinovirus is probably spread primarily via formites


Until the COVID19 pandemic, nearly everyone thought that most infectious respiratory diseases were transmitted via fomites and droplets, but unfortunately, this was based on shockingly poor evidence and assumptions. The material you've seen is based on this outdated consensus.

As I pointed out before, there are mechanistic reasons to doubt that pandemics can arise from fomite transmission.

However, if I squint hard enough, I can kinda, sorta see how young children in daycare might be infected by sharing toy... (read more)

3Martin Trouilloud7mo
That Wired article is fantastic. I see this threshold of 5 microns all over the place and it turns out to be completely false and based on a historical accident. It's crazy how once a couple authorities define the official knowledge (in this case, the first few scientists and public health bodies to look at Ward's paper), it can last for generations with zero critical engagement and cause maybe thousands of deaths. I'm confused about the distinction between fomite and droplet transmission. Is droplet transmission a term reserved for all non-inhalation respiratory pathogen transmission (like touching a droplet on a surface and then touching your face, or the droplet landing on your mouth), so it includes some forms of fomite transmission? I'm seeing conflicting sources and a lot that mention the >5 μm rule so don’t seem too trustworthy.
Concrete Biosecurity Projects (some of which could be big)

This discussion is about preventing and mitigating pandemics that could potentially end civilization, and stuff similar to AIDS (regardless of how you want to categorize it) is off topic because transmission would not be rapid enough to end civilization.

5Davidmanheim6mo
But obviously, there are transmission modes other than airborne and sexual, so I think you are missing my point about too-narrow thinking. Because your claim is, effectively, a near-certainty that only airborne transmission could be threatening. And my response was, in effect, that this isn't correct, and that even eliminating airborne disease transmission completely wouldn't sufficiently address risks of future bioengineered pandemics, even if it would greatly reduce the number of viable such cases.
5Alex D7mo
I don't necessarily agree but don't want to say more.

I don't think accusations of off-topic-ness at this point are very helpful.

You have been making strong claims about "pandemics" in general, which others have responded to by pointing out examples of pandemics that don't fit your claims. If by "pandemics" you meant "civilisation-ending pandemics" only, I think it was on you to make that clear.

2slg7mo
I think he was explicitly addressing your question of sexually-transmitted diseases being capable of triggering pandemics, not if they can end civilization. Discussing the latter in detail would quickly get into infohazards—but I think we should spend some of our efforts (10%) on defending against non-respiratory viruses. But I haven't thought about this in detail.
Concrete Biosecurity Projects (some of which could be big)

AIDS is considered to be an epidemic, not a pandemic, but can a sexually-transmitted disease similar to AIDS lead to a pandemic? I doubt it, because pandemics are dangerous (in part) due to rapid spread, a feature which a sexually-transmitted disease will never possess. I'd be a slightly more worried only if everyone was a lot more promiscuous.

The AIDs epidemic is widely considered a pandemic (pandemics are a subset of epidemics). And one of the deadliest pandemics of the 20th century, at that.

In the 19th century, cholera, a faecal-oral pathogen, caused several pandemics, killing very many people. It doesn't do that any more thanks to sanitation in rich countries, but it's certainly not impossible for non-respiratory pathogens to achieve rapid global spread.

Everyone agrees with you that respiratory viruses are the biggest concern, and you've provided some good resources in this thread that I appreciate. But I do think you are being undernuanced and overconfident here.

Yes, respiratory diseases are far and away the most likely causes of GCBRs, but even there there is risk from other types of disease. But we're discussing pandemics, and there you seem a bit misinformed.

First, the WHO has recently classified AIDS as an endemic disease, changing from its earlier classification as a pandemic. (Just like we'll do with COVID-19 in a couple years.) But that didn't make it not a pandemic until that point. And not only has AIDS killed 35m+ people - easily twice the total for COVID-19, but somewhere between 500k-1m more people wer... (read more)

Concrete Biosecurity Projects (some of which could be big)

Why would you be surprised if airborne transmission was the only way that any respiratory pathogen could cause a pandemic?

I haven't seen any strong empirical evidence that fomite transmission is even a thing and mechanistic reasons to doubt that it could cause a pandemic even if it were a thing. My mechanistic reasoning is this: fomite transmission would be too convoluted (e.g., nose → hand  → variable period of time → door knob → variable period of time → hand  → variable period of time→ nose) to be compatible with the sustained and rapid spread... (read more)

5Linch7mo
I can't find the source anymore but I remember being fairly convinced (70%?) that rhinovirus is probably spread primarily via formites, fwiw. The main thing is that snot can carry a lot more viruses than aerosols. It's also suggestive to me that covid restrictions often had major effects on influenza and RSV, but probably much less so on rhinoviruses [https://virologydownunder.com/rhinovirus-rampant-or-testing-triumphant/]. I also don't think we should necessarily overindex on viral respiratory diseases/pandemics, even though I agree they're the scariest.
Concrete Biosecurity Projects (some of which could be big)

Why are suits and substances used to sterilize surfaces (e.g., hydrogen peroxide, bleach) mentioned in relation stopping pandemics? Another post by one of the authors (ASB) of the current post mentioned a self-sterilizing suit regarding the same subject.

Suits and surface sterilization seems unnecessary, because that stuff does nothing to stop airborne transmission of viruses, which seems to be the only way that pandemics can ever arise.

Airborne transmission of respiratory viruses
https://doi.org/10.1126/science.abd9149

Just want to note that there are, in fact, 2 ongoing pandemics, and the earlier one, AIDS, isn't a respiratory virus. And those two obviously don't comprise an exhaustive list of possible transmission vectors.

In order for us to be safe from future pandemics, it's really important we don't overindex on the pandemics of the past (or the present).

SARS-CoV-2 doesn't really spread through surfaces/fomites much, if at all.

I'm sure the linked post is right to say that this is also true of "several respiratory pathogens". 

However I'd be surprised if it were true of all respiratory pathogens, let alone other diseases. Gastric/diarrhoeal diseases such as norovirus, rotavirus, or, indeed, ebola can spread through fomite transmission.

In short, I disagree that airborne transmission of viruses is the only  way that pandemics can ever arise.

Why SENS makes sense

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

Why SENS makes sense

Mutant mitochondria.

Why SENS makes sense

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

1InquilineKea2y
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.
Why SENS makes sense

Cytoskeleton damage can be upstream/causal

Too much tau junk → too much cytoskeleton damage

Lipofuscin

Too much lipofuscin/A2E → AMD

what SENS does right now is not sufficient

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

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

1InquilineKea2y
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.
Why SENS makes sense

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

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

Why SENS makes sense

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

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

Yes, this can get tricky. Do you have to directly fix everything ... (read more)

Why SENS makes sense

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

Why SENS makes sense

bowhead whales

birds

naked mole rats

more saturated cellular membranes...more resistant to ROS

deuterated PUFAs

protein variants expressed by centenarians

This is all messing-with-metabolism. How are you going to slow metabolism in humans? Supposedly, hyaluronic acid is what keeps naked mole rats from developing cancer. Do you think it would be a good idea to start injecting people with that stuff? Also, none of those animals avoid aging. Centenarians still age and die. More saturated cellular membranes and deuterated PUFAs might be more resistant to ROS, but... (read more)

Why SENS makes sense

it's much easier to fix oxidative modifications

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

200+ oxidative modifications

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

The scope of the aging problem is so vast

use all techniques

This would only matter a lot if you want to disentangle what me... (read more)

1InquilineKea2y
Preventing every single lipid and protein from going bad is precisely a problem that "AI" could help solve - one could envision artificially designed enzymes that can get into the cell and specifically modify every unnecessary oxidative modification. This is a bold claim that presumes that you and others know "all the right things to do" (rather than are adaptive) + underestimate the pure complexity of biology and very few people would believe you/SENS, and the tendency of SENS foundation people to make such claims are a reason why many doubt its credibility (some of the doubt is clearly unjustified, and stems from the uncharitable motivations of skeptics, but SENS people could at least be better at qualifying their claims).
Why SENS makes sense

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

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

1InquilineKea2y
Cytoskeleton damage can be upstream/causal if it affects lysosomal positioning [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201012/] (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/ [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.
Why SENS makes sense

cytoskeletal aging

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

map out causes of aging

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

dysregulation

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

1InquilineKea2y
https://www.sciencedirect.com/science/article/abs/pii/S1566312408600528 [https://www.sciencedirect.com/science/article/abs/pii/S1566312408600528] The cytoskeleton is how the neuron is able to transport mitochondria, proteins, lysosomes, and other organelles where they're supposed to be. Disruptions in axonal transport that happen due to cytoskeletal damage prevent the neuron from being able to transport cargo to the right places, especially to synapses). Dendritic size (and "stubs") often shrink wrt age in part due to decreased maintenance (the smaller spines shrink/die off more). and yes => the cytoskeleton IS how the neuron transports lysosomes to where they are needed, particularly in neurons. See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201012/ The process of CDA involves targeting autophagosomes to lysosomes, which requires a certain kind of spatial localization that can only happen when the proper spatial cues still exist [and anything affecting autophagy is extremely central to aging reduction/"reversal"]
Why SENS makes sense

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

Oxidation damage inside cells is caused by mutant mitochondria, and the SENS solution is to insert copies of non-mutant mito genes into the nucleus. This should prevent the cell... (read more)

Why SENS makes sense

AI/ML

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

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

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

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

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

1InquilineKea2y
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 [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/ [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536880/] The scope of the aging problem is so vast that we need all possible routes to discover all of the interventions (including ALL the > 200+ oxidative modifications that happen to proteins), and we may never get at all of the interventions without better tools. They might theoretically not be must-haves, but better be at the safe side and use all techniques. From Allen Brain Institute and Janelia and other institutes, we're seeing significant advances in our ability to image the cell and to get high throughput "-omic" data from cells, without needing too much human intervention [ever notice how Ed Boyden and Adam Marblestone are all into making better tools, even though they don't directly do bioscience research the way other biomedical researchers do it?]. Better tools help reduce the intense labor and time costs involved in figuring out the mechanism of an intervention. They also need to be paired with better post-PDF-publication platforms as the data they generate is not easily made available via PDFs. They're also the only way we can get to developing nanotechnology that can also play a role in identifying and removing damage.
Why SENS makes sense

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

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

Why SENS makes sense

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

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

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

Yeah... (read more)

1InquilineKea2y
Yes, damage to long-lived NPCs can be causative given that mislocalized nucleocytoplasmic transport can be causative in reduced autophagy with age. From Autophagy in aging and longevity Phase separation is important too... (an this only became a research fad 2 years ago)
1InquilineKea2y
SENS also doesn't mention cytoskeletal aging (eg https://www.molbiolcell.org/doi/10.1091/mbc.E18-06-0362 [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, [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.
1InquilineKea2y
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 [https://dagshub.com/blog/datasets-should-behave-like-git-repositories/]] 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/ [https://www.10xgenomics.com/spatial-transcriptomics/] can make everything in the future more machine-readable.
1InquilineKea2y
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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710712/]. The quote below is quite powerful~~
2InquilineKea2y
Lol, everyone in the SENS program tells people"GIVE US MORE MONEY AND MAGICAL THINGS WILL HAPPEN", but like, this seems to make other people feel like they can't contribute to changing the mission of SENS, given that it seems to delegate all control to whoever controls SENS. I know SENS creates mission reports and such, but so far they still haven't been great at convincing most HNWIs that SENS has made any real progress in the last 10-15 years. Funding may be necessary for progress and the chance to make a dent is probably worth it, but it's still not convincing enough for most people. There are far more ways to make an impact on aging than just donating more to SENS, and like, most of the anti-aging money seems to be flowing into ventures other than SENS (though expanding the number of possible routes people can take to slow aging rate is always helpful, even if it means doing silly N=1 things like injecting stem cells into one's own body) Is Balaji sufficiently convinced enough to donate a good fraction of his networth into SENS in the same way that Vitalik is convinced? You created a good example.. Regeneration/rejuvenation should ideally be guided by natural progenitor cells that don't require surgical precision. I agree we should still emphasize SENS-ish issues of removing protein aggregates (both intracellular and extracellular) in the brain. https://www.ted.com/talks/jocelyne_bloch_the_brain_may_be_able_to_repair_itself_with_help/transcript?utm_content=2021-1-18&utm_source=facebook.com&utm_medium=social&utm_campaign=social&fbclid=IwAR1IwHG5Wyp7KN6CKi0_IpeYPxPJ7B70kMBD8KNvkAlfpIxQfuBoLJng_OE I mentioned bowhead whales earlier, and while it may be true that they have slower metabolism, their longevities are still relevant in the same way that the longevities of birds (esp kakapo, sulfur-crested cockatoos, hyacinth macaws, and andean condors) are relevant - the birds are most relevant b/c they have faster metabolisms than humans (we know at least that they
Why SENS makes sense

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

Why SENS makes sense

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

... (read more)
1InquilineKea2y
more on mosaicism - https://twitter.com/jpsenescence/status/1084560766735450113 [https://twitter.com/jpsenescence/status/1084560766735450113] https://www.nature.com/articles/d41586-018-07737-8 [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...)
1InquilineKea2y
Also haven't you heard of the use of lasers to disrupt/destroy amyloid plaque? (which could presunmably also be useful for protein aggregates?)
5InquilineKea2y
#ALLTIMEIMPORTANTTHREADS #IMPORTANTTHREADS #INFLECTIONPOINTS #ALLTIMEMOSTIMPORTANTPOSTS #YOUWILLREGRETNOTINCORPORATINGMOREOFTHIS #ALLTIMEFAVORITEANSWERSOFAKC https://www.nature.com/articles/s42255-020-00304-4 [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 [https://www.google.com/books/edition/Aging_of_the_Genome/BIQSDAAAQBAJ?hl=en&gbpv=1&dq=jan+vijg+aging+of+the+genome+mosaicism&pg=PA201&printsec=frontcover] I would guess, that genetic mosaicism leads to a lack of intercellular coordination that manifests in reduced biological resilience/frailty (which can be measured by factors such as heart rate variability, neuroplasticity/learning speed, wound recovery rate, reductions in grip strength/general weakness, or dynamic morbidity index [https://www.biorxiv.org/content/10.1101/618876v1.full] - you need all the cell proteins to be positioned+posttranslationally modified at the right positions and amounts in order to correctly sense/signal, actuate and vary heart rate contractions). Cancer and cell senescence are much easier to detect/sense than other forms of age-related damage, but even if we removed ALL the leading causes of death (NONE of which C elegans die from), you still have the loss of biological resilience that causes ppl's respiratory capacity/FEV1/heart rate variability/grip strength to decrease with age that ultimately lead to weakness and death, like pharyngeal weakness found in C elegans (we know impaired proteaostasis plays a major/primary part of that in C elegans). Peter Nygard is another example (I KNOW he was talking to church lab people on this). You're only listing the most prominent indi
Why SENS makes sense

If you still feel unsure about the 7-KC thing, the following reasons should put your doubts to rest:

1) Although 7-KC accumulates, it doesn't aggregate.

2) If Hallmarks really thought that lipid accumulation belonged to the proteostasis hallmark it would have said so.

3) Hallmarks completely ignores 7-KC as a causative factor of atherosclerosis and instead ties atherosclerosis to "uncontrolled cellular overgrowth or hyperactivity" which is nonSENSical.

Why SENS makes sense

The proteins that the proteostasis hallmark talks about refers to proteins like beta-amyloid and tau that misfold and subsequently form aggregates. Proteins that are crosslinked aren't misfolded but rather they become "glued" together by a chemical reaction and don't form aggregates. 7-KC isn't a protein and doesn't misfold; it's an oxidized lipid.

1Emanuele_Ascani2y
Edited my comment slightly before yours appeared. Wanted to specify the reasons more but resolved to delete them since I was going to modify the post anyway. The rationale was that 7-KC, even if not a protein, is still an aggregate that overwhelms lysosomes and actively causes their dysfunction (loss of function of lysosomes and other degradation mechanisms being accounted for in the loss of proteostasis paragraphs in the Hallmarks).
Why SENS makes sense

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

The miscategorizations have only been partially corrected. 7-KC isn't related to Hallmarks, and the crosslink projects should be classified as "extracellular crosslinks" or "extracellular matrix stiffening."

1InquilineKea2y
Isn't early detection of cancer (and intervention) more feasible?
1Emanuele_Ascani2y
Yep, seems like for some reason I, err... aggregated extracellular matrix stiffening and extracellular aggregates together. Mistake corrected.
Why SENS makes sense

Well, it's complicated. Hallmarks is missing crosslinks, intracellular junk like lipofuscin and lipids like 7KC, and damaged elastin. SENS is partly missing genomic instability at least in SENS 1.0 (as you've mentioned), but it does include mitochondrial mutations which Hallmarks considers to be one aspect of genomic instability and mentions cancer as a consequence of nuclear mutations which are another aspect of genomic instability. SENS is also missing epigenetic alterations but might consider them for SENS 2.0. SENS doesn't consider telom... (read more)

1Emanuele_Ascani2y
I think SENS doesn't consider telomere attrition because the solution would be the same as the one for cell loss (and telomere attrition is a direct cause of cell loss). Also note that at SRF they consider the strategy against cancer less and less likely to be necessary (and I hope so, since it is the most far fetched and difficult). Edit: categorization mistakes corrected :)
Why SENS makes sense

I'd like to point out a few things.

1) The key reason why SENS makes the most sense as a way to cure aging is that—as with any physical system—structure determines function; by repairing damage that accumulates in the body's molecular and cellular structures, the normal, disease-free functioning of the body should also be restored.

2) A more detailed version of the SENS roadmap is available at SENS' original website.

3) You've miscategorized some of the SRF's projects.

4) SENS and Hallmarks aren't as similar as they ... (read more)

5InquilineKea2y
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) [https://www.biorxiv.org/content/10.1101/2020.10.09.331918v1] There should be more discussion on improving the general "efficiency" of biomedical science research (eg increased automation),
1Emanuele_Ascani2y
3) If you point out what categories I got wrong and why, I can correct if needed. 4) It seems to me that the biggest point of difference is the genomic instability hallmark, which is not present in SENS because de Grey believes it acts more slowly and probably belongs to a "SENS 2" panel of therapies. The others either mostly overlap or they are closely causally related. Do you agree?