All of Florin's Comments + Replies
Rather than focusing on ventilation, I suggest thinking about recommending the voluntary use of respirators (preferably the elastomeric kind) instead. The problem with ventilation (even if it was theoretically 100% effective) is that it's only as good as how it was setup and maintained, and during a dangerous pandemic, I wouldn't trust any of these external systems to function properly.
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.
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."
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...
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.
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.
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...
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.
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.
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...
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...
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.
There's no compelling evidence that these kinds of mutations cause bad stuff to happen in a normal lifespan.
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.
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.
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.
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 ...
This sounds like (or is) the TDP-43 and FUS aggregates gumming up the nuclear transport system that was mentioned earlier.
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...
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...
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.
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.
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...
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.
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.
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...
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.
...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
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.
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.
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."
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...
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 ...
It should be emphasized that experts should start recommending that every single person in the world obtain their own effective (preferably elastomeric) respirator as soon as possible. This would eliminate any supply chain issues and most (and all with a good monitoring system) GCBR-type pandemics. As better respirators are developed, people with the older kind would be encouraged to upgrade.