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 telomere attrition as a significant type of damage, and in fact, SENS advocates removing the ability of all cells to extend their telomeres as a strategy to prevent cancer. Besides the differences regarding aging damage, the most crucial difference between SENS and Hallmarks is that most of the interventions that Hallmarks mentions won’t help out that much in reaching LEV.
Now, it should be even easier to figure out how to correct those miscategorizations.
Florin
- 2 Feb 2021 6:50 UTC; 3 points) 's comment on Anti-Aging: State of the Art by (LessWrong;
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.”
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.
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.
FWIW, both SENS and Hallmarks neglect the mentioning of A LOT of other kinds of damage but which are mentioned in Jan Vijg’s book (eg genetic mosaicism, improper stoichiometric ratio of synthesized proteins, histone loss, proteins and DNA not being localized in places they should be localized, accumulation of extracellular metabolites that get trapped in the cell and don’t get extruded out). SENS has many of the right high-level initial ideas regarding how to repair damage (it helps train people WHAT to look for regarding damage), but there are many more types of damage than what people have originally mapped (eg protein carbamylation, aspartic acid racemization, changes in membrane unsaturation index).
One has have to be careful about distinguishing between categories of damage and specific damage and whether what seems to be damage is associated with pathology or not. For instance, genetic mosaicism would belong in SENS’ “mutations in the nucleus” damage category. But there’s still some controversy about whether genetic mosaicism really leads to any age-related disease or condition, and that’s why SENS doesn’t target that particular form of damage yet. DNA damage in the nucleus can cause cancer and cell senescence and is targeted by OncoSENS and ApoptoSENS respectively. Bad stuff that accumulates inside cells would fall under SENS’ “intracellular aggregates” damage category, but if the stuff is inert or accumulates too slowly, it can be safely ignored. Protein carbamylation may accumulate too slowly to matter (since it’s excreted to some extent), but this isn’t well established. Aspartate racemisation was also thought to accumulate too slowly to matter, but recent evidence suggests that it might need to be a SENS target. I doubt membrane unsaturation should be a target, but I’ll look into it.
It’s unfortunate that a comprehensive and continually-updated list of specific SENS damage targets doesn’t exist anywhere. For instance, SENS doesn’t refer to asparagine isomerisation or medin amyloid accumulation as damage targets, but they are. I’ve wanted to create such a list for awhile, but I don’t know if I’ll find the time to make one.
There’s far too little discussion on bowhead whales—the warm-blooded organism that can live 200+ years. We know that living for 200+ years is organically possible in a warm-blooded organism, so we should figure out why. Some of the researchers who are most bullish on our ability to achieve LEV within 100 years come from the field of ecology/comparative metabolomics (eg Steve Austad, Michael Rose of UCI), precisely because they’ve seen the intense variation in longevity seen in different organisms.
SOME researchers have considered CRISPR’ing bowhead whale ERCC1/DNA repair genes into human tissue.
There’s probably not that much that can be learned from ageless animals and that can also be applied to humans. Whales are huge and have slower metabolism than humans; that’s probably why they live so long. So, slowing metabolism in humans won’t work.
There can be more discussion of novel techniques in bioengineering that haven’t received as much coverage (eg exosomes—which can be used to transport waste material into the cell and out of the cell), immunotherapies (cells can export SOME “junk” to be degraded/processed by immune cells like macrophages)
As long as those novel techniques don’t mess with metabolism, SENS could certainly make use of them. For instance, immunotherapy might be repurposed to eliminate senescent cells. However, I suspect that exosomes probably can’t be made to target specific junk or transport the junk where it can be safely eliminated.
There should be more discussion on improving the general “efficiency” of biomedical science research (eg increased automation), many which will make “boring” bioscience research occur faster (and also, ideally, not have most of their details get lost). Aging demands different/unconventional techniques in research dissemination where one’s precious research is interoperable with the research of everyone else and where intermediary work you do isn’t lost (eg there is A LOT of data that’s lost even with the publication of a journal article). FWIW, since aging is so different from other areas of biomedicine (and ideally should also be funded differently from all the other areas), it should respond to different incentive structures that aren’t seen in other biomedical fields.
Efficiency is outside the scope of SENS, but I agree that it makes sense to try to find ways of significantly speeding up more efficacious biomedical research by increasing outside-the-box thinking. And that’s why I sort of re-invented the idea of creating a DARPA-like agency for medicine to do just that, a few years ago. Something similar was proposed two decades ago by Lou Weisbach and Richard Boxer and was unsuccessfully championed by politicians such as Joe Lieberman. The 21st Century Cures Act and the NIH also fund high-risk, high-reward biomedical research, but the specific criteria for selecting which research projects get funded is kind of vague.
Also, from the POV of many people (esp billionaires and their family), it is in their rational self-interest to donate a significant fraction of their funds into fulfilling Pascal’s Wager—putting in millions of your dollars into tractable biomedical research per year is the only way to plausibly improve your “life satisfaction” once you realize that they have far more money than they have time available, and there are a huge number of understudied areas that deserve more basic research. I know juvenescence recently did a poll showing how many “rich people” would be willing to invest, say, 10% of their net income per year into living an extra 10-20 years if they were convinced that the extra money would help (this is kind of tantamount to Jim Mellon’s thesis).
Except for a few high-networth individuals like the Google bros (Calico), Larry Ellison (Ellison Medical Foundation), Jeff Bezos (Unity), and a few others, most HNWIs aren’t convinced that any amount of money would help or that it’s even a good idea (Bill Gates, Elon Musk).
They also don’t discuss the most obvious solution—gradual replacement (or transplantation) of all aged organs with new lab-grown or artificially produced organs. Growing new organs is a tractable problem that may be solved within a few decades—if this happens—the only thing left is repairing damage to the brain/head, and methods of neuronal replacement (eg what Jean Hebert discusses in his latest book), as already practiced in Parkinson’s patients, could be the most promising. It may also be possible that a human might be able to experience at least a few more decades if given a proper body transplant (eg reductions in GFR, or gradual kidney failure, that reduce the rate of “waste clearance”, causing waste accumulation to further accelerate.)
[also, the faster we can develop/grow replacement organs, the less suffering people get from chronic diseases = the slower rates at which they age]. I’m really surprised Aubrey de Gray hasn’t discussed this yet given its tractability.
Gradual neuronal replacement, by itself, would take too long to repair the brain; you’d still need SENS to repair the brain, and if you use SENS on the brain, you might as well use SENS on the rest of the body and avoid organ replacement altogether.
You should follow Jose Luis Ricon btw—he thinks that the issue is an engineering challenge and is solveable, and he is even collaborating with Adam Marblestone on that front.
While digital technology like mind uploading (if that’s what you’re referring to) should be pursued, biomedical methods to achieve immortality like SENS have a higher likelihood of succeeding, because it may turn out that consciousness is not substrate independent, and mind uploading is probably harder to achieve than SENS.
The question of substrate independence can be sidestepped by an approach that’s a hybrid of tissue engineering, digital technology, and nanotech: grow a new body without a brain, copy the old brain’s connectome, and nanotech the old brain’s connectome inside the new body’s skull (or grow it outside and insert it later). Unfortunately, this is probably a lot harder to achieve than even mind uploading.
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.
I would guess, that genetic mosaicism leads to a lack of intercellular coordination that manifests in reduced biological resilience/frailty....
As I mentioned before, it’s just a guess at this point whether or not genetic mosaicism is actually a problem that has to be dealt with right now, and that’s why SENS isn’t focused on it. If it becomes a problem hundreds of years from now as mutations accumulate, it’ll probably be an easy bridge to cross.
They don’t have to be convinced about immortality to really care about living longer for healthier....
Yeah, but the problem remains: they don’t think SENS is likely to succeed at significantly improving health or don’t have the expertise to evaluate it and the experts that they ask about it, tell them to just support non-SENS biomedical research instead.
...this convincing progress may still be dependent on general speedup of biotechnological tools that still might not fully manifest for another 10 years].
Actually, the most important limiting factor is the funding of the right research. There’s just no way around that regardless of how good tools become.
If you read Jean Hebert (and also ppl in the Gage lab at Salk—ESP Dylan Reid), you’ll see that people have already been starting to do gradual neuronal replacement on Parkinson’s patients....
But we’re talking about the entire brain here, not just the part that causes PD. If 1 cubic mm of brain tissue could be replaced every day, it would take about 3,561 years to replace all of it (the brain’s volume is about 1,300,000 cubic mm).
...solving one issue means there will only be ANOTHER rate-determining step of aging....
Right, so we’ll just have to whack ALL of the moles that matter in a normal lifespan, and monitor old-but-rejuvenated primates and people to see if and when any new moles (like genetic mosaicism) popup later.
We can collaborate....
If you have have a good understanding of SENS, you (and anyone else reading this) could search for active SENS-focused research projects in medical research databases and notify the SENS Research Foundation about them. This can help the SRF prioritize what research it funds and collaborate with projects funded by other organizations. This strategy is low-cost, high-impact, and I know it works well.
...(even all the current interventions suggested by SENS cover a small percent of ALL aging related damages....
If you know of any damage that’s not covered by SENS, let me know.
Also, it turns out that membrane unsaturation doesn’t need to be targeted.
...we can probably INCREASE the number of possible interventions if we write out ALL the forms of aging damage + all the forms that biotech HAS been advancing) in a format that’s MORE accessible/readable than yet another annoying journal article PDF because we are ALL force-fed more PDFs than we can deal with AND the amount of sensory contrast in PDFs [with each other] is SO low that they all blend in with each other in our sensory field, causing ALL of them to become indistinguishable with each other....
There are lists that track progress in the development of interventions (like LEAF’s Rejuvenation Roadmap), but unfortunately, they’re not comprehensive or SENS-focused. Along with that comprehensive damage list, I also wanted to create a comprehensive SENS project/intervention/company list, but the time thing got in the way.
...if you want to access the best thinking, you want to look at other fields/frameworks and not stay within the aging-framework....
I don’t see how a “better” framework than the repair-the-damage-without-messing-with-metabolism kind can exist. If anything will work at curing aging, it has to be damage repair almost by definition; it’s the whole structure-determines-function thing I mentioned earlier.
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.
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.
Slowing the rate at which damage accumulates is generally a bad idea, because damage will continue to accumulate until it kills you. Instead, SENS proposes to periodically repair that damage in order to keep it below the threshold at which it would cause pathology. However, there are a few exceptions to periodic-repair rule such as when dealing with mitochondrial mutations and WILT.
Oxidation damage inside cells is caused by mutant mitochondria, and the SENS solution is to insert copies of non-mutant mito genes into the nucleus. This should prevent the cell’s degradation machinery from being overwhelmed by having to process too much oxidized protein junk. Declines in cellular function are partly caused by mutant mitos, and this may also explain why 20S Proteasome function can also decline.
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.
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.
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 metabolism is doing (which is vast) and try to get it to do the impossible: prevent every single lipid and protein from going bad. I doubt even an AI god could make that happen, nevermind mere mortals equipped with what amount to fancy expert systems.
Better tools help reduce the intense labor and time costs
Better funding is better than better tools. If SENS got $100 million per year starting in 2004 or even as late as 2010, we’d already have immortality in the bag or know that SENS couldn’t deliver the goods and moved on to something else.
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 that will only slow aging at best, not reverse it. There’s just no reason to think that MWM could ever cure aging.
Protein traffic jams
isn’t mentioned by SENS and can occur even w/o protein aggregates or lipofuscin
Actually, they occur due to TDP-43 and FUS aggregates gumming up the nuclear transport system. The SENS solution is to get rid of this aggregate junk, of course. These specific aggregates aren’t mentioned by SENS, but they fit within the SENS damage category of “intracellular aggregates.”
mitochondrial transfer
as an alternative to mitoSENS
Yeah, but what happens to the mutant mitos?
And in any case, this can be considered a different approach to MitoSENS, not an alternative. Yet another approach is the Shift effect. MitoSENS isn’t wedded to the notion of copying non-mutated mito genes into the nucleus.
IPSCs and epigenetic/genetic reprogramming
iPSCs are useful for stuff like WILT and to replace cells that aren’t so easily replaced in organs like the brain.
Transient reprogramming is also potentially useful, but more research is needed to determine whether or not it could lead to cancer.
glycosylation
This seems more like age-related changes in glucose and hormone levels that should return to normal once the relevant damage is repaired, rather than something for SENS to target directly, but I’ll need to double check.
This sounds like (or is) the TDP-43 and FUS aggregates gumming up the nuclear transport system that was mentioned earlier.
Spliceosomes are super-relevant too given how they are upstream of everything else (William Mair has shown that dysregulation in these accelerates aging, and correcting the defects can up lifespan)
You can argue that “ER + aging”, “golgi + aging”, or any “cell process/component + aging” is going to cause some downstream effects on aging, and to fix everything, you have to “fix” the ER, fix the spliceosomes, fix the cytoskeleton, fix the golgi, fix the NPCs, fix the histones, whatever.
Yes, this can get tricky. Do you have to directly fix everything that goes wrong? If not, how do you know what damage to directly fix?
The stuff that needs to be directly targeted in the cell (ideally, before cellular structures are damaged too much) is damaged or aggregated lipids and proteins and mutations in the mitochondria. This is the primary damage that generates secondary damage to cellular structures (like cytoskeletons and nuclear transport systems). Mutations in the nucleus aren’t targeted directly but are dealt with by WILT (or whatever could cure all cancer forever) and senescent cell killing via senolytics or whatever could get rid of them. So, fixing this primary damage should prevent most of the secondary damage from ever occurring, and if lots of secondary damage has already occured (like in older people), the repair of the primary damage may allow the self-repair machinery of the cell that still works to repair itself and the rest of this secondary damage.
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.
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.
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.
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 first appear. Sometimes, there’s no overlap between SENS and Hallmarks. And unlike SENS, Hallmarks advocates lots of messing with metabolism.
5) Human Bio never took off and now Repair Biotechnologies has replaced it.
6) SRF publications are available here.