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.
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.
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.
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
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)
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.
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)
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.
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.
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).
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”]
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.
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.
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.
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.
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.
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.
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)
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. ”
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.
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.
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).
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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’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)
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.
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)
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.
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.”
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 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.
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.
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)
This sounds like (or is) the TDP-43 and FUS aggregates gumming up the nuclear transport system that was mentioned earlier.
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.
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.
Do you have evidence that this may be a cause of normal human aging rather than of progeria and aging in worms?
The SRF is always on the lookout for new categories and kinds of damage.
This is the structure = function thing again. Fix the structure and function should return to normal by definition.
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”]
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.
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.
Too much tau junk → too much cytoskeleton damage
Too much lipofuscin/A2E → AMD
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.
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.
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.
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.
Mutant mitochondria.
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.
Again, better tools are nice-to-have, not must-haves.
It’s way easier just to clear them out...
...like this. But it’s already part of the (SENS) plan.
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/
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.
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.
How many of those actually matter? I’d expect that most get degraded, and the rest float around doing bad stuff or form aggregates.
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 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.
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).
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.
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~~
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.