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.
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.