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.
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.