aka Alex K Chen
more on mosaicism - https://twitter.com/jpsenescence/status/1084560766735450113
João Pedro MagalhãesThe large number of mutations with age recent studies are finding in some human tissues showcase how difficult it will be to significantly intervene in aging because we can't easily get rid of mutant cells and replace them by pristine cells.
João Pedro Magalhães
The large number of mutations with age recent studies are finding in some human tissues showcase how difficult it will be to significantly intervene in aging because we can't easily get rid of mutant cells and replace them by pristine cells.
https://www.nature.com/articles/d41586-018-07737-8 is very deep too - actually it hints that many older cells are dominated by pro-growth/pro-survival mutations that don't complete all the necessary conditions for cancer (but it just shows how cancer is the adaptive response of A LOT of other responses that are pro-growth/survival in ordinary cells that USUALLY don't result in cancer...)
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.
On moral progress - I think it's highly plausible that future generations will not be okay with people dying due to natural causes in the same way that they're not okay with people dying from cancer or infectious diseases.
Too much tau junk → too much cytoskeleton damage
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.
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.
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).
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 autophagyThe 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)
Do you have evidence that this may be a cause of normal human aging rather than of progeria and aging in worms?
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.
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/
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"]
It's way easier just to clear them out...
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.
Isn't there a difference between creating entirely new frameworks, and just adopting frameworks to different species in parallel?
For instance, it seems that adopting frameworks to different species in parallel often ends up happening over time (as we've seen people gradually adopt cognitive ethology from chimpanzees and captive dolphins into wild dolphins, elephants, african grey parrots, kea [where academic labs do exist to study them], capuchin monkeys, and new Caledonian Crows). It seems that some species of animals are intensively studied, and the vast majority of others not so much (like, WHERE are the Irene Pepperbergs on storks and pelicans or Andean Condors or deer?).
One thing I've often noticed is how little attention is spent on studying individual orders of protists and very small animals (especially nematodes that aren't C. elegans or most species of invertebrates), which should presumably have even more genetic diversity than what we see in charismatic megafauna.I know there is a conference specifically for tardigrades, but it hasn't gotten much attention..
As for cognitive ethology - people like Louis Herman, Joyce Poole (of elephants), Andrea Marshall (of manta rays) all seemed to get funding through independent research institutes. It seems that sometimes they get support from sources that overlap with sources that support zoos?
John Marzluff def gets a lot of academic support for studying crows (and before that, prairie dogs)