InquilineKea

aka Alex K Chen

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Some unfun lessons I learned as a junior grantmaker

Just out of curiosity - how much time is wasted on evaluating half-ass'ed proposals?

>People are often grateful to you for granting them money. This is a mistake.

Sometimes they're resentful if you reject them (though this depends on community and is probably highly asymmetric).

How could Twitter be tweaked to promote more rational conversations, now that Elon is on the board?

Categorizing one's favorites (or putting them in folders) so one doesn't have to scroll through them all to the beginning.

Call For Distillers

At what point can large language models start to do distillation, especially of the early LW sequences?

Why SENS makes sense

more on mosaicism - https://twitter.com/jpsenescence/status/1084560766735450113

 

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...)

Why SENS makes sense

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.

Effects of anti-aging research on the long-term future

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.

Why SENS makes sense

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.

Why SENS makes sense

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.

Why SENS makes sense

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).

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