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Small molecule cognitive enhancer reverses age-related memory decline in mice
- strangattractor 4y agoI was just getting use to calling whatchamcallit thingamabob:)
- michaelangerman 4y agoEventually we will figure out how these chemicals work to combat a disease that is currently not well understood. Great news !
- csdvrx 4y agoIt says in the first line "The integrated stress response (ISR) is activated during aging" Odds are the same basic mechanism is activated by many other things, including some inflammation process.
- galangalalgol 4y agoYeah, I am considering purchasing ISRB "for research". Some people I love suffer with chronic inflammation due to various autoimmune diseases. I know plenty of amateur body builders buy chemicals "for research" but use them as supplements. They keep tabular and video artifacts like most body builders do, so I wonder to what degree the activities are illegal?
- csdvrx 4y agoNo idea, but unless it's on a restricted list (classified by the DEA), I think "not at all".
- voldacar 4y agoThe problem with ISRIB is that it isn't water soluble. I'm not convinced that people who take it (usually subcutaneous injection or snorting it) aren't just experiencing placebo. I don't know of any way of actually getting the molecule to your body's cells in a consistent manner.
- galangalalgol 4y agoThe study dissolved it in DMSO, then that in polysorbate 80, then that in polyethylene glycol. Then injected that intraperitoneally. That seems doable.
- whatshisface 4y agoI could be missing something, but since your cells are separated by water, it doesn't matter how many steps you take to get it in your body.
- galangalalgol 4y agoDMSO is soluble in both polar and non polar solvents. I assume the insolubility in water is precisely what they used it to solve. Im any case, their delivery mechanism worked in mice, so it would work in people. The part that might not carry over to people is the effect once in the cell.
- voldacar 4y agoIntraperitoneal injection isn't really done in humans, the closest equivalent would be subcutaneous or maybe intramuscular injection. I don't know about the safety of injecting DMSO into humans but it's probably not too bad since it seems perfectly safe when used for transdermal drug delivery. The bigger problem is that you're injecting a water-insoluble compound mixed in a small amount of solvent into what is essentially a big bag of water. Once that DMSO/PEG/whatever is injected, it will just mix with the water in your body, so the ISRIB will just precipitate out of solution since it is now surrounded by 99% water molecules. So it will never get distributed to all your organs, which is the goal.
- oaktrout 4y agoI am cringing so hard imaging someone injecting something intraperitoneally. Good luck missing your intestines.
- IndigoIncognito 4y agoI need this, I just caught covid recently and I struggled to read the title
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- mrtesthah 4y agoYour microglial cells are overly reactive. https://www.sciencedirect.com/science/article/pii/S0092867422007139 https://www.sciencedirect.com/science/article/pii/S009286742... Try NAC, CBD, PEA (Palmitoylethanolamide; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9406356/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9406356/), DHA/EPA (fish oil) and other things to reduce brain inflammation. But trans-ISRIB looks exactly on point in its particular mechanism. You can already import it in bulk from manufacturers like nutrabiotechchem.com.
- mrtesthah 4y agoIt looks like low-dose naltrexone works, too: https://www.reuters.com/business/healthcare-pharmaceuticals/addiction-drug-shows-promise-lifting-long-covid-brain-fog-fatigue-2022-10-18/ https://www.reuters.com/business/healthcare-pharmaceuticals/...
- derefr 4y agoHow about cerebrolysin? A friend of mine who suffered a traumatic brain injury swears by it.
- jokowueu 4y agoNever heard of netrabio before and I'm generally knowledgable about such sites Also Are you currently on any discord servers ?
- norwalkbear 4y agoJust a reminder mouse physiology is not human. This is a great start but hacking biology is not the same as pcs. I add this warning because I'm seeing a lot of younger software engineers try out custom peptides to boost their iq, memory, and work ability.
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- Avicebron 4y agoAlso laboratory mice are not necessarily comparable to the diversity in genetics of even wild mice (or the genetic diversity of the human population if we want to extrapolate).
- causi 4y agoI add this warning because I'm seeing a lot of younger software engineers try out custom peptides to boost their iq, memory, and work ability. Eh, I say let 'em. People need to stop pretending aging isn't a tragedy just because it's our natural state. We should be as bold with treatments for it as we are with treatments for other fatal diseases.
- generalizations 4y agoJust get them to write down their results somewhere. Enough anecdotes might turn into anecdata.
- treeman79 4y agoDid this a lot when I was having severe dementia problems. Would track results on various medications to see what worked. 95% made a bad situation much worse. Memantine Had a moderate boost. Went on a Blood thinner and everything resolved.
- mota7 4y agoDo you know why the blood thinners helped? (I'm assuming there was some underlying condition that this treated?)
- csdvrx 4y agoAs usual, I fear comments will focus on the "in mice" part, forgetting that for most base circuits (ex: brain, nerves ...) and physiology (scarring, aging, inflammation ...) they are extremely close. Also, other "cognitive enhancers" have usually found effects in both rodents and primates.
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- BoorishBears 4y agoAnd instead as usual, any useful commentary will be drowned out by people rushing over themselves to point out that humans aren't mice.
- glenstein 4y agoExactly. I feel like it's the equivalent of the Onion article that pokes fun at that type of behavior: >Learned Sage Points Out That Powerball Not As Much After Taxes https://www.theonion.com/learned-sage-points-out-that-powerball-not-as-much-afte-1819578523 https://www.theonion.com/learned-sage-points-out-that-powerb... Whether it's mice or powerball, the lowest hanging fruit is the Learned Sage comment, noting that things aren't quite as they seem.
- civilized 4y agoAnd then someone will come in and tell you that most things tried in mice don't work out in humans, and we will issue a collective shrug as we don't know what to believe.
- csdvrx 4y agoWhat doesn't work in mice is typically for mouse-models of diseases: we try to replicate a disease based on what we think causes it, then try to cure it. That's typical for cancer, Alzheimer etc. No wonder the things tried in the toy problem don't work out when faced with the real problem! The problem isn't so much the mice being so different, but the disease itself being very different from the toy problem.
- dzink 4y agoMice will take over the world. We’ve fixed aging, cancer, and a lot of other issues in Mice, so now they will outlive us.
- sinenomine 4y agoOf course translational research is necessary with such results. Explicit goal of developing cognitive enhancing therapies set by NIH would greatly help motivate such research.
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- Stupulous 4y agoI would love to see a project to raise optimized mice using the tremendous amount of research on them. Is anyone doing that already?
- stjohnswarts 4y agoThat would be pretty good, apply the best cancer prevention, longevity producing, cancer protecting treatments available to 100 mice, compared to the diet of a typical American in 100 other mice (not very ethical I know) and see what happens.
- Silverback_VII 4y agoI for one do not understand that we do not share our discoveries with nature. After all these animal experimentations we have big debt. It would only be decent to give something back. I think we already made stronger and smarter(with human brain cells) mice. What if make every wild animal smarter in the same fashion? Can we also improve photosynthesis?
- dzink 4y agoBecause we compete for resources with animals and there is no inhibition to prevent them from deploying additional intelligence to hurt, hunt, or starve humans.
- ProjectArcturis 4y agoI'll offer 100-1 odds that this never turns into a human treatment.
- computerphage 4y agoI'll take the bet. I pay you when it "never" does, and you pay me if it ever does. How does $1 and $100 sound?
- ProjectArcturis 4y agoEngineers are the worst.
- qart 4y agoThe bet might work in your favor. Lots of candiate drugs are discarded for reasons like... having harmful side-effects, being found useless, etc.
- computerphage 4y agoJust because something is dismissed today as a promising candidate doesn't prove it'll never be used for something else in the far future. Many toxic drugs later found use in chemotherapy for cancer; it was suddenly good they were toxic
- RichardCNormos 4y agoI, too, keep my specifics in the pedantry.
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- gthippo 4y agoISRIB is licensed by Calico which recently initiated phase I trials for its use in ALS (https://www.massgeneral.org/news/press-release/investigational-drug-initiates-design-phase-for-healey-als-trial https://www.massgeneral.org/news/press-release/investigation...)
- derefr 4y agoFor what it's worth, just as an amateur chemist staring hard at the molecule, it looks like the ligand (the outer bit that plugs into receptor binding sites) consists of a monochlorinated benzene ring. Which would likely put this in the same drug class as https://en.wikipedia.org/wiki/Bromantane https://en.wikipedia.org/wiki/Bromantane, whose ligand is a monobrominated benzene ring — and which is also a "cognitive enhancer" nootropic with a thusfar not well understood mechanism-of-action. The naive assumption some people make is that bromantane (and so probably also ISRIB) would have an at least partially similar MoA to amphetamine, given that amphetamine has a plain old benzene ring hanging off of one end of it; but IIRC that is incorrect, as, in amphetamine, the benzene is not the ligand — rather, the amide group on the other end is.
- toddm 4y agoComputational chemist here, working at the moment on small molecule ligands in the context of drug discovery. The small molecule itself is the ligand. There is interaction of the ligand with the binding site amino acids via hydrogen bonds to several locations on the ligand. Have a look at the RCSB PDB entry for 6EZO - ISRIB bound to eIF2B (the 3D view is https://www.rcsb.org/3d-view/6EZO https://www.rcsb.org/3d-view/6EZO), turn on Dynamic Bonds and click on the ligand. While this static shot does not reveal all the interactions (such as those that are longer-range, cation-pi, water-mediated, and so on) that one would see in a molecular dynamics simulation or by docking, it's very useful. Finally, when benzene is attached to something, it's a phenyl group; amphetamine is the ligand; and the functional group is amine, not amide.
- derefr 4y agoThanks for that. Is there a term for a part of a molecule that takes part in “medium range” interactions — making the molecule electrostatically attracted toward/repulsed away from specific macromolecule binding sites, like is happening with the hydrogen bonds here — but which don’t then take part in any kind of redox or polymerization reaction once the molecule reaches close enough for such to take place? Because that’s what I meant here by trying to distinguish which part of these molecules is the ligand: which part is getting directly chemically reacted with / away (triggering the state change in the receptor), vs. the part being interacted with only indirectly in the sense of “a key that fits into a molecular lock vs. a key that doesn’t”. What I’ve been told is that the phenyl group in amphetamine isn’t reacted with / reacted away by a DA receptor binding site, but rather just gives it its binding affinity by being the right shape to fit into (and the right charge + mass to be attracted by) DAR and DATR binding sites without the indirect forces of the “walls” of these receptors repulsing it. Under this logic (if it’s sound, which you seem to be saying it’s not), a brominated phenyl group would really just be a bromide ion in direct reaction terms — it’d theoretically attach to any chloride channel. The phenyl group it’s riding on, would — along with the rest of the molecule — serve to ensure that the bromide ion only gets to come into contact with chloride channels inside receptors that allow a phenyl group inside them, rather than repulsing phenyl groups, or not being the right shape to accept phenyl groups. (This logic — again, if sound — would also suggest that chlorhexidine would have a similar nootropic effect if it could cross the blood-brain barrier.)
- pfisherman 4y agoIf you are looking for a cognitive enhancer then caffeine and modafinil / provigil have been proven to enhance focus. I believe that latter of those is used extensively by fighter pilots and other military to stay alert; and the former is used by pretty much everybody for the same purpose. I know drink a cup of coffee is probably not the answer a lot of the nootropic heads are looking for; but I don’t think there are any silver bullets here.
- x86x87 4y agoOn top of that coffee also contains chlorogenic acid which allegedly is good for longevity
- stjohnswarts 4y agoThis is one of the reasons I switched to fine mesh coffee filter (metal) a while back, instead of paper filters, hoping to get more of the goodness of coffee in me. Although it does let cafestol through as well, but that doesn't seem like much of a big deal if you don't have any cholesterol issues.
- giardini 4y agoTry a Vietnamese coffee maker: they're little more than a stainless steel filter and cost only a few bucks. The coffee is strong: https://www.wikihow.com/Make-Vietnamese-Coffee https://www.wikihow.com/Make-Vietnamese-Coffee Oh, the usual coffee is "Cafe Du Monde" (in the orange can).
- zoklet-enjoyer 4y agoI've taken adrafinil off and on over the years and it doesn't do much of anything for me. Not sure if I'm expecting too much or what's going on with that.
- giardini 4y agoA cup of coffee beats provigil's side-effects: skin rash or hives, blisters or peeling, mouth sores, trouble breathing or swallowing, fever, swelling in your legs, dark urine, yellowing of your skin or eyes, or swelling in your face!? And there's more: https://www.drugs.com/provigil.html https://www.drugs.com/provigil.html Modafinil/provigil might be worse than crack!
- SnowHill9902 4y agoWhat’s the catch? It’s usually less plasticity.
- everybodyknows 4y ago(2020)