[HN Gopher] Small molecule cognitive enhancer reverses age-relat...
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Small molecule cognitive enhancer reverses age-related memory
decline in mice
Author : clockworksoul
Score : 100 points
Date : 2022-10-15 15:20 UTC (7 hours ago)
(HTM) web link (pubmed.ncbi.nlm.nih.gov)
(TXT) w3m dump (pubmed.ncbi.nlm.nih.gov)
| IndigoIncognito wrote:
| I need this, I just caught covid recently and I struggled to read
| the title
| [deleted]
| mrtesthah wrote:
| Your microglial cells are overly reactive.
| https://www.sciencedirect.com/science/article/pii/S009286742...
|
| Try NAC, CBD, PEA (Palmitoylethanolamide;
| 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.
| jokowueu wrote:
| Never heard of netrabio before and I'm generally knowledgable
| about such sites
|
| Also Are you currently on any discord servers ?
| derefr wrote:
| How about cerebrolysin? A friend of mine who suffered a
| traumatic brain injury swears by it.
| norwalkbear wrote:
| Just 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.
| [deleted]
| Avicebron wrote:
| Also 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 wrote:
| _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._
|
| 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 wrote:
| Just get them to write down their results somewhere. Enough
| anecdotes might turn into anecdata.
| bglazer wrote:
| Me and every one of my friends have seen this horse named
| Hans, very clever, that could understand everything its
| trainer said. He could do arithmetic too! I don't
| understand why big psychology won't take our data seriously
| and finally accept that horses are capable of long
| division.
| treeman79 wrote:
| Did 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 wrote:
| Do you know why the blood thinners helped? (I'm assuming
| there was some underlying condition that this treated?)
| tsol wrote:
| >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.
|
| We don't encourage people to experiment with self medicating
| themselves for cancer and multiple sclerosis, because it's
| dangerous and most people have no idea what they're doing.
| It's pretty much the same thing here. I know it'll happen
| either way, but I wouldn't recommend it to the average
| person.
| causi wrote:
| _I know it 'll happen either way, but I wouldn't recommend
| it to the average person._
|
| Hence "let them", not "encourage them". The average person
| doesn't have the slightest idea what a "custom peptide" is.
| whatshisface wrote:
| But you're responding to a warning with "let them," not a
| bill in congress.
| pfisherman wrote:
| If 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 wrote:
| On top of that coffee also contains chlorogenic acid which
| allegedly is good for longevity
| stjohnswarts wrote:
| This 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 wrote:
| Try 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
|
| Oh, the usual coffee is "Cafe Du Monde" (in the orange
| can).
| giardini wrote:
| A 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
|
| Modafinil/provigil might be worse than crack!
| HyperSane wrote:
| I have used provigil and had zero side effects. All it does
| is allow me to code for many hours.
| zoklet-enjoyer wrote:
| I'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.
| csdvrx wrote:
| As 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.
| stjohnswarts wrote:
| then why do 98% of these "promising" results turn out to be
| ineffectual in humans if we're that close biologically?
| [deleted]
| BoorishBears wrote:
| And instead as usual, any useful commentary will be drowned out
| by people rushing over themselves to point out that humans
| aren't mice.
| glenstein wrote:
| Exactly. 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-
| 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.
| mtlmtlmtlmtl wrote:
| It's not just a question of efficacy, but also safety, which
| can depend on more than just the systems relevant to efficacy.
| civilized wrote:
| And 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.
| ethanbond wrote:
| The nice thing is that you don't need to decide what to
| believe. You just keep doing experiments and, if well
| designed, they'll tell you what's true anyway. These animal
| model experiments are not intended to prove applicability to
| humans, they're intended to prove that you can take the next
| (tiny) step along the (extremely long) road to human
| applicability.
| glenstein wrote:
| Which in and of itself is sufficient to proceed with "huh,
| cool! keep up this line of research!"
| gfodor wrote:
| Mice shedding
| csdvrx wrote:
| What 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.
| civilized wrote:
| So how is the enhancer mouse research different from the
| disease mouse research that you acknowledge often doesn't
| work?
| csdvrx wrote:
| It isn't tried on a disease model, but on a core
| mechanism: aging.
| Avicebron wrote:
| spherical mice.
| civilized wrote:
| This all hinges on the idea that, while disease is too
| different between species for insights to transfer well,
| aging isn't like that?
| glenstein wrote:
| Right. Their first comment was about the similarity of,
| in their words, base circuits and physiology.
| civilized wrote:
| I just don't know if it's obvious that aging is a matter
| of base circuits and physiology and disease is less so.
| strangattractor wrote:
| I was just getting use to calling whatchamcallit thingamabob:)
| SnowHill9902 wrote:
| What's the catch? It's usually less plasticity.
| michaelangerman wrote:
| Eventually we will figure out how these chemicals work to combat
| a disease that is currently not well understood. Great news !
| csdvrx wrote:
| It 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 wrote:
| Yeah, 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?
| voldacar wrote:
| The 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 wrote:
| The study dissolved it in DMSO, then that in polysorbate
| 80, then that in polyethylene glycol. Then injected that
| intraperitoneally. That seems doable.
| voldacar wrote:
| Intraperitoneal 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.
| whatshisface wrote:
| I 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 wrote:
| DMSO 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.
| csdvrx wrote:
| No idea, but unless it's on a restricted list (classified
| by the DEA), I think "not at all".
| derefr wrote:
| For 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, 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 wrote:
| Computational 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), 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 wrote:
| Thanks 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.)
| dzink wrote:
| Mice will take over the world. We've fixed aging, cancer, and a
| lot of other issues in Mice, so now they will outlive us.
| Stupulous wrote:
| I would love to see a project to raise optimized mice using the
| tremendous amount of research on them. Is anyone doing that
| already?
| stjohnswarts wrote:
| That 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.
| [deleted]
| Silverback_VII wrote:
| I 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?
| sinenomine wrote:
| Of course translational research is necessary with such
| results. Explicit goal of developing cognitive enhancing
| therapies set by NIH would greatly help motivate such research.
| ProjectArcturis wrote:
| I'll offer 100-1 odds that this never turns into a human
| treatment.
| minifridge wrote:
| ISRIB has toxic effects on the liver, afaik from presentations
| i have seen. So yeah, unlikely it is going to pass any clinical
| trial
| computerphage wrote:
| I'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 wrote:
| Engineers are the worst.
| qart wrote:
| The bet might work in your favor. Lots of candiate drugs
| are discarded for reasons like... having harmful side-
| effects, being found useless, etc.
| RichardCNormos wrote:
| I, too, keep my specifics in the pedantry.
| [deleted]
| dang wrote:
| " _Please don 't post shallow dismissals, especially of other
| people's work. A good critical comment teaches us something._"
|
| https://news.ycombinator.com/newsguidelines.html
| [deleted]
| gthippo wrote:
| ISRIB is licensed by Calico which recently initiated phase I
| trials for its use in ALS
| (https://www.massgeneral.org/news/press-
| release/investigation...)
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