ISRIB (the molecule discussed in the article) seems _very_ promising for brain health. But people who (recklessly?) self-experimented with it had strange cardiac issues. A study on dogs discovered heart anomalies. It’s nicely summarized here: https://forums.phoenixrising.me/threads/isrib-to-treat-me-cf...
Wow, that sounds pretty incredible. Part of what makes it sound promising to me is the extent of the "no free lunch" aspect: anecdotal reports of not just cardiac issues in humans and dogs but increased brain fog (mitigated with feed consumption...?), blunted emotions, inability to get drunk (maybe a plus?), accelerated cell death, psychosis and hallucinations - in exchange for, allegedly, reversing Alzheimer's and repairing lifelong brain damage:
>One report of a person who gave ISRIB to their grandmother who had terminal stage Alzheimer's. She began to remember everyone. But died after 4 months (this may have been from old age and her type 1 diabetes).
>One anecdotal report of a short course of ISRIB permanently fixing some prefrontal cortex brain damage in a Russian guy, caused by a car crash when he was a child. The repair to the brain was confirmed by MRI scans taken before and after the ISRIB treatment.
Plus a pretty clear mechanism of action. Definitely sounds like it's worth significant study.
I mentioned this in another thread [1] but this idea of "no free lunch" is nothing more than a human aberration. There are many things in life that are free lunches, including drugs you put in your body but we as humans have such an overriding need to balance the scales of life we conveniently overlook them.
Pattern recognition is helpful to a certain extent in life but we should be careful applying it arbitrarily and try to be aware of when we are doing it.
I took a host of weird nootropics when I was younger. The most experimental was NSI-189. My experience is plenty of these drugs were gratis lunches but I wasn't enrolled in a study and don't have hard numbers to show you.
The scariest (potential) downside to nootropics to me is an increased risk of cancer. Because if your normal cells are healthier, cancerous cells are also healthier. As a younger person, cancer is less of a risk so nootropics are less of a risk too.
So I was curious, with that in mind, where the free lunch drugs are? As in, which ones did you enjoy most and why stop taking them?
In my opinion, a free lunch drug is something like lion's mane, a mushroom, which depending on the study we're looking at can induce neurogenesis, improve cognitive function and reduce anxiety. [1]
It's something I still take today.
I'm clinically prescribed modafinil for ADHD, which has immeasurably improved my life. I can guarantee I would not be employable as an SRE today without it. Low dose modafinil (50 mgs) is a free lunch for me and, if you believe the anecdotes, for tons of redditors out there. At the dose I recommend, it's all upside (I feel I must emphasize for me with a clinical diagnosis).
Those are the two I have extensive experience with that I see no downside to regular consumption of.
Yes, that's a real risk. Check out this thread, which /r/Nootropics has wisely kept stickied for a while: https://www.reddit.com/r/Nootropics/comments/pbz9mx/warnings.... It's an anecdotal report of nootropic use not necessarily inducing cancer but potentially making cancer spread much more aggressively.
One definitely shouldn't try nootropics without very thoroughly studying the risks. I sometimes take certain (seemingly) low-risk ones, like racetams combined with choline supplements. (For example, oxiracetam + alpha-GPC.)
> So I was curious, with that in mind, where the free lunch drugs are?
Nothing in life is "free lunch", not even free lunch. At the very least you have to expand time to fetch it, eat it and deal with a slightly increased risk of food poisoning afterwards.
But that is often times a very fitting metaphor when comparing the upside of a lot of drugs to their downside: It does not have to be free, to be free. If you have an infection that would otherwise kill you, an effective antibiotic is close enough to free to be a no-brainer.
The idea behind the no free lunch principle is that if a small molecule drug exists that can realistically be biologically produced in humans (ie not penicillin) we would probably have evolved that ability already, because we're very well optimized by now.
I don't think so, we don't even produce vitamin B12. The "no free lunch" only applies to things we already produce, like we already produce dopamine so getting more will have consequences for healthy people or we would have evolved to produce more.
The no free lunch idea is mostly a question of trade offs. For example Humans naturally produce antibiotics, however prescribing them in large numbers could be very risky potentially significantly compromising everyone’s immune system worldwide.
That said, it’s very possible for diseases to have very simple cures that people simply aren’t producing enough of. Evolution is great at population level optimizations over time, but it can really suck for individuals.
You can’t just evolve to produce any random molecule especially anything with actual chemical complexity. Scores of extremely complex enzymes are needed to produce cholesterol and pretty much all small molecule steroids we produce are derivatives of it. Plants have a vast repertoire of enzyme pathways to produce many small molecules which they can mix and match quickly to produce compounds of great chemical complexity but humans cannot.
Evolution is not going to evolve longer-life genes beyond a certain point. Something's going to kill you: disease, accidents, predators. Any gene that would, for example, help humans to live to 200 in the wild is useless. If it did evolve, it could mutate into a broken state and never be missed.
The phrase "no such thing as a free lunch" comes from economics — the study of making choices when your resources are finite. The insight conveyed by this phrase is that there's always some opportunity cost (the cost of the next-best-thing you could be doing, instead of eating the free lunch).
If you are not using it in that context, it loses its insight value. There is presumably some energy cost to the cell actually manufacturing the protein, but it's entirely possible that's the whole cost of the "lunch", and it is a price readily paid. Or it might not! That's really up to biology now, as you say.
The phrase comes from saloons in the United States providing free food, but requiring purchasing of drinks. You can't get"something for nothing". (And if you do there is a hidden cost or an externality.)
Agreed that it’s not a given that you can never get a free lunch, just that it’s rare.
Also I don’t think you’re painting yourself as a picture of confidence that you just took unapproved mind altering drugs and have come out of it with no issues so you’re logical or anything.
I was debating whether or not to post some of those self-experiments.
I'm aware of a couple more forums where people tried ISRIB and still claim to have lasting problems from it. One group was led by professional chemists who seemed like they knew what they were doing when it comes to testing and validating the product was pure.
It's amazing what people can access now, but self-experimentation with these compounds is a terrible idea.
Developed a weird dementia at 39. Doctors Spent 2 years trying every prescription drug they could think of. Almost everything made matters worse. In some cases drastically. Complete nightmare. Those are with approved ones. Scary to try experiential.
Eventually learned it was a blood disorder and a simple blood thinner was the answer.
Wow. It sounds like you're better and hope you're better! That's an incredible story. Good on you for not giving up. You just lit a fire under my butt.
Very interested in this. So your c-reactive protein, d-dimer (sp?), etc etc showed negative? How did you find the clots? When you say "tiny", in medical terms do you mean mili or micro meters (I think that's right).
You might like the #1 book on Amazon under cardiology currently. Its thesis is cholesterol has nothing to do with heart diseases, its all in the clots. Good detail of the clotting process and relatively understandable.
Had a Pulmary embolism. Was gasping for air and coughing up flecks of blood.
At the Er the Blood work was perfect. D-dimer, everything. Genetic testing came back positive later on. So they put on blood thinners.
A few days later my dementia was gone. Was solving complex programming problems with ease once more.
Every time I try and go off them all the symptoms come back. So it was this that micro-clots was determined.
Also when drawing blood nurses kept complaining that my blood clots to fast.
> It's amazing what people can access now, but self-experimentation with these compounds is a terrible idea.
I think it depends what the alternative is. If you have something like Alzheimer’s and no other alternatives, maybe self-experimentation is not such a bad idea.
Reminds me a bit of cerebrolysin self-experiments I've read. It can either permanently make you smarter or permanently give you brain damage. Or both, perhaps.
(For anyone unaware, it's a bunch of neuropeptides harvested from pig brains that you typically either inject or - fittingly, due to the source - snort directly into your brain through your nose.)
Totally side effect free if we ignore the risk of stroke from cardiopulmonary bypass (at least 0.5%), infection of the chest cavity (0.5-3% incidence of mediastinitis after median sternotomy), anesthesia complications, post op pulmonary embolism, pneumonia, UTI, etc.
Open heart surgery - let alone replacement - isn't likely to be side effect free in our lifetime. A detached sternum is also a side effect, after all, requiring a couple months to recover to basic function...
It's probably going to be interpreted as cynical b/c it's HN but I do honestly believe that solving heart function will be lot easier than solving cognitive decline, and a win on cognitive decline is huge news (hopefully not paired with not pig hearts, but it's a reasonable proof of concept).
I guess it depends on how long the bad effects on the heart last after taking ISRIB. If it keeps lingering, you may need new pig hearts over time. Or.. Just keep taking ISRIB and just schedule a yearly pig heart transplant.
"In the 1980s and 1990s, Walter demonstrated that when too many unfolded or misfolded proteins—which are characteristic of neurodegenerative diseases—were detected inside a cell, it triggered the equivalent of an emergency shutoff switch that halted all protein construction until the problem was solved. The action, which Walter dubbed the “unfolded protein response,” was akin to a blaring red alert at a busy worksite, stopping work; cellular repair crews would then converge on the site, attempt to fix the problem, and if all else failed, eventually order the cell to commit suicide."
So... if the body will naturally restart protein production when the problem is resolved, and if ISRIB forces it to restart without solving the problem...
Is this going to result in a few months of improved performance followed by a collapse as cells start dying for good?
Desperate people will do whatever they can to improve themselves. Imagine you have neurogenerative disease and in few years you will be stuck to wheelchair forever.
Eh, people have different risk appetites and not everybody wants to wait for an authority figure to say something is safe (especially when that authority figure is always slow, sometimes makes mistakes, and sometimes makes decisions based on politics). I don't fault people with a little self-experimentation as long as they're given the opportunity to understand the risks and rewards they're facing.
Not even research chemicals my Dad had IPF and from what I could find Metformin was a promising off-label cure. But there was no way to try it. People get desperate sometimes not even the people who are sick but their caregivers.
Sorry for your loss. Did you or your dad tried talking to doctors for a prescription? Metformin is a very common drug and has a safe profile, some doctors would be able to prescribe it off-label.
Thank you. And yes I even printed off some peer-reviewed studies about IPF and Metformin for Dad to take with him to the doctor. The doctor would "look into it" but I suspect that Dad who was not great at anything technical would have agreed with the doctor and not challenged him.
My mother has type 2 diabetes so Metformin was right there in the house. It's infuriating to think Metformin could have made Dad's life better. Maybe not cure him but at least help a tiny bit.
The other problem severely ill people who have been sick for years give up before they even know it. I saw it in Dad but I couldn't see the effects of anxiety which was also there until it was too late. Anxiety is what eventually killed him more than his disease.
Maybe they're in particularly desperate situations? I do concur if these people are healthy/young though, seems insane to take something with side effects this concerning that don't even need proper trials to manifest if you're not working to fix a preexisting problem that hurts your lifespan/quality though.
Isn't it Web 1.5-ish? E.g., we have browsers but devs aren't satisfied with them as app platforms, so they use various techniques (in “original” web 1.5, applets or plugins or downloading a file that would be opened by a native app) to use web links to trigger running an app in a native, or at least more-to-the-devs-liking, environment rather than using web-native tech?
I assumed they just want notifcation permissions to spam people that don't know how to turn it off, so they can hijack their attention, and location permissions to make their ads more valuable through spying.
I use Sync on Android. You can make reddit links open there by long pressing on the app icon and making sure the links are setup to open there. https://imgur.com/a/4qKCgSB
Honestly, the tone of this article is so hyperenthusiastic that it makes me skeptical. Calling something a "miracle molecule" and describing it as a potential panacea without strong evidence doesn't give me confidence; it sounds more like a sales pitch for a dietary supplement.
> the list of potential therapeutic applications for that molecule sounds almost too good to be true.
Excerpts: "the molecule was licensed by Calico Labs, the Silicon Valley biotech established by the founders of Google to find drugs based on the biology of aging"
" In February, Calico announced that human safety trials had begun on the first drug candidate for neurodegenerative diseases it had developed based on the molecule, and that a study in ALS patients was slated to begin later this year. Other possible drugs for Parkinson’s disease and traumatic brain injury are likely to follow."
I imagine some number of them endured brain damage as part of the increasingly acrobatic nature of that "challenge". So maybe they will be downstream beneficiaries to the extent this drug's development advances the field of neural regeneration.
Feel like I was just reading a comment on here today, in another thread, about how those stupid Google billionaires wasted all their money on this dumb Calico thing that will never amount to anything.
The interesting story here is why Calico would license the molecule whereas traditional pharma was not as interested. Age related incurable conditions are the happiest targets for blockbuster drugs. In all likelihood, someone with actual domain expertise would realize that there was already data which indicated the drug wouldn't make it to market. The team with the rights seized the moment of silicon valley longevity hype, and good for them.
Calico has a very strange pipeline of drugs that don't have much in common. The last paper about Yamamaca factors looked quite interesting, but Altos is much more focused on understanding just that one technology. Other successful new companies are platform companies, which Calico isn't.
> Calico has a very strange pipeline of drugs that don't have much in common
Aren't they all related to fighting the effects of aging, which is the company mission?
I've observed that when some people have solved their money problems, the next challenge they face is their own aging and mortality - so they try to solve for that too.
This is true, I'm also in that category of people: I'm rich enough that money is not a problem for me, but too poor to invest in solving aging meaningfully.
What Calico didn't get right is that it was super secretive for a long time and not collaborated with the underfunded antiaging community. It got better in the last few years, but I have much more hopes for Altos (and I really hope people there push back on being secretive on something, where making the highest possible return is not the most important goal for the investors).
According to the Huberman podcast, simply elevating your legs at night can improve the glymphatic system's ability to clear out junk from our brains. I haven't been able to find any links to actual studies on that though.
Wouldn't it be elevating your head, rather than your legs? Most sources I've seen[1] that discuss inclining your bed have your head be higher up than your legs.
When your foot is swollen from a sprained ankle people recommend elevating it to "drain" it (I'm not sure if that is the real explanation for why, could just lower blood flow and not drain anything).
I can't complain about people doing medical research for good, but it's kinda strange that we live in a world where we can't have medical research unless online ads.
This is false. Calico is the exception, not the rule, and even they receive money from big pharma. For the most part, we have new drugs because we have older drugs that generate revenue (from Medicare / taxpayers).
Excerpt : "The molecule has restored memory formation in mice months after traumatic brain injuries and shown potential in treating neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Lou Gehrig’s disease (also known as amyotrophic lateral sclerosis, or ALS)."
its like something I would say in my comedy skit before doing a Bill Burr style impression of someone on life support before insulting the audience for laughing. and then complain that everyone’s too sensitive.
Why is the word so bad? Not sure if it's a real word or not, but it seems apt. Someone that is brain dead is referred to as someone in a vegetative state and someone that has some neurons that ceased to function could maybe be referred as neurovegetative. But that kind of makes it sound like the person is completely brain dead. Maybe partial neurovegatative state would be better?
I was a part of a group of people who obtained and took ISRIB a year ago. We made contact with another group from the Baltic’s who had a chemist in their ranks who had already synthesized and taken it, before we took delivery of ours.
The most important thing I learned is that you form a tolerance to it. At least that’s what the experiential effects indicated.
One person took it and developed heart rhythm problems.
Another person took it and became full of energy. Some people reported being much smarter and being able to socialize at a much higher level than before. Some people said they had hyper realistic dreams and compared it to schizophrenia. There were many stories but I can’t remember them all. I’m the end nobody took it long term.
The NMR results made it clear that everyone was taking pure ISRIB and not some adulterant.
One person said he gave it to his grandmother with Alzheimer’s and it made her better but she died shortly afterward. Some people said this is normal and it was a coincidence. We don’t know.
I never took it because right before we had secured a supplier I had a bad reaction to another experimental drug which has given me a permanent injury.
Yeah, the research itself sounds excellent and this is indeed good news. The fact the biotech firm is a subsidiary of possibly the premier proprietor of surveillance capitalism is fairly concerning to me. I don't personally want a supercorp that sees dystopian sci-fi as an instruction manual to be developing medical treatments.
It's absurd to complain about this when they are one of the few institutions working on fighting aging, arguably the most important problem humanity has ever faced.
Yeah, it sounds great now. There's no way I want a multinational corp with unprecedented vision into our private lives also researching and producing medical treatments.
This kind of armchair criticism is really frustrating to see. Here, you have a company tackling arguably the most important and devastating problem humanity has ever faced. At least they are doing something that helps humanity solve aging, where almost no one else is.
Who cares if it's capitalist-driven? It's not like governments don't, or never, had the opportunity to attempt to tackle the same problem - they simply never took it, focusing on the trivial day-to-day issues, while overwhelmed with bureaucratic tape. And it's not like nonprofits attempting to solve the same problem don't exist either (https://www.sens.org/, https://www.lifespan.io/), with limited success. A massive financial juggernaut backing this initiative is exactly what it needs.
I think the incremental ROI they would need to involve themselves in a new area would be pretty high. They aren’t going to dedicate a 9-10 digit sum to anything without expecting a much higher sum in return.
Google started a lot of "moonshot" projects, expensive things that are very unlikely to produce any returns. This is one of those. If Google didn't fund this then this work wouldn't get done. Now it might look promising, but this is a 8 year old part of Google, they have been working for a while now.
This is fair commentary for any under-regulated industry. I say that as a staunch "stay out of my business" conservative. Proper regulation ensures that companies are financially vested in the well-being of those they affect.
Whether or not pharma in the US is properly regulated to ensure the well-being of their consumers is... debatable.
Are they forcibly injecting you? This is for people with desperate symptoms who are willing to take on more risk. I have no opinion on its efficacy fwiw.
I'm curious why it is referred to as "molecule" everywhere. It may be a molecule, but...so is everything else. This is the first time I have seen this term used to describe a drug or treatment.
There is a distinction in drug development between the biologics (large proteins, e.g. https://en.wikipedia.org/wiki/Adalimumab, molecular weight ~144kDa), and small molecules
