Recently it was shown that the chemical ISRIB can “undo” traumatic brain injury. It turns out that when you get a concussion, the mechanical stress results in a metabolic self defense mechanism being triggered. Everyone thought the neurons were dying but they were just themselves latent. ISRIB interferes with this defense mechanism, turning the neurons back on.
And it turns out that this metabolic defense mechanism is triggered in many scenarios, not just concussion.
I became involved in a group of people who were interested in taking ISRIB. We engaged in an effort to synthesize it, and along the way we dredged the internet for any information we could find about other people who had taken ISRIB — the molecule has been known about for a long time. There are a handful of plausible stories, and it appeared that ISRIB would have no effect in one person and be life changing for another, both seemingly healthy. The common pattern was increased intelligence, an insatiable appetite for new and novel information and a marked reduction in the amount of sleep needed to function.
We eventually came into contact with a group of Russians. They had already synthesized it and taken it. They reported the same effects from the accounts we had found. They also reported, surprisingly, the development of a tolerance among those who took it repeatedly. One person had an episode of very realistic hallucinations, dreams that seemed real. Another person gave it to his grandmother who was sick with dementia. She became lucid again but died a day or two later. We speculated that one of the reasons cells turn themselves off is because they are too dysfunctional to operate — so turning them back on brings the benefit of having that signal again in the case of neurons but also revives any dangerous behavior that was being suppressed. We acquired ISRIB from the Russians and the first person to get it didn’t notice an effect although he didn’t take much. At this point I fell out of contact because I was having a medical emergency from experimenting with a totally unrelated compound. It nearly killed me, I spent weeks in the asylum and still have lingering effects. After that my shulgin itch became satisfied permanently.
One interesting thing about cognitive diseases that are metabolically rooted like schizophrenia, dementia, etc is that there are simple ways to coax the cells into metabolizing carbohydrates correctly again, as this article demonstrates. There is also another kind of chemical completely that can be used for energy, beta hydroxy butyrate, totally bypassing the problem. The field of metabolic restoration is the next big thing for sure.
> Another person gave it to his grandmother who was sick with dementia. She became lucid again but died a day or two later.
Lucidity before death has been reported before for patients suffering from dementia and other neurological illnesses, so this might have been coincidence. The term is "Terminal Lucidity" if you want to search for it.
It always helps to expand abbreviations when talking about things that only a few readers will already know about. Typing it out is O(1), having N people look it up is O(N) if you allow me to abuse the notation like that ;)
>Typing it out is O(1), having N people look it up is O(N) if you allow me to abuse the notation like that ;)
Thank you; this is a perfect way to put it. I always include links, and ideally inline text, when posting because I always try to think from the perspective of a lazy and/or context-switch-averse reader reading the comment. (Easy to do, since that's my actual perspective 99.9% of the time.) One of my highest-upvoted HN comments was just pasting the contents of a tweet someone else posted to save people a click. (https://news.ycombinator.com/item?id=25260896)
ISRIB works just as well as "integrated stress response inhibitor." There are multiple stress response inhibitors in the body, so it's not like the name tells you anything. Both are just arbitrary names.
I am currently learning a lot about the cellular Integrated Stress Response for my research. It is fascinating. There is one curious problem I particularly love. Even though a lot of neuronal communication can be through transient calcium signaling, the ISR is also signaled through calcium. Because they use the same signal, it makes sense that something like overactive neurons could eventually lead to stress. And yet somehow the two signals are differentiated.
It really shows how everything in biology is basically a gaussian curve and you always want to be near the center, but if you steer too far towards either end things start to break down.
She became lucid again but died a day or two later. We speculated that one of the reasons cells turn themselves off is because they are too dysfunctional to operate — so turning them back on brings the benefit of having that signal again in the case of neurons but also revives any dangerous behavior that was being suppressed.
That's a pretty big leap to make given that you don't even know if there is, in fact, some kind of causal relationship between giving her ISRIB, her sudden lucidity and subsequent death. According to what you have said, it was a one off event and you are positing a hypothesis of how the body works based on a one off event where you don't even know if x led to y led to z and your hypothesis is based on the assumption those things were, in fact, causally related.
> because I was having a medical emergency from experimenting with a totally unrelated compound. It nearly killed me, I spent weeks in the asylum and still have lingering effects.
You should name this in case others might be, present or future, using the same substance.
It is an inhibitor of whats called the Integrated Stress Response. A “normal” cell is one that uses glucose to create energy and create additional fuel for mitochondria to make LOTS of fuel (caveat- not every cell, this varies a lot, but often enough). This fuel is used to power everything and keep it working well.
Under stress, a lot of that normal machinery is shut down, which means a neuron may not communicate anymore, as all these normal things need lots of energy.
I am not as sure on this point, but I think stress generally means a cell takes in less glucose; it shuts down mitochondria, and overall produces less energy.
Excessive blood sugar, then insulin spikes, and over time type 2 diabetes. It used to take a life time to acquire type 2 diabetes and historically it was called adult onset diabetes.
The first case of type 2 diabetes in a child was only diagnosed in the 1983...now it’s common in children. Generally about 1/3 of the US is prediabetic, this population will generally also suffer from other chronic (metabolic) conditions like inflammation and obesity.
If ISRIB works as well as research seems to suggest then we all need to keep an eye on it to make sure big pharma doesn't suppress it so then their own patentable products can exist in the market.
researchers also found that greater physical activity at the start of the study lessened APOE e4-related cognitive decline two years later by an average of 0.007 points.
So that sounds meaningless to me. Throw the numbers into the statistics machine I guess, but I bet a decline of 1.33 isn't meaningfully different than a decline of 1.323, even if you can confidently say you measured the difference.
Google's quick questions+answers:
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I'm curious how they could control for the general benefit of exercise or if it this study is more "parkinson's does not prevent benefit to exercise". I wonder if future generations will look back on this and say "they were exceedingly lazy to the point of serious mental disease and decline"
The easiest exercise to do is the kind that is routine and integrated into your routine so much you don’t even think about it. When I lived in New York I walked a few blocks to the bus stop, down the stairs to the train, down the stairs to another train, and then a few blocks to work. And that was just the commute; not counting walks to the coffee shop for a break, the walk to pick up lunch, the walk to the subway to the bar or a friend’s house after work, etc.
The problem is that, at least in the US, most people walk within a building or from the door to the car and that’s about it, and then we have to create silly rituals like culty group bicycle classes or 10,000 steps challenges to actually get the minimum exercise in.
We don’t necessarily need to go back to everyone working the fields all day levels of work, but the sedentary lifestyle in the US is not helping matters.
We survived because of movement, and other natural attributes. "Progress" (i.e., a forced shift from proactive living entities to reactive consumers) comes along and suddenly our evolutionary past is denied (usually for profit). There's nothing wrong with profit, unless it is the primary measurement of success and progress.
Of course there's collateral damage, we're denying a massive chunk of our evolutionary makeup, our very nature. Another study to confirm this? Perhaps we're not the advanced species we make ourselves out to be?
A limitation of the study was that participants reported their own levels of physical activity, so there is the possibility that they would not remember their levels exactly.
Instead of involving a RCT, we have a survey study.
That is a safe assumption if you are deciding whether or not to exercise, but that doesn't mean we have learned everything there is to learn about the effect of exercise.
And it turns out that this metabolic defense mechanism is triggered in many scenarios, not just concussion.
I became involved in a group of people who were interested in taking ISRIB. We engaged in an effort to synthesize it, and along the way we dredged the internet for any information we could find about other people who had taken ISRIB — the molecule has been known about for a long time. There are a handful of plausible stories, and it appeared that ISRIB would have no effect in one person and be life changing for another, both seemingly healthy. The common pattern was increased intelligence, an insatiable appetite for new and novel information and a marked reduction in the amount of sleep needed to function.
We eventually came into contact with a group of Russians. They had already synthesized it and taken it. They reported the same effects from the accounts we had found. They also reported, surprisingly, the development of a tolerance among those who took it repeatedly. One person had an episode of very realistic hallucinations, dreams that seemed real. Another person gave it to his grandmother who was sick with dementia. She became lucid again but died a day or two later. We speculated that one of the reasons cells turn themselves off is because they are too dysfunctional to operate — so turning them back on brings the benefit of having that signal again in the case of neurons but also revives any dangerous behavior that was being suppressed. We acquired ISRIB from the Russians and the first person to get it didn’t notice an effect although he didn’t take much. At this point I fell out of contact because I was having a medical emergency from experimenting with a totally unrelated compound. It nearly killed me, I spent weeks in the asylum and still have lingering effects. After that my shulgin itch became satisfied permanently.
One interesting thing about cognitive diseases that are metabolically rooted like schizophrenia, dementia, etc is that there are simple ways to coax the cells into metabolizing carbohydrates correctly again, as this article demonstrates. There is also another kind of chemical completely that can be used for energy, beta hydroxy butyrate, totally bypassing the problem. The field of metabolic restoration is the next big thing for sure.