“Although the research focused on a single person, it reverberated through the world of brain science and even got the attention of the (then) acting director of the National Institutes of Health, Lawrence Tabak. “Sometimes careful study of even just one truly remarkable person can lead the way to fascinating discoveries with far-reaching implications,” Tabak wrote in his blog post about the discovery.”
Very cool - they found an extended family in Medellin, Colombia where virtually everyone got early-onset Alzheimer’s. Except for one guy. Studying his genome revealed a variant related to Reelin, and subsequent studies suggest that Reelin is indeed neuroprotective.
Depends on your culture. In many places dealing with bad things humorously is preferred to being all stone-faced about them. One of my grandparents has dementia and since nobody can change that, the family generally tries to be light-hearted about it. Sure, it's tough for everyone involved, for those who he doesn't recognize, those who take care of him, and for himself, but there's no need to make it drag you down more than necessary. Imagine you're struggling with some condition that affects your every remaining waking moment and impedes your ability to interact with those around you, and everyone is all stone-faced about it to boot. Humor is a way to make the best out of a bad situation.
Everything has it's time and place of course, but this was one of the least-bad places one could've made that particular joke. Everyone knows dementia sucks, but for now it's an inevitability for many people. There's no need to make it worse by being all doom and gloom about it.
One of the ways that we learn is "do X -> reward" and "don't do X -> no reward". But this is only training us one way - a positive way - about what is desirable.
How do you learn what is not desirable. "Don't touch the oven when its on" is something that you learn through "do Y -> punishment" ... but is there a "don't do Y -> reward" path that can be found? Is there a way to positively train the "don't do Y" paths?
A mother says to her son "don't forget to sweep the corners." The son replies "don't worry, I swept everything into the corner."
You are rewarded for laughing at that joke. Why? Because it is something that you shouldn't do. In this joke, we have expressed an undesirable state to be able to learn from in a rewarding way rather than a punishing way.
And somewhere, long ago, I recall a web page that had a short summary of each theory of humor and a joke that was not funny according to that theory. I doubt there will ever be a Grand Unified Theory of Humor.
Are there theories of humor that don't boil down to "setup expectation juxtaposed with punchline reality"? If there was ever a grand unified theory of humor, that would be my guess.
This would likely fall under the Incongruity Theory of humor where the mismatch of expectation and actual result with the punchline.
There's a song that I find rather funny. This is to be sung to the tune of M*A*S*H's theme.
Through the upturned glass I see
a modified reality--
which proves pure reason kant critique
that beer reveals das ding an sich--
(das ding an sich is Thing-in-itself which is the philosophical statement that things are what they are independent of observations).
Consider this video https://youtu.be/rUibuIDNANg - is it funny? If so, why? Would "laughing at the misfortune of others" be a better explanation than "setup of expectations and punchline?"
Or consider some of the many PBF Comics. Consider https://pbfcomics.com/comics/nude-beach/ (NSFWish - there are nipples). This falls more into the "sneaking past the censors of taboo" classification.
https://pbfcomics.com/comics/battleship/ (this one is safe for work) also doesn't fall into the "setup expectation" since, what is the expectation of a rat and a bat playing battleship? If it is "the first frame is funny because of incongruity - then why is the third frame funny?" Would https://pbfcomics.com/comics/sir-leopold/ be better described with relief theory?
I suspect that a selection of PBF comics would be an excellent test of "pick which theory of humor best describes {comic} and why" for a philosophy class. Is it relief? misfortune of others? benign violation?
We've all got different ways of handling it so the best we can hope for is some mutual compassion and thoughtfulness. One factor in that is to realize that the effect is more relevant than the intention.
> Trying to avoid hurting anyone turns you into a person who would hurt everyone.
Other than the citation needed, it is possible to avoid hurting _some_ people, with surprisingly minimal effort, even if you can never avoid hurting anyone ever.
The black-and-white argument you've presented - in its many forms of "if 100% outcome is not possible, it's worth 0% effort" - exists purely to absolve people of the responsibility to try.
Eh, I wouldn't go that far. The key to sensitive jokes is to know your audience. Throwing one out into a public forum isn't very likely to land, but in the right situation it might cheer up a person who is suffering from the very topic at hand.
> Purified recombinant Reelin was injected bilaterally into the ventricles of wild-type mice. We demonstrate that a single in vivo injection of Reelin increased activation of adaptor protein Disabled-1 and cAMP-response element binding protein after 15 min. These changes correlated with increased dendritic spine density, increased hippocampal CA1 long-term potentiation (LTP), and enhanced performance in associative and spatial learning and memory.
Would expect to see research focused on compounds that increase Reelin expression too, in addition to direct supplementation. A mouse study a couple years later showing nicotine increasing Reelin expression: https://pubmed.ncbi.nlm.nih.gov/23385624/
Nicotine has been really interesting for Dementia or Alzheimer's so this checks out. The one study I know that is ongoing is mindstudy.org. It's well tolerated, cheap, and widely available.
Not a Doctor but if I had a loved one at-risk or experiencing age-related cognitive impairment, it's probably worth trying rather than waiting for scientific consensus which may take years and will probably be blocked by the FDA so some pharma company can develop patented neuro-nicotine or whatever.
Huberman has also espoused nicotine's benefits, so before someone reading this runs headfirst into a nicotine addiction, please be aware of the withdrawl symptons.
Don't forget the many, many negative issues SOME people get from nicotine.
I loved nicotine, but it terribly exacerbates my rheumatoid arthritis in my hands, inflames blood vessels in my lower arms (to the point of waking with my arms completely numb in the middle of the night) and gives me terrible heart palpitations that woke me up (if I consumed nicotine a few hours before bed).
I had to get some surgery on my fingers, and the staff seemed relieved to learn I don't smoke. Something about narrowing blood vessels making this kind of operation less successful. Not sure if they were just trying to cheer me up or it's an actual thing :-)
Very interesting. Though nicotine also has a lot of potential side effects that can make it really counterproductive for the health of an elderly person.
That's a funny thought, we experiment on mice, then one day we accidentally create super mice while trying to solve diseases. From that day, it will be the mice who dominate our world.
From my layman's understanding, in the US, it is almost impossible to get FDA approval for drugs that "improve" or "enhance" human biology.
The tl;dr is if you invented a drug tomorrow that stopped human aging, you wouldn't be able to get FDA approval to sell it.
This sadly means that research into how to improve human life and potential are very limited.
An alternative explanation is that it may just be super hard to make into a useful pill or convenient injectable, limiting commercial viability! Most drug companies aren't going to dumping $ into a chemical that may cure a disease but has no practical way to get it to the target site!
Because our society is rooted in puritanical, old and crude notions of what it means to be human. This makes its way into legislation.
It is one of the reasons I despise the FDA, it is an incredibly narrow-minded institution. If you made a drug that immeasurably improved QoL for 99.99% of users, you still wouldn't be allowed to sell it. The administration sucks.
Studies won't be done on long term risks in young adults taking it.
Do you want to take a drug that rewires your brain but has had exactly 0 studies done on what happens to users after 20 years? Alzeimer's drugs don't need 20 year follow up studies because, with the exception of early onset, the patients are, to put it bluntly, dead.
Actually right now Namenda is being used off-label for cognition enhancing properties, and suffers from the exact issue that its impacts on healthy adults is mostly unstudied. (FWIW I had negative cognitive side effects with it to the extent that I had to abandon it, but plenty of people seem to like it!)
If you want to talk even higher risk profiles, there are plenty of substances that may very well increase neural growth if given to children, but there is no way in hell any ethical medical team is going to ever run those studies.
For one thing, we know that plenty of awful diseases are the result of too much activity in the brain. No one wants to be the lead author on a study titled "Boosting IQ by 10 points in adolescents, with only a 20% risk of seizures."
You can only make drugs to treat medical problems of some sort. I think the argument is that the cost/benefit is never positive for drugs that aren't attempting to just bring you back to baseline.
Basically imagine you are perfectly healthy, and you take a drug that has a 99.9% chance of increasing your IQ by 20 points, or a 0.1% chance of reducing your IQ by 5 points.
The FDA would basically say "no way in fucking hell, you don't need the extra IQ points to cure any problem, and there is a risk of brain damage".
Now if that same drug was instead marketed towards helping people with traumatic brain injuries heal, then it could maybe get approval.
There was a petition a few years back to the FDA to change this to allow research into life extending drugs, but AFAIK it didn't go anywhere.
The entire drug research sphere outside of the US is miniscule. Unless you can sell the drug in the US there's very little point to investing in the large scale research needed to truly determine efficacy. Yeah there's some minimal state sponsored stuff outside of the US. BUt it's like comparing Little League to the MLB.
Ok, I think your list, and the fact that HALF are in 1 Country VS the entire rest of the world qualifies my statement. As well Roche, ASZ, and GSK do the bulk of their research in the US.
On top of that the largest outside of the US is China and there is very little trust of data coming from there in the Western World.
Maybe from the fact that half of all pharmaceutical revenues come from the US (and likely a much higher share of the profits). Single-payer systems are more cost-effective but definitely provide less revenue to pharmaceutical companies.
The Chinese government ran a huge research effort to try and determine the genes for intelligence. From what I understand it was a failure, as the genetic causes of intelligence are too spread out and varied to be easily isolated.
I'm pretty sure if the project had succeeded that the Chinese government would have had no moral qualms about gene-engineering a population with an IQ of 130+ and the US would be permanently behind in every field forever after.
> the Chinese government would have had no moral qualms about gene-engineering a population with an IQ of 130+ and the US would be permanently behind in every field forever after.
The US is already a key brain-drain destination for Chinese elites, why would that change?
> Chinese government would have had no moral qualms about gene engineering
Anyone cares to shed a tear for IQ 85/90 people that have to navigate increasingly complex world?
Look at the amount of legal documents, EULA’s, software, and complex corporate structures that an average Joe has to deal with today vs 50 years ago. How long u till average person can no longer cope?
If this great science fiction scenario were to come to pass, I’m pretty confident that it wouldn’t be only the FDA that would be pushed to the side.
The impact of a population in an organised, technologically advanced society being one standard deviation of intelligence higher than a strategic rival population … would be immense.
Even if just temporarily boosting intelligence, something like a militarised Flowers for Algernon scenario is pretty terrifying.
Someone I know pointed out that there’s a feedback effect: groups where everyone is smarter do better not just because of the first order effect but also because they can cooperate better. There’s a roughly quadratic effect on productivity.
Mass enhancement of the general population would have far reaching consequences.
Why? It will only result in more and harder dictatorship, more direct terror and fear, and even more unhappy society.
Democracy works best when people are easy to manipulate through mass media. Smart people will need to be coerced by force.
Maybe in fact, to a degree this is what already happening. Superior education in China makes democratic transition next to impossible.
Maybe the observation that countries with the best education tend to be authoritarian is not because "dictators are good at educating people" but other way around - because it's a natural selection and if a highly educated country tries to transition to democracy, it either ruins democracy, or education, or country itself.
Any model of governance mainly solves the problem of "how to satisfy interests of the stakeholders - i.e. the elite - without ruining things"; there are many ways to ruin things (even elite itself can bring about it's own downfall), but the one everyone fears most is when people get too angry. Democracy is a good way to shift responsibility back to people itself, thus defusing this threat. But it requires people being sufficiently dumb to bite it.
> Democracy works best when people are easy to manipulate through mass media
This is a huge statement that seems wrong to me. Democracy works best when the population are engaged and hard to manipulate.
Also the "observation that countries with the best education are authoritarian" seems wrong to me too. The data I see has the top 10 entirely filled with democracies, with Singapore as the first nondemocracy coming in at 11th place. Check the economist democracy index, the correlation between democracy and education is imperfect but strong.
And those are arguments based on data. There are also arguments based on logic. Authoritarianism and education are fundamentally opposed, because authoritarians hate the teaching of things that disagree with their own specific viewpoint and suppress it.
> Democracy works best when people are easy to manipulate through mass media. Smart people will need to be coerced by force.
Been there done that, it’s called Russia.
I don’t agree with your worldview, but if I was presented with the choice is between dumb, fake democracy and clever competent dictatorship, I might as well choose the latter. At least trains will run on time.
We can give a lab mouse any form of cancer and cure it. We can reverse their aging symptoms... yet we've only been able to extend their lifespan by a measly third at best. It's safe to say we're very far away from getting anywhere close to solving aging in humans if we can't even make an immortal mouse despite a century of throwing every possible thing at them without holding back.
MRI was only invented in 1977, first commercial CT scanner came out in 1970’s, same for ultrasound. Before 1970’s we didn’t have antiviral drugs or DNA sequencing
Medicine a hundred years ago was brutal and medieval
Believe it or not, lab mice have been used for medical research for over 150 years.
We're all high and mighty with our moderns scanners, yet we still do surgery with chisels and hammers, drill teeth, put broken bones in plaster, have sick people congregate all in one place so they get infected with each other's diseases plus get some antibiotic resistant bacteria or two on top. And well, whatever the hell they do in the ER. Medicine is still pretty brutal when it comes down to it.
That may be so, but it's absolutely fundamental to know where to cut, and to cut in the right place. How are you going to diagnose cancer at an early stage if you have no way to scan and detect anything? Exploratory surgery?
I recently spoke with someone in biotechnology who was doing a deep dive on "exercise pills". she told me that it would only be approved if it treated a specific disease, like muscular dystrophy, because the FDA views any potential negative side effect as too risky to approve for healthy people. Long term negative side effects are tolerable in Duchenne muscular dystrophy because those people are going to die without intervention. Once people with DMD show the safety profile it can be evaluated for more conditions.
> if you invented a drug tomorrow that stopped human aging, you wouldn't be able to get FDA approval to sell it.
Due to the chaos it would kick off, I'm assuming. The FDA just needs to ask themselves "What happens if we OK this?" and if the answer is "I have no idea." they withhold approval.
> I think the rationale is to minimise both committee biases and corporate influence
I don't see how it really addresses corporate influence; normal behavior from a corporation is to donate to every politician that might conceivably affect them.
The FDA would be wise enough to know a political hot potato when they see one.
If you think the riots would be massive for a ban, imagine the riots if there wasn't worldwide access immediately. Biological immortality is very much a situation where you want to bring enough gum for everyone.
> It wouldn't matter; you'd still be free to sell it as an unregulated supplement.
Patent protections on supplements are very weak compared to the protections afforded to FDA approved drugs.
That alone limits research into supplements.
Also what counts as a supplement is limited, companies cannot just declare any random drug to be a supplement. Dietary supplements have to have some tenuous connection to being from a natural source. (Though obviously that line gets skirted a lot, such was with DMAA prior to 2013)
My thinking as well. I’m fine with the FDA not giving drug approval to a substance as long as they don’t ban it. There are a few drugs I take regularly that are not FDA approved in the US (I.e Moclobemide as there are no approved reversible MAOIs in the US) but I’m still legally allowed to import them and usually it’s pretty cheap.
The almost daily information I'm hearing about Alzheimer's research is reassuring. My wife's grandmother died of it, and her mother is probably in the first 1/4 of its development. Today's gains may be too late to help her, but I'm hoping they will develop into useful treatments before my wife would start developing symptoms.
I'm in a similar boat, Mother, Mother-In-Law, and previously grandparents on both sides suffered from Alzheimer's. Best lead I've come up with is that somehow increasing influx of CSF has a lot of potential. The APOE4 or whatever gene impeded CSF influx, leads to the plaque build up.
I've also seen inulin, and glutathione quite a bit. I had read some about nicotine before as well, but I don't remember reelin specifically.
Cerebrolysin has potential.
But I keep getting back to the CSF influx, and potentially one easy thing that increases CSF influx is sleeping on your side.
Hydration may also be very important. And stay far away from Anticholinergic drugs like diphenhydramine.
HBOT seems like it could also potentially increase CSF influx.
My mom died of it, and at least one of my brothers worries about it a lot. But it's not typically familial, and my mom's parents both lived to their late 80s without any signs of dementia.
My favourite research is that quality nutrition is what you need, however, this means a whole food, plant based diet. What that means is no animal fats or refined animal fats as these have been blocking arteries since the 1950s, or whenever it was that Ancel Keys did his landmark studies that made saturated fats bad.
I am okay with that.
The keto diet community believe that Ancel Keys was not right and that sugar is the enemy that causes all of the problems, probably including blocked brain arteries. The whole food, plant based diet does not include refined sugar, so, hedge your bets by staying off the animal fats and added sugar. By staying off the sugar, that eliminates processed foods that invariably have refined fats and oils such as palm oil and much else that gets saturated in processing.
Humans have been eating animal fat for millenia. Cutting excess sugar is a good plan though. We would have gotten some from fruits and berries but nothing like the quantities that are included in many foods today.
During the summer humans would have gorged on fruit while it was available, as well as ultimately learning to preserve and store it for later. Today that urge does us injustice in the form of 1200 calorie Starbucks at every corner.
Polio is actually an interesting case. Polio did exist for millennia, but severe outbreaks did not occur until the industrial era. Constant exposure to the virus gave most people natural immunity, and then improved sanitation meant that first exposure often occurred in later childhood or teenage years, when the virus was much more dangerous.
> Just because people in the medieval times and before did it is no reason to presume that it was good for health.
It is reasonable to assume that if your ancestors for a sufficiently large number of generations ate some diet it means that natural selection has ensured that diet is reasonably optimized for your health.
It is reasonable to consider such hypotheses, but until you have some evidence it isn't very convincing. It's on about the same low level of intellectual rigor as assuming that "progress" is all wonderful. Neither good-old-days nor progress-is-always-good are valid modes of logical inference.
Take, for instance, the farming-based diet that our ancestors have eaten for millenia. In fact, there is evidence that it was worse than what went before. But there is also evidence that modern diets are healthier (in terms of robust development to biological potential). It isn't all one way or the other.
Oh, absolutely there was peaks and troughs in terms of the healthiness of historic diets; the Romans noted the German diet produced a very obvious superior outcome. A more recent trough occurred in the late 1800s/early 1900s: mid-Victorians lived much longer, and grew much taller, than late Victorians in England. We've only relatively recently recovered from that (mostly - not in terms of life expectancy at age 5, but certainly on other factors like height.)
You definitely have to take a very expansive view.
Not really. It's reasonable that it didn't kill them before they had children.
There isn't much selection against diseases that affect us after our children have grown, and what little there is (grandmother care effects, say) was likely swamped in most of human history by other causes of mortality.
Humans are social animals. The grandfather/grandmother effect is much stronger than merely "helping take care of kids", lots of living older relatives can have a dramatic influence on your social standing and therefore ability to reproduce.
Yes, this is a huge potential source of disease. We definitely didn't evolve to sit at a desk for long periods. (Or to stand at a desk, for that matter.)
Humans have been enslaving other humans for millennia, still individuals and organizations stands and fights for freedom equality.
On the contrary, industrial farming because possible very recently thanks to antibiotics, international logistics (for food and alive livestock) and modern biocides/fertilizer to grow enough crop for feed.
This is so out of touch, having a healthy diet is obviously going to help reduce the risk of getting Alzheimer's disease, but it is in no way the ultimate cure.
You must be new here. Hackernews has known for some time things that mainstream science has yet to fully understand: namely, that diet dominates as a cause of big-ticket diseases like cancer and dementia, and that Alzheimer's specifically is type 3 diabetes; accordingly, dietary changes, especially fasting and vegan diets, are absolutely 90% cures.
I am just saying to keep off the HFSS, in line with government policy in the UK. Stay off the saturated fats, the salt and the sugar. The arteries should look after themselves with a modest amount of exercise. And yes, the saturated fats means animal products. There is no crank science there, just no junk food.
Not vegan. I just stay off the animal fats, processed food, sugar and salt. That is just being sensible. I believe veganism is ethics first, save the animals. I just don't want to be a vegetable.
I would never use an ampersand in either context. I have more style than that.
All seriousness though—this pedant appreciates you giving me an English grammar rule to brush up on. My pronoun work has been strictly en el español of late.
GP is probably thinking of "My dad and me"; not sure how far back it goes but I've certainly heard it quite a bit from native speakers. You might hear someone say, "Him and me, we go way back", but that's slightly different; but "Him and I" mixes the subject/object case, which must be wrong (and I've never heard before).
ETA: I generally don't bother "correcting" the grammar "mistakes" that native speakers make (like "My dad and me did X"); but if I think it's pretty clearly a non-native speaker, I'll correct them, because that's what I would want someone to do for me if I were speaking in their language.
I always hated this because English is not so simple. To my eye, “me and him went to the store” or “him and me went to the store” both sound good to my ear. But “he and I went to the store” sounds slightly weird, and “I and he went to the store” just sounds awful. Which makes me think this rule is bogus, and that when you compose pronouns with “and”, English actually prefers the object case even when in the subject position. If it were as simple as the rule you suggest, the order of the pronouns would not matter. I’ve also heard people say (e.g.) “he did it with X and I” which makes me think “She and I” in the subject position (for example) is more of a prescriptive grammatical virus than actual English.
I asked ChatGPT which behaviour results in Reelin being present. It's physical exercise, cognitive activities and social interaction. Behaviours that reduce Reelin are stress, drugs and bad nutrition. Maybe it's just correlation.
It amazes me that we do not have a publicly funded initiative to cure death. It makes me incredibly angry and frustrated at both the general populace and the government.
First, the idiocy of the general populace to not prioritize death as a problem when it will inevitably be one for them, their children, and everyone they know; and second, for the government to waste trillions of dollars on useless initiatives when that could instead be invested in curing an ailment that has plagued every human to ever live.
If we cared as much about curing aging and death as we did about investing in even a single fighter jet program, we may well be there by now.
I feel like I live in a clown world where the average person hems and haws over trivial problems when they are literally about to fucking die.
I'm not sure how you're getting the 4 genes away thing, I'm seeing like 20-30 genes and more than 2 megabases of distance in between RLN and ACHE. I'd be surprised if they were even in the same topologically associated domain.
Is there some place on the internet that shows this "4 genes away" evidence? I'm imagining that there is some tool that those involved in this work are aware of that I am not.
"Reelin is transcribed 4 genes away from $ENZYME" sounds like it is of the same general category as "Humans share 98% of their DNA with a chimpanzee and 97% of it with a banana" or whatever. Is that me just not understanding it? I would think 4 genes could have huge impact on functionality.
I believe they're using "4 genes away" as a proxy of basepair distance, not similarity. It's all very messy business but it's not unreasonable that transcription promoters for those other genes also promote reelin transcription.
Is this (genes physically close together, but not contiguous, being affected by the same/related promoters) something commonly seen? I'd love to learn more about it if so!
There is evidence even from the early days of genomics that recombination and thus evolution worked in (approximate) units at a time. This means that when a new mechanism for regulation appeared, it often regulated many pathways coded in idiosyncratic ways. That leads to the observed local commonality of mechanism.
The place that I saw this in my own work was in the way that ends of intervening sequence (introns) was coded for excision during expression of proteins. The different ends of different introns behaved differently and introns in different parts of genomes had slightly different dialects.
The relationship of similarity and locality in regulators is different from this, but is another case of proximity being a proxy for similarity.
Very cool - they found an extended family in Medellin, Colombia where virtually everyone got early-onset Alzheimer’s. Except for one guy. Studying his genome revealed a variant related to Reelin, and subsequent studies suggest that Reelin is indeed neuroprotective.