Klotho – There May Be a Drug to Turbocharge Your Brain. Who Should Get It? | Hacker News Reader

Klotho – There May Be a Drug to Turbocharge Your Brain. Who Should Get It?

nytimes.com

159 pointspseudolus149 comments

The article refers to Klotho as a "hormone." It appears to be an enzyme instead, and a membrane-bound enzyme to boot:

> Klotho is a transmembrane protein that, in addition to other effects, provides some control over the sensitivity of the organism to insulin and appears to be involved in ageing. ...

https://en.wikipedia.org/wiki/Klotho_(biology)

That means that you're probably not going to make a drug my injecting Klotho or with Klotho tablets. Instead, your best bet is to make small molecules that inhibit or promote the activity of Klotho.

Then the article compounds the problem with:

> Now Dr. Dubal and other researchers are trying to build treatments based on these results. Either by injecting Klotho into the body or by stimulating the brain to make more of the hormone, they hope to treat diseases like Alzheimer’s.

Later:

> When Dr. Dubal injects Klotho into mice, for example, the hormone doesn’t actually get into the brain. It must trigger some series of reactions in the body — but no one can say what they are.

This is why an injectable of the enzyme itself seem so unlikely:

1. Brain penetration is difficult to engineer into molecules, and especially so with proteins. Small tends to be a requirement, and peptides rarely fit the requirement.

2. An enzyme requiring to be bound in a membrane makes a terrible drug target because no only must it escape the body's housekeeping machinery, but must somehow survive with its membrane intact or miraculously become bound into the membrane of a passing cell. I'm unaware of any examples of that.

Can't say for sure since I'm not in this field, but some reddit research led to this:

>Whether acute klotho elevation represents a strategy that can rapidly enhance cognition, motor functions, and/or induce brain resilience is a gap in our knowledge of its therapeutic potential. Here we show that αKL-F, a fragment of the α-klotho protein similar to its secreted form, can acutely improve cognitive and motor functions following peripheral administration. It does so despite apparent impermeability to the blood-brain barrier in young, aging, and hSYN transgenic mice. Further investigation of αKL-F-mediated molecular mechanisms revealed activation of glutamatergic signaling and enhancement of synaptic plasticity.

https://www.cell.com/cell-reports/fulltext/S2211-1247(17)309...

So the research around klotho may produce something which doesn't actually need to cross the BBB as a retail drug, but on a simultaneous front, we have gene manipulation via CRISPR that would also increase klotho production.

You want to CRISPR yourself to gain a few IQ points?

Anyways that's at the least two decades away if even that, for what can at best be defined as recreational gene therapy.

>You want to CRISPR yourself to gain a few IQ points?

Depends on the side effects, depends if you can safely and reliably reverse the decision.

Would I personally be patient zero? No, not likely. Will someone be patient zero? Yeah, of course, there's always people willing to be on a new frontier.

> depends if you can safely and reliably reverse the decision

Can you safely and reliably reverse a find/replace on a program's source? Generally, unless you have a backup, the answer is no. There's also a lack of any kind of guarantee that the resulting program will compile, or if it does, that it will run without any more bugs than it had before.

CRISPR is just about the same way. We need to do research in ethical and humane ways, ways that balance the possible gains with the possible losses. We've already had an incident where human DNA was edited, and not particularly ethically or responsibly. I'd really wish that people not bring sci-fi futurist fantasy thinking to this particular table.

> Can you safely and reliably reverse a find/replace on a program's source? Generally, unless you have a backup, the answer is no.

Bad analogy as source code is one of the things that is super easy to reliably reverse anything as it is always in version control.

I think in this context that would count as having a backup

You can and I have done so, it's just quite difficult when you don't have backups so we usually try not to do this.

> You want to CRISPR yourself to gain a few IQ points?

Would you CRISPR yourself to not get Alzheimers or Dementia when you get old?

Nope. CRISPR is a research tool, not a therapy.

Hell, not OP, but I'd CRISPR myself to get rid of a pimple.

Making myself smarter or healthier or stronger would be a no-brainer.

I think you're overlooking the implication that modifying your genes the way CRISPR does is never going to be risk-free. The question probably isn't "Would you get rid of a pimple if there were no other consequences?" but more like "Would you accept a 2% risk of slow, painful death to get rid of a pimple?"

Are there even reliable ways to measure enzyme levels in the brain? I'm trying to imagine what research they would have to do in humans to show that they've effectively increased the levels of Klotho available in the brain, but in my (admittedly entirely amateur) reading about neuroscience I can't recall anything about measuring enzyme levels. I know just measuring neurotransmitter levels in specific parts of the brain is very difficult.

As with everything in biology: It depends.

If the enzyme is sufficiently represented in the cerebro-spinal fluid (CSF), then all you need to do is take a sample of that. Lumbar punctures/spinal taps aren't without risk, but they are considered safe [0]. If the enzyme is not well represented in the CSF, then you'd likely need a tissue sample. You may get lucky and find that the enzyme is represented in the meninges (the membranes that separate your brain from your skull) and take a sample of that [1]. This would not be easy and would have more complications than a spinal tap, of course. If you still don't have good representation of the enzyme, then what's left is an actual brain tissue sample. Likely, you'd take something from the parietal lobe, to minimize cognitive losses and standard of living issues.

Honestly, all these forms of sample recovery are absurdly unethical and would never pass an IRB. Since the enzyme is only being used to 'enhance' people, it's very unlikely you'd ever be allowed to get samples like these. Urine, sure. Saliva, sure. Blood, unlikely. CSF, never. The core issue is that since no harm is being done via these enzymes (supposedly) you can't introduce further harm that these samples require to obtain them. THe ethical issues are pretty black-and-white.

[0] https://www.mayoclinic.org/tests-procedures/lumbar-puncture/...

[1] https://en.wikipedia.org/wiki/Meninges

Selective Klotho Re-uptake Inhibitors? SKRIs?

You’re on the right track with the inhibitor / activator method to target Klotho. It's a funny protein. It forms a complex with FGF23 for binding to the FGFR. My bet is that there's some relationship to ECM remodeling and the function of Klotho, given it's relationship to glucuronidases. That's just a guess though, but it's very interesting.

For a vision of how the ethical / legal landscape will probably unfold, one needs only look to stimulant drugs. They have approved therapeutic use in treating ADHD, but are frequently used as performance enhancers and recreationally by neurotypical people. In small (theraputic) doses, the deleterious effects are minor, but recreational use is often high enough to cause psychosis and addiction, so invites legal restriction.

Perhaps the most relevant question would be: what is the effect of having too much Klotho?

These new mind enhancing drugs need not go down the path of adderall or other ADHD drugs. From my understanding those are based on amphetamine salts, with a host of well known societal issues like you mentioned.

Maybe they would follow the route of birth control instead. Initially seen as a moral repugnancy by many, but eventually accepted pretty much universally. It alters the body in significant ways achieving the desired effect as well as a few other hard to quantify ones.

We should be cautious of bad side effects, but they are not a given.

As I understand it, birth control is designed to mimic the hormonal characteristics of pregnancy; a state which is otherwise natural and usually well tolerated by the body. I'd say the use of this drug for Alzheimer's patients is more similar to hormone replacement therapy (HRT) for menopause. Use in neurotypicals to increase intelligence, would then be similar to hormone therapy as used by transsexual and intersex people, and possibly warrant a similar risk analysis.

From a social point of view, I'm thinking our 'reward functions' are already massively under attack. From app notifications to fast food, gambling machines to dopamine triggering drugs

Society is evolving, and the victors will be more resistant to all forms of addiction than we are today, just by sheer necessity

To play devil's advocate (of sorts)... Maybe the pathology-treatment paradigm needs challenging. Dangers/costs exist for "neuro-untypical" people too, as well as benefits.

Anyone will concede that costs can outweigh benefits for some diagnosed (neuro-untypical/pathological) patients. Is it impossible that benefits outweigh costs in neurotypcal patients? My experience is that professionals are uncomfortable with that thought.

I was one of the kids prescribed stimulants in the early days, circa 1990. Even as a kid, I smelled wierdness.

One doctor prescribed the medication, and asked for teacher feedback. If the drug did its job, then I had ADD. The test was comparing behaviour on & off the drug. If I didn't have ADD, the drug wouldn't work. Later on, the doctor told my mother: "If you take it, it'll do the same thing. It boosts concentration in everyone." This was a slip, kinda. They prefer if patients (and professionals) pretend that "the drug only works if you have the pathology, and is very dangerous if you don't."

I think the medical system is uncofortable about "enhancement" generally. For something to receive treatment, it needs to be a pathology, untypical... I sympathize with the reasoning, "first, do no harm" and also the potential reality of such drug use becoming more common.

Often times, this gets abstract... "what is normal, man."

Anyway, I don't think ADD drug benefits or costs are, in reality, very closely correlated to your unmedicated baseline. Besides biilogy, a big factor is your job/school/environment, and what it takes to perform in that environment. If you're a football player or a film director, add drugs probably won't do much. If you're a chess player or ceo, they probably will, regardless of your unmedicated norm.

Agree with everything you said except for this last bit:

> If you're a football player or a film director, add drugs probably won't do much.

It's obviously not a useful data point, but my own personal experience is that my physical endurance is greatly increased on the days I've taken my Adderall prescription.

If you read up on amphetamines, it's pretty interesting. They known to provide significant physical enhancement in a number of dimensions. The trick is keeping the user from developing a physical dependence.

Interesting. It's been a long time for me, but I don't recall those sorts of effects.

What I meant was that the importance of concentration (or really any drug-enhanced something) varies a lot by activity. You might be add-as-hell, but in your daily life that's fine. OTOH, you might be "neurotypical" but up to something where any enhancement is felt.

>What I meant was that the importance of concentration (or really any drug-enhanced something) varies a lot by activity.

I think it's important not to undersell the universal utility of focus. Even if you ignore the obvious physical advantages afforded by PED-stimulant drugs, like decreased reaction time or increased endurance.

If you model decision making in a zero-sum adverserial context like football or chess as an OODA loop[1], then a drug that decreases your processing time and decision making time is going to grant you an advantage by shortening that OODA loop.

1: https://en.wikipedia.org/wiki/OODA_loop

Just to add another data point, I also felt like my physical performance in the gym was greatly enhanced during days I used Modafinil, to the point where I would schedule my Mod days with when I did a leg workout in the gym (which I otherwise despised). I've discussed this with friends and they all also agree. It could well be placebo, but that's not to say it still isn't an effective training enhancer.

>If you're a football player or a film director, add drugs probably won't do much

FYI, the NFL considers amphetamines and substituted amphetamines to be performance-enhancing drugs. As does the International Olympic Committee.

Doctors won't prescribe enhancers just for enhancements, but all stimulants (except modafinil I guess) were OTC for at least a time, so we'd expect an enhancer (if safe) to be regulated as a supplement. Caffeine is "the one good drug" and I don't see that changing, and that's even though there are fatal overdoses on it and the side effects are pretty bad (but not psychosis bad), so it's not a terribly high bar to clear for a new compound.

It'll be interesting to see if new compounds have tolerance or withdrawal effects -- something that made you smarter for 4 hours but unable to tie your shoes for 2 days would be a non-starter, as would a smart drug that then permanently lowered your non-drug IQ and raised your chance of Alzheimer's. If anything if I remember my course on the subject correctly pretty much all psychiatric drugs have withdrawal effects that are worse or longer lasting than stimulants do, and while that's not something that would cause them to be made illegal, it would make doctors very reluctant to prescribe them "just to try" the way some have with ADD. (I also don't think a compound that has fatal withdrawals would be allowed as a food or supplement today, alcohol is pretty much grandfathered in.)

Doctor: Here's a drug that may improve your intelligence but it's relatively untested and since we don't have a good understanding of the nature of human intelligence or how it interacts with other personal characteristics or society as a whole we have no idea what the actual outcome will be for you.

Me: Don't care. Hit me.

Takes pill.

Me: Old me was stupid to make that decision. However I cannot regret his passing despite the acute melancholia that is now the cornerstone of my existence.

I would never in a million years wish upon another human being the degree of suffering that having a turbocharged brain has caused me throughout my life. Seeing people chase this is like watching a slow motion train wreck. I can think of no more effective way to reduce happiness, success, and human connection. It’s a lonely and distant place to be. Nothing is worth this price. Don’t pay it.

If everyone had it then most of those problems would go away no?

There are a full complement of problems that have nothing to do with other people. For example, imagine never being able to rest your mind again, no matter how intense the leisure, no matter how strong the intoxicants, no matter how tiring your thoughts. Sleep isn’t restful either. Most people would crack in 30 days or less.

How specifically is your brain "turbocharged"? Is this something you have been diagnosed with? Have you always had it? Is it hereditary? Why do you think most other people would not be able to cope with this condition? Has this condition conferred any advantages such as professional success?

I think most people would not be able to cope because they undervalue the importance to their self and sanity of brain downtime: daydreaming (and idle websurfing), zoning out (and intoxication), and sleeping (and dreaming).

are you turbocharged or just suffering severe insomnia and anxiety?

The first diagnosis was at 18 months old, so I’m not sure how to answer the question as framed since I don’t have clear memories from that time.

You were diagnosed with having a turbocharged brain as a toddler?

That happened.

They were composing their first Reddit post as they came through the birth canal.

"I....I'm sorry to inform you, your baby has a turbo-charged brain" sobs burst out

>> Nothing is worth this price. Don’t pay it.

I hesitate to pass judgement on another's life choices. Some people want to do certain things and are willing to sacrifice everything, including their own happiness, to do that thing. If you want to be an astronaut, if you want to win an Olympic medal, you will sacrifice. If this drug allows a person to pass a test, to win a position that they otherwise would not, who am I to deny them?

Try spending time with military pilots, astronauts or elite mountain climbers. They can be very nice people, until you get between them and work. Don't ask an astronaut to delay a flight for a wedding, or to donate a kidney. Every one of them would take this drug if that allowed them to beat out the competition. Happiness, theirs or anyone else's, is secondary.

I've generally found that the most intelligent people have had overall delightful dispositions, and it's the above-average-intelligence folks who, being obsessed with smartness, are far less happy.

I think you'll find that only a smallish subset of above average intelligence folk are obsessed with smartness. Those are probably the less happy ones.

You should read up on some history. The most intelligent people ( newton, einstein, etc ) were far from being delightful people with delightful dispositions and far from being happy.

Just from the other day, "A study of ethicists finds they’re no more ethical than the rest of us".

https://news.ycombinator.com/item?id=19529374

I think people are simply people, no matter how smart or educated they are. Prone to jealousy, pettiness and subject to all of human pitfalls. Of course the smarter and more educated you are, the more damage you can cause.

What? It's completely possible to be smart and still be able to relate and connect to other people. Your intelligence isn't what's isolating you, it's your mindset. I used to think this way when I was younger and it's incredibly unhealthy.

/r/iamverysmart

Please don't do this here.

Intellectually humble people tend to possess more knowledge, study finds -- Psypost 31/03/2019

https://www.psypost.org/2019/03/intellectually-humble-people...

You can mentally train your way out of that. For instance, some monks can generate gamma waves off of the proverbial charts when doing a compassion meditation. For the more cerebral aspects of self-inflicted suffering and with a lower barrier to entry, cognitive behavior therapy should yield some results.

I don't think the issue is intelligence but how were you raised and what values were emphasized by your parents.

'You are smart!' is one of the worst things you can say to your children. It places their own self image on a dependency of results in an ever increasing difficulty of tests.

'You did a great job this time! I hope you enjoyed the challenge!' places their own self image on their effort, not on the results.

It seems a small change, but the resulting mindset could not be more different.

I don't want to take a drug to improve my performance while having to monitor for side effects, deal with withdrawal and worry about potential and unknown long term damage.

In particular I don't want to feel like I would have to take a drug just to keep up with everyone else who is on gear. That's how it seems to be in professional sports, but that's a niche. Brain drugs would be attractive to a large part of society.

This competition is already the case with amphetamines. They are not necessary but IMO they do provide a productivity benefit over those who do not take, on average.

It's an acute benefit though, isn't it? I've noticed that people coming down off of amphetamines are not as productive as they might otherwise be.

Do you know of an acute performance-enhancing/experience-enhancing drug that doesn't have a shitty come-down phase?

That's true, but meth mouth is a particularly shitty side effect.

They could beat you in their productive phase and suffer while coming down. Lose-lose.

Probably, it'd be hard to say for sure. I personally don't take it every day and sometimes just take half of my dosage, to reduce tolerance. There definitely is a tolerance though and also a bit of Yerkes-Dodson law type deal at play, e.g. if I take to much I am also not productive.

I would definitely say it increases my productivity output though overall.

Correctly dosed and this isn’t an issue

This is one of the main reasons I like watching soccer. The smallest dude can dominate the world and it doesn't feel like I'm watching people destroy their health for a chance at making it big.

Soccer players still ‘benefit’ from drug use. A much larger issue was largely ignored by professional bodies. FIFA still only has a 2 year ban for someone caught, and does not try that hard to find users.

According to a statement of one of UK Sport's Independent Sampling Officers (ISO), "If a club knows in advance we're coming, and the club suspects one of their players, they keep him off training and his name doesn't appear on the list I am given." In the 1999–2000 season, testers were present at just 32 of the over 3,500 league matches, taking samples from two players of each side. Compared to other sports in the UK, like cricket, cycling or athletics, footballers are far less likely to be tested.[13] A case of high-profile was the one of Rio Ferdinand, who missed a drug test in September 2003 and found himself punished for it, being banned for eight months.[14] https://en.m.wikipedia.org/wiki/Doping_in_association_footba...

I think any sport that is more like an art is gonna be like that. Soccer is more of an art. There are positions where the performance enhancing drugs definitely will help you. (And I'm sure a lot of players use those drugs if they are at those positions.) But you won't become Pogba, Messi, or Neymar by shooting up. Those guys are artists.

Basketball is like that too. Shoot up with whatever you like, it will have no effect on your 3 point percentage. You want to shoot like Steph Curry? Then you'll need to be just as good an artist. You want to handle the ball as well as Kyrie Irving? You'll have to be just as good an artist.

I know people might disagree with this one, but I think some hockey positions are like that. People should try this experiment, go to your local ice rink, and try weaving through traffic at top speed on skates and putting the puck in that 6 inch window that a keeper might give you to the back of the net. Steroids aren't gonna help with that.

Those are all sports where a little guy can come in and just dominate through sheer asymmetry of skill. It's a beautiful thing to watch.

The drugs enable more time spent practicing.

PEDs can help with the things you describe because they allow you to train significantly longer and more frequently because you recover far better/faster.

I once worked with a professional cyclist. His attitude about PEDs were largely similar to yours: less about increasing your maximum ability and more that they allowed for better recovery between training/racing sessions. This is anecdotal, of course. No idea if it’s true.

There absolutely are PEDs that increase your maximum ability when it comes to endurance sports, like EPO. A reporter tried microdosing EPO (https://www.bbc.com/news/uk-scotland-32983932) and experienced a 7% increase in maximum performance in 7 weeks.

for the basketball and hockey arguments you made...i'm fairly certain things like stimulants can be and are used to help maintain focus during practice. 3 point shooting is a boring mechanical repetitive motion. Doing that motion 1000 times a day is boring. Taking a stim might allow you to continue to focus and get the reps in that will allow you to perform the motion better. Taking the right drugs might allow you to avoid injury and reduce fatigue.

My favourite "conspiracy theory" is that PEDs are rampant in football/soccer. It's not a high profile issue because those in charge of running the sport don't want to look under the carpet for fear of what might be there.

> Soccer is more of an art.

True, skill is paramount versus other more physical sports, but the main purpose of PEDs is to recover from injury not to bulk up or make guys bigger or stronger.

Interestingly, Messi was given HGH before reaching adulthood in order to overcome a growth hormone disorder[1] (completely legal). Without HGH it's unlikely he'd be half the player he is.

Pep Guardiola tested positive for a banned substance during his playing career, although he was later exonerated.

Arsene Wenger has publicly stated in the past that he reckons the sport is full of drug cheats.[2]

Operation Puerto in Spain[3] involved a lot of blood samples, including those from footballers, being destroyed. Around that time, Barcelona and the Spanish national team were absolutely ripping it up.

There was a doctor filmed in the UK[4] who allegedly supplied Arsenal, Chelsea and Leicester City with PEDs. Leicester went from relegation fodder in 2014-2015 (bottom of the league for quite some time), to winning the premier league in 2015-2016 season. They were 5000-1 odds to win the league, played a high intensity counter attacking football, with more or less the same 11 every week.

I wouldn't swear in court that any of the above examples are definitely doping, but it's incredible that none of this is seriously being investigated.

[1] https://bleacherreport.com/articles/1492546-lionel-messi-and...

[2] https://www.theguardian.com/football/blog/2015/nov/14/footba...

[3] https://en.wikipedia.org/wiki/Operaci%C3%B3n_Puerto_doping_c...

[4] https://www.telegraph.co.uk/news/2016/04/03/cyclist-at-centr...

Plenty of doping and cheating in soccer.

https://www.theguardian.com/football/2013/feb/08/arsenal-ars...

The problem is that soccer/FIFA is so lucrative and corrupt that there is very little testing or it's simply ignored.

'm pretty sure physical enhancers would be more attractive to the general population than mental enhancers, although the HN community probably varies on this issue.

It depends on what you mean by “physical enhancers” and “mental enhancers” - my understanding is that stimulants are already much more widely used than steroids. I certainly agree that some theoretical physically enhancing drugs would be more popular than some theoretic mentally enhancing drugs.

A physical enhancer enhances some physical aspect predominantly, and a mental enhancer enhances some mental aspect predominantly or allows you to do better at enhancing the particular aspect yourself.

physical enhancers I can think of: Steroids, Viagra

mental enhancers I can think of: Modafinal (and similar, mainly, can also argue it is a physical enhancer), psychological drugs focused on better focus etc.

half and half - amphetamines. you can stay up to study but you don't pay attention so you could also stay up to party.

physical enhancers I can think of offhand: drug makes you beautiful, drug makes you physically tough, sharpshooter drug etc. etc.

mental enhancers I can think of: increase short term memory, photographic memory, increase reading speed, language processing improvements.

I guess I see that passing the GED drug mentioned in the other comment but intelligence is as a general rule not something people aspire to in this society (IMHO) therefore I would expect intelligence altering drugs would not receive as much funding as drugs that effect the things that society values, and those things tend to be physical.

Or to paraphrase Idiocracy the best minds would be devoted to enlarging penis size not making people smarter.

I don't know man?

Where I'm from out here in flyover country there are an awful lot of people stuck in dead end jobs that would literally jump at a drug like that if its effect was dramatic enough.

Getting that GED in a weekend? You better believe there are a lot of people out here in trailer park and opioid land who would be all over that. Doesn't mean much to us, but the GED opens up raises at their current jobs, and even jobs that they currently are not able to get. That's not even counting the waitress types trying to get through college at night without waking up their kid. Those single mom types would definitely take it. It wouldn't even be a question for them.

Only way an illicit drug like that would not be consumed around where I live, is if the people around here couldn't find out about it. (Even that though would be hard, because I'm sure we have drug dealers around here who are probably pretty good at marketing stuff like that.)

This is how I felt as a kid on ADHD medicine, except for the "keep up with everyone else who is on gear" part. Instead it's "to conform with the traditional notion of how a student should behave".

It's really horrifying that they already give these types of drugs to elementary school children, none of whom are capable of weighing the pros and cons.

> In particular I don't want to feel like I would have to take a drug just to keep up with everyone else who is on gear.

That's what I do to deal with my ADD. Adderall has some obnoxious side effects. And also: that's why I wear a CPAP every night, and believe me wearing a mask every single night is annoying as hell.

So on one hand, I get you—it'd be nice to not have to do these things just to get back to baseline. But on the other, I'm glad I have the option to do so, and I do them knowing the side effects, because it's worth it.

"That's how it seems to be in professional sports, but that's a niche."

That niche is a bigger than you realize. One of the 'benefits' of amphetimine is productivity. Many meth abusers use it before work for this reason. Both physical and mental effort can be sustained for much longer periods.

People already take adderall to pass exams and to do well at work. Some people do their best work drunk or after smoking pot. Some people even microdose psychadelics (and in biology, we wouldn’t have PCR if it weren’t for a fateful acid trip).

People take these performance enhancers because they work. The only thing stopping everyone from taking their gramme of soma a day is cost, access, and a willingness to experiment. Sometimes I wonder what could be achieved if we lowered these barriers we’ve put up based on antiquated views of moral character. Imagine if Einstein met Hoffman!

If true that it enhances healthy people, I wonder why we didn't evolve to produce more of it? Why didn't mice?

Maybe side effects? Maybe being too smart is an evolutional disadvantage on an individual level or in small groups? Maybe producing the hormone is too costly?

Seems like too easy of a "hack" to improve such highly optimized systems such as humans or mice.

Because that's not how evolution works. Depending on the environment, initial conditions, boundary conditions, some traits may arise and some may not simply because of random chance. Evolution doesn't have a goal, if something survives because of some mutation and propagates, then it might be seen in future generations.

I think there's a fallacy there: the joint assumptions that evolution has "already happened" and has produced fully optimized systems.

If we adopt a flawed "evolution as agent" model, there is zero evidence that it has tried everything, or even most things, in order to optimize species.

If we adopt a more accurate model, evolution doesn't optimize or produce optimized systems. It can (but does not always) produce reliable (as in reproduction/survival) systems. There are plenty of ways Klotho could be beneficial but not produced by selection: mutations which increase production of this chemical may have occurred but had negative effects on fitness, or may have happened to occur along with other mutations with negative effects; there may not be any mutations which increased production (it's tempting to think of e.g. hormone levels as "knobs" for which there are mutations that turn up/down output, but that metaphor completely fails in many cases); beneficial mutations to increase Klotho production may be possible but not have occurred in nature because of chance or complexity of changes required to actually manifest the "right" change.

There might also be a mob-reaction against beeing gambled too much, resulting in conspiracy theorys and goverments built to execute those framed in those in conspiracies.

In other word, hacking your fellow mens livelihood might shorten your longterm survival.

I am curious what you are on.

Maybe Klotho!

If you are smart, you do not work hard. Instead, it turns into a sort of competition, who has to work the least, to extract the most benefits and do the least amount of work. Hacking in that regard, is a competition of parasites.

My pet theory is, that having suffered for nearly 10.000 years under castes of priests and noble men unwilling to lift a finger, humanity has developed a near instinctive hatred for "parasitic" entitys, who ledge themselves to society extracting value without returning anything to society.

The moment, external circumstances in such a system create a down turn, the whole thing explodes, viciously attacking the non-contributors, trying to exterminate them and redistribute there ill gathered gains back to society.

Take a look at france during the revolution for example. Sometimes the parasites, manage to redirect the hatred towards internal or external outgroups, like the jews in germany during ww2, but in the end, the mobrule undoes most of the parasitic growth anyway by sheer brute force and endurance of turmoil.

The article mentions people who produce more Klotho, so clearly that variation has occurred:

> Some people carry a genetic variation that causes them to produce higher levels of Klotho than average in their bodies. Dr. Dubal and her colleagues identified a group of healthy old people with the variant and tested their cognition.

> They scored better than people who make an average level of Klotho. “It’s not like they didn’t undergo cognitive decline,” said Dr. Dubal. “It’s just that they started off higher.”

I'm a bit torn between your perspective and the parent comment. I accept the logic of your argument.

But that doesn't mean the parent comment couldn't be correct. Klotho could have side effects (doesn't everything have side effects?) and that could be why we (and mice) don't produce more of it. I don't think that's a bad hypothesis.

Of course it's just a hypothesis and, as you point out, it doesn't logically follow that our production of Klotho is perfectly optimized (Optimized for what? Fitness? Fitness is a moving target). But, on the whole, I'm skeptical of a hormone that makes us smarter and wards off brain degeneration but does nothing else.

The only thing evolution by natural selection tends towards is survival of genes (by definition). In order to assume evolution was open-endedly optimizing for greater intelligence, one would first have to make a strong argument that such greater intelligence would result in greater genetic success.

I think many people view humans and intelligence as something evolution has always been working towards, following a gradient like a river meandering to the sea. The reality is that such intelligence satisfied a niche adaptational advantage.

It's not a far fetched idea. At least up to a certain point, higher intelligence means a higher chance of survival and thus better chance of passing on the genes.

That's why I said open-endedly optimizing. Obviously some amount of intelligence is beneficial to humans' survival, procreation and protection of offspring, but only to a point. If evolution tended towards ever greater intelligence, you'd expect to see the most intelligent individuals having on average a greater number of offspring. Instead, studies generally show a negative correlation between intelligence and fertility. This would instead suggest that evolutionary pressure on intelligence was not open-ended, but in equilibrium.

I tend to think like this too. If the change is small/easy evolution probably tried it already. A standard guess for a "downside" would be increased energy expenditure (but only a guess). Also, Klotho seems to decline with age, and old people are not as well optimized by evolution, since they don't procreate (directly).

rapid reproduction/death (mutation) rate would be evolutionary advantageous, or at least a requirement, no?

Why haven't we evolved photosynthetic skin? Why haven't we evolved the ability to regrow lost limbs and organs? Why haven't we evolved a better defensive system, delivering us from sickness and cancer?

The answers to all those questions are the same: evolution doesn't "care" about you being comfortable, or optimized. I quoted "care" because evolution is a process; it lacks a conscience and thus it cannot "care". But it has drives. Regarding you, evolution's drives are that you pass your genetic material down to your offspring, that you have as many offspring as possible, and that they repeat the cycle after you are gone.

All the benefits that you as an individual get from are either a direct consequence those drives, or a happy random accident, because there's a high degree of randomness involved.

The fact that there's randomness, plus the fact that individual comfort or productivity is not a drive, means that there could be places where us humans can "supplement" evolution - that's one of the roles of modern medicine. I'm not saying this particular compound will work as advertised; just that the room for improvement exists.

Bad examples. Increasing the amount of some substance produced vs re-growing limbs?

Evolution is an optimization process. It can get stuck on a local maxima, but it's not a local maxima, if it can be trivially improved upon with no harmful side-effects. And it's not like producing more Klotho requires complicated mutations that are unlikely to happen. We know they happen.

So - asking why it's not already widespread is perfectly reasonable. It probably involves some trade-offs.

Although I also disagree with the GP, I think phrasing evolution as an optimization process is a mistake. Evolution is a diversification process that exploits variation within a population to make the population as a whole more resilient to changes in the fitness function.

The net result is the same -- even if Klotho production is neutral in the fitness landscape, you would expect it to be quite common. For it to be naturally as rare as it is probably implies a significant fitness cost in other ways.

It could very well be, however, that the particular problems with Klotho production are factors which are no longer relevant in the current fitness landscape, but we (and other animals) evolved a certain resistance to Klotho production that has yet to be overcome by the irrelevance of the underlying costs. For example, if Klotho production significantly reduced reaction times or the time it takes to ramp up adrenaline production, then it might be that we are at a point where the downsides are no longer as relevant as they once were.

to me I conceptualize evolution as just a process like water filtering through a sieve is. So I don't see why using the word 'drives' is justified either.

Unfair conparison. Growing titanium bones is most likely unfeasible, if even possible. Producing Klotho is not infeasible, it is being done in our bodies. The question is the amount, which I assume should be already finetuned. That's why I called it too easy of a "hack".

> Regarding you, evolution's drives are that you pass your genetic material down to your offspring, that you have as many offspring as possible, and that they repeat the cycle after you are gone.

It also doesn't help that lower IQ correlates to higher offspring, according to some studies.

https://en.wikipedia.org/wiki/Fertility_and_intelligence#Int...

That’s only true since the 1800’s. From the dawn of agriculture to industrial civilisation there might have been very weak selection for intelligence. It can’t have been strong because otherwise we’d all be Von Neumanns.

Gregory Clark's work on social mobility is fascinating if you find this topic interesting. Start with either A Farewell to Alms or The Son Also Rises.

"It can’t have been strong because otherwise we’d all be Von Neumanns."

But the type of intelligence that secures safety and access to reproductive opportunities is the sort which wages war and waits for the right time to backstab and/or do away with one's rivals.

With agriculture you get the monopolization of surplus resources which greatly increases the rewards for autocratic and oligarchic formations.

Funny that you mention von Neumann. His background is Hungarian Jewish, a trait he shares with a number of other super-geniuses. In fact, von Neumann went to the same Budapest high school as Edward Teller and Eugene Wigner. Quite a few other geniuses and Nobel laureates hail from Budapest. Scott Alexander has a fascinating write-up on this phenomenon [1].

[1] https://slatestarcodex.com/2017/05/26/the-atomic-bomb-consid...

I agree. Personally, I'm very annoyed with myself at times at the tendencies that drive me that are constantly at odds with productivity or good health etc etc. as like you said it, evolution does not have the capacity to care about the desires of humans. In a macro-scale sense, humans figuring out how to overcome this is a type of evolution via intellect possibly as our intellect results in tools etc. via evolution.

It might also be something like limited resources as a driver in environmental pressure such as food being available to older members that did not pull their weight and a tribe had a better survivability if these individuals naturally died off earlier than later.

I hope to formalize my thoughts on this in the future but this is precisely my hypothesis- that as a whole we have reached peak intelligence; any smarter and we will start "seeing" the futility of life and just be more prone to suicide or other acts. It can also go the other way where no fully intelligent individual sees the need to cooperate and you end up with a lot of extremely selfish intelligent individuals killing each other.

I also think that's why traits like intelligence are not completely genetically determined within our species. It looks like evolution has programmed stochasticity into intelligence so that the distribution is kept intact within the population while no individual lineage gets an unfair advantage.

>If true that it enhances healthy people, I wonder why we didn't evolve to produce more of it? Why didn't mice?

We don't evolve towards some perfection.

Just randomly walk through evolutionary paths as much as needed to be fit for our environment.

https://www.gwern.net/Drug-heuristics

> If we compare the smartest people in the world now like Terence Tao to the smartest people of more than half a century ago like John von Neumann, there seems to be little difference. Eliezer Yudkowsky expands the thought out in his essay “Algernon’s Law”, stating it as:

>> Any simple major enhancement to human intelligence is a net evolutionary disadvantage.

...

> COSTS Intelligence is an almost unalloyed good when we look at correlations in the real-world for income, longevity, happiness, contributions to science or medicine, criminality, favoring of free speech etc18. Why is it, then, that we can find quotes like “the rule that human beings seem to follow is to engage the brain only when all else fails - and usually not even then”19 or “In effect, all animals are under stringent selection pressure to be as stupid as they can get away with”20? Why does so much psychological research, especially heuristics & biases, seem to boil down to a dichotomy of a slow accurate way of thinking and a fast less-accurate way of thinking (“system I” vs “system II” being just one of the innumerable pairs coined by researchers21)? Because thinking is expensive and slow, and while it may be an unalloyed good, it is subject to diminishing returns like anything else (if it is profitable at all in a particular niche: no bacteria needs sophisticated cognitive skills, nor most mammals) and other things become more valuable. Just another tradeoff.

The environment doesn’t require such enhanced levels of intelligence for individuals to survive long enough until they can reproduce.

If we required IQ tests of a certain score as a prerequisite for breeding children, then maybe you would see progress in human evolution in this area.

Evolution works in mysterious ways. E.g. Whales aren't very intelligent but use their very large brains to keep themselves warm.

A lot of the replies are making true statements, but not getting to the core of your point.

First, there is a whole class of improvements that evolution can't do because they involve a non-local refactoring that therefore can't happen through random variation plus selection.

But you're right, as a general rule, any simple local improvement that turbocharges capability like you've described is something we should expect evolution to have already done. There's a name for that heuristic, but I can't find it at the moment. That's why it's so hard to find a single chemical that costlessly improves intelligence.

This is akin to asking "if evolution is real why do we still have apes!?".

The answer is of course "Because that's not how evolution works.".

If I understood this correctly, all the results with mice came from genetic modifications that, I guess, produce more Klotho since birth. Would be interesting to know if the same results can be obtained by injecting the hormone later in life.

From the article:

> she injected the hormone into the bellies of mice, to have a point of comparison. Within a few hours of the injection, the mice started doing better on cognition tests.

A link there points to a study that says it worked on both young and aging mice: https://www.cell.com/cell-reports/fulltext/S2211-1247(17)309...

Great, thanks. I wasn't focused enough while reading :)

What a ckickbaity title for the times and what a strange way to talk about a new medical discovery.

Is there some kind of secretive cabal that decides who gets drugs? Yeah the price will be high at first very likely and if there is huge demand and an efficient way to produce it that price will likely come way down.

Why does everything have to be some kind of unfairness conspiracy?

Eyeballs! We want your eyebaaaals!

Not a drug. Not a hormone. Ginned up controversy written by someone with only a rudimentary understanding of biology and a deadline.

Headlines today: "Shapely Blonde With Piercing Blue Eyes May Have Discovered Cure For Cancer Or Something".

It's the idiocracy. Give up.

Prescription drug prices are in no way coupled to the cost of production.

It almost feels like the beginning of a real-world Flowers for Algernon. One wonders if we just haven't found the downside yet.

Flowers for Algernon and maybe Planet of the Apes. It would interesting to contemplate the effect such a hormone would have on apes and chimpanzees. I certainly doubt they'd push up anywhere even close to human intelligence but would the incremental gain be such that humans would squirm with discomfort?

Disruptive Startup Idea: inject apes with this, train them to work in a factory. The ultimate labour regulations hack, as they could literally be paid in peanuts.

I can't decide whether it's journalistic malpractice not to mention Flowers for Algernon, or an incredible act of journalistic restraint and/or editing.

Is this even required reading anymore? I think we read it in 7th grade or so.

This sounds more about optimization overall as a whole and the brain benefits rather than only for the brain? Mice live 30% longer so it must be not only about the brain.

The irony of this potential drug is that we currently aren’t smart enough to know any better. This potential drug plays mind games with you before you take it.

I am somewhat sceptical of any easy chemical ‘enhancement’ treatments. If there was a simple chemical treatment that could enhance human performance with no down sides, given millions of years of evolution you’d think out bodies would have figured it out by now. Especially if it’s an enzyme our bodies already produce. If it were a simple as produce more enzyme in the right place = better performance, why aren’t our bodies already doing it?

Of course performance enhancing drugs of various kinds do exist, but there’s always a risk or down side to go with it. The benefits are usually fairly marginal too. Maybe enough to bump the third best athlete in the world to being the best athlete in the world, but that doesn’t actually take much in objective terms. Furthermore the greater the potential benefits from a drug like this, in order for our bodies not to have already exploited it presumably the down sides must be commensurately bad otherwise the tradeoff would be worthwhile.

So ok, such a treatment might work and might be useful in certain circumstances but I think a very healthy dose of caution and scepticism about easy medical fixes is in order.

Evolution doesn’t optimize for intelligence or lifespan, it optimizes for reproduction

And therefore for those attributes which make one more likely to survive and reproduce in a given environment.

On it's own, being stronger could be expected to make one more likely to have surviving offspring, but if it's at the cost of other detrimental effects like paranoia, excessive resource usage, shorter life span, etc then it might not be worth it. Similarly higher intelligence would be an advantage to survival and reproduction, but only if it doesn't come with excessive mitigating costs.

See you say that, but evolution is a slow process and is ongoing, and is a blind idiot god dancing to a tune which has no consistent time signature.

Unless a mutation is heritable enough/commonly occurring enough, and useful enough when it is only a minor change it won't be selected for. It might continue on and become useful eventually anyway if it isn't a detriment and that genetic line just happens to continue.

Why do our bodies age? Because a collection of little mutations that are only detrimental years after reproductive maturity it turns out don't have a huge impact on the survival of those genes.

Why can't we see as many colours as bees? Evolution figured that out for them.

Why hasn't evolution figured out how to give us night vision or an extra set of clear eyelids like camels have? Those would be useful. Animals exist with all those traits so they are entirely possible. If you're objection is "evolution would have figured it out" you only need look to the animal kingdom and see how crappy humans are in lots of ways to realize that is a pretty crappy objection

Title reminded me of 'Limitless'

Same, and there was a whole tv show based off the movie.

Can we not first try this on a few apes and other primates preferably at an ape sanctuary run by a sadistic person ? Maybe someone can then make a documentary or movie based on this?

Island City (1994 film)

Hormone "K".

Reference: https://archive.org/details/TedChiangUnderstand

With what side effects, short term and long-term? How about resistance or dependecy?

So in order to get really smart must qualify by getting really stupid first.

They need to make this drug available before the 2020 presidential election.

Evil and dumb can be manageable. Evil and intelligent is frightening

> frightening

I really don't know why people use this term. Nothing is frightening in the world of man.

It's like this:

Whatever can be made by man, can be destroyed by man.

Edit: So many frightened people...

Nothing is frightening because everything can be destroyed? That’s a new world view to me.

Here's some examples for your world view.

A man with a knife intent on doing harm, is stopped by one with a gun.

A man who develops a virus for a plague to kill people, is stopped by one who develops the cure.

A man who develops icbms to devastate a nation, is stopped by one intent to develop a missile defence shield.

There are many examples that I could continue with. The key takeaway here is that whatever some one does, in time there is an equal opposite reaction to counter it.

That's my world view. I personally don't fear anything. But then that's could be just how I'm built.

"A man who develops a world view to look badass on the internet"

What if the man with the knife stabs you in the stomach before the guy with the gun gets there?

You should read the Basic Laws of Human Stupidity, which concludes in the fifth law that a stupid person is the most dangerous: http://harmful.cat-v.org/people/basic-laws-of-human-stupidit...

However, while we can debate whether giving the drug to politicians would be a good idea, giving it to voters seems to have fewer downsides.

All i can think of is Ghostbusters - "I am Vince Klo(r)tho keymaster of Gozer!"

Doubt this works.

Pretty sure intelligence is related to the general metabolic setup of the brain, which is almost certainly genetic after controlling for healthiness.

While metabolic health is almost certainly related to intelligence, what makes you think it's the defining factor? Wouldn't that mean all diabetics were less intelligent than non-diabetics? Also, almost all children have better metabolic health than almost all adults, and even their fluid intelligence is lower up to a certain age.

I do agree that increasing intelligence is probably very difficult. However, there are probably some limiting factors set by evolution (amount of energy consumed, heat produced, etc) which might be overcome through modern methods.

Metabolic setup isn't fit to a one dimensional line of bad to good.

I stand my ground. Children have the most neuroplastic brains capable of learning multiple languages simultaneously and having them become instinctive.

Adults are largely screwed on that front.

Most masters of various practices started when they were children and people that got into the practices later on often can never come close to the same level.

Age 18-23 or whatever where people say they are the sharpest is just like the point where you know the most before neuroplasticity starts degrading faster.

https://pediatrics.aappublications.org/content/28/5/764

This somewhat suggests that the episodic physiologic consequences of diabetics are linked with iq differences, which makes sense considering hypoglycemia and acidosis are direct hindrances to metabolic output and integrity.

Why would running make you smarter? It is known it does 100%. Well running improves the efficiency of mitochondria and at a larger scale the blood flow to the brain. But of course that won't endlessly improve your intelligence. It'll hit a cap at your systems maximal efficient output. Similar to genetic muscular strength.

Energy consumption and heat production are directly related to metabolism.

Intelligence can mean a great many things.

If we are simply making people better at cognitive tests then whats the point really? Nothing exciting there.

If we are making more Einsteins and Steve Jobs then Im more inclined to say we are increasing our intelligence in a meaningful way.

I think we need to be careful about our scales and definitions when speaking on the true nature of human intelligence and intellect otherwise we're all just blowing hot air. IQ is an antiquated measure of intelligence for example. If we are talking about extra IQ points then who cares.

Cognitive testing is actually the most statistically sound stuff we've ever come up with in psychology.

Attention and single mindedness is practically an intelligence booster and much easier to obtain

I think the question they’re asking is already observable. Who is privileged to have finances that can pursue a healthy lifestyle compared to the person having to order off the dollar menu. Who can afford supplements, exercising and leisure time without stress. No matter it’s unfair and people have no trouble not caring when they’re the privileged. Nobody’s going to take the fallacious high road with any drug that increases lifespan or lifestyle and give it to the less privileged or unfortunate compared to themselves.

Pretty much. The common mythology of the fat rich guy is mostly untrue. Its the wealthy that have time to devote to weightlifting and even hiring a personal trainer, eating expensive protein shakes and supplements, possibly even getting TRT from a doctor.

Wealth supports health for most folk unless they are slimes like Harvey Weinstein who would rather rape and eat grapes and drink bottles of wine like a heathen.

Though you don't see the health -> wealth progressions lauded as often, this does not mean they don't exist.

The best solution is the obvious one - if proven safe and effective mass produce it and make it cheap enough for everyone. Drug production is usually expensive to set up but cheap to run - especially with biosimilars. It is also a hormone too which should mean non-patentable in itself.

Any government not bleeding stupid should subsidize it heavily or make it themselves for the economic gains.

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