
Klotho – There May Be a Drug to Turbocharge Your Brain. Who Should Get It? - pseudolus
https://www.nytimes.com/2019/04/02/health/klotho-brain-enhancement-dementia-alzheimers.html
======
apo
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)](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.

~~~
0xDEFC0DE
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...](https://www.cell.com/cell-
reports/fulltext/S2211-1247\(17\)30990-7)

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.

~~~
ramraj07
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.

~~~
0xDEFC0DE
>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.

~~~
striking
> 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.

~~~
eikenberry
> 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.

~~~
arama471
I think in this context that would count as having a backup

------
gnode
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?

~~~
dalbasal
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.

~~~
ryandvm
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.

~~~
dalbasal
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.

~~~
Macross8299
>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](https://en.wikipedia.org/wiki/OODA_loop)

------
scandox
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.

~~~
floatingatoll
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.

~~~
thaumaturgy
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.

~~~
Angostura
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.

------
UweSchmidt
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.

~~~
thekingofh
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.

~~~
bilbo0s
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.

~~~
tcoff91
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.

~~~
germinalphrase
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.

~~~
fudgie
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](https://www.bbc.com/news/uk-
scotland-32983932)) and experienced a 7% increase in maximum performance in 7
weeks.

------
proto-n
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.

~~~
otikik
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.

~~~
sebringj
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.

~~~
sebringj
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.

------
danmaz74
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.

~~~
DennisP
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...](https://www.cell.com/cell-
reports/fulltext/S2211-1247\(17\)30990-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124717309907%3Fshowall%3Dtrue)

~~~
danmaz74
Great, thanks. I wasn't focused enough while reading :)

------
anm89
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?

~~~
ackfoo
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.

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

~~~
roywiggins
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.

~~~
ams6110
Is this even required reading anymore? I think we read it in 7th grade or so.

------
IowaBoyInMN
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.

------
simonh
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.

~~~
empath75
Evolution doesn’t optimize for intelligence or lifespan, it optimizes for
reproduction

~~~
simonh
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.

------
NKCSS
Title reminded me of 'Limitless'

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

------
manishsharan
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?

~~~
forensium
Island City (1994 film)

------
distantaidenn
Hormone "K".

Reference:
[https://archive.org/details/TedChiangUnderstand](https://archive.org/details/TedChiangUnderstand)

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

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

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

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

~~~
no1youknowz
> 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...

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

~~~
no1youknowz
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.

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

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

------
Madmallard
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.

~~~
ZeroFries
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.

~~~
Madmallard
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](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.

~~~
fjabre
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.

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

------
bellerose
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.

~~~
goldenkey
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.

~~~
acct1771
Though you don't see the health -> wealth progressions lauded as often, this
does not mean they don't exist.

