4 ms·

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,

by apo 8y ago

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 8y ago
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)30990-7 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.
- ramraj07 8y ago
  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 8y ago
    >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 8y ago
      > 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 8y ago
        > 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 8y ago
        I think in this context that would count as having a backup
otakucode 8y ago
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.
- Balgair 8y ago
  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/about/pac-20394631 https://www.mayoclinic.org/tests-procedures/lumbar-puncture/... [1] https://en.wikipedia.org/wiki/Meninges https://en.wikipedia.org/wiki/Meninges
DGAP 8y ago
Selective Klotho Re-uptake Inhibitors? SKRIs?
hirenj 8y ago
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.

by apo 8y ago

0xDEFC0DE 8y ago

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)30990-7 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.

ramraj07 8y ago
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 8y ago
  >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 8y ago
    > 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 8y ago
      > 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 8y ago
        I think in this context that would count as having a backup

otakucode 8y ago

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.

Balgair 8y ago
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/about/pac-20394631 https://www.mayoclinic.org/tests-procedures/lumbar-puncture/... [1] https://en.wikipedia.org/wiki/Meninges https://en.wikipedia.org/wiki/Meninges

DGAP 8y ago

Selective Klotho Re-uptake Inhibitors? SKRIs?

hirenj 8y ago

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.