Mucins keep the brain safe and could guard against ageing(nature.com)
nature.com
Mucins keep the brain safe and could guard against ageing
https://www.nature.com/articles/d41586-025-00554-w
60 comments
I’m also surprised that a slight change in C1GalT1 expression has such a big effect on the glycocalyx. That enzyme is notoriously high-capacity, so you’d think it runs at near-saturating levels most of the time. My hunch is that something else in the pathway is hitting a bottleneck, possibly a chaperone like Cosmc that’s needed for proper enzyme folding, or maybe there’s some substrate competition with parallel glycosylation pathways. Once that bottleneck is reached, even a small shift can have an outsized impact on final glycan structures. In mice specifically, there might be unique regulatory quirks that amplify this effect, and you end up with a dramatic change in the mucins even though the enzyme itself seems too powerful to be the limiting step.
Yes, something along these lines, and maybe the other pathways as the most interesting possibility. I don’t know if there any reports of sTn in older mice, but that would be pretty wild.
thanks for doing work on this and thanks for commenting on it on hn!!
Copper and calcium seem to stimulate some mucins.
explainer: https://archive.is/vMfmZ
open access paper: http://doi.org/10.1038/s41586-025-08589-9
> We demonstrate that we can improve BBB function and reduce neuroinflammation and cognitive deficits in aged mice by restoring core 1 mucin-type O-glycans to the brain endothelium using adeno-associated viruses. Cumulatively, our findings provide a detailed compositional and structural mapping of the ageing brain endothelial glycocalyx layer and reveal important consequences of ageing- and disease-associated glycocalyx dysregulation on BBB integrity and brain health.
open access paper: http://doi.org/10.1038/s41586-025-08589-9
> We demonstrate that we can improve BBB function and reduce neuroinflammation and cognitive deficits in aged mice by restoring core 1 mucin-type O-glycans to the brain endothelium using adeno-associated viruses. Cumulatively, our findings provide a detailed compositional and structural mapping of the ageing brain endothelial glycocalyx layer and reveal important consequences of ageing- and disease-associated glycocalyx dysregulation on BBB integrity and brain health.
This isn't my field, so apologies if I'm off-base, but this seems to make viruses do what they couldn't do previously, and moreover, target the brain. Wouldn't that qualify as GoF research? And if so, after millions dead and trillions lost, how prudent is it to conduct this kind of research?
"Gain-of-function" doesn't refer to adding literally any function to a virus, it refers to making it more virulent or transmissible -- that's why lots of people are so against it, because the cost-benefit ratio seems so obviously lopsided. Adding unrelated functions to viruses and using them as vectors isn't included in that, both in that it has lots more uses (some vaccines are made this way, for instance) and much lower downside risk (viruses used as vectors are often rendered unable to replicate, so the risk of them spreading at all is small).
> Wouldn't that qualify as GoF research? And if so, after millions dead and trillions lost, how prudent is it to conduct this kind of research?
While this isn't the main point, I feel like I should point out that (if I'm understanding you correctly) there seems to be something fundamentally wrong with your reasoning here. Whether or not it's a good idea to conduct this particular research is a matter of the facts of this particular case. How you categorize it doesn't change that. Learning what is or is not considered "gain of function" should have zero effect on your opinion here! Here's a good essay on this topic: https://www.lesswrong.com/posts/TyQSMmoJpRG3HBv5S/cleaning-u...
> Wouldn't that qualify as GoF research? And if so, after millions dead and trillions lost, how prudent is it to conduct this kind of research?
While this isn't the main point, I feel like I should point out that (if I'm understanding you correctly) there seems to be something fundamentally wrong with your reasoning here. Whether or not it's a good idea to conduct this particular research is a matter of the facts of this particular case. How you categorize it doesn't change that. Learning what is or is not considered "gain of function" should have zero effect on your opinion here! Here's a good essay on this topic: https://www.lesswrong.com/posts/TyQSMmoJpRG3HBv5S/cleaning-u...
I should have asked GPT before wasting everyone's time. GPT4.5 says that while lethal and transmissible pathogens can be built with adenoviruses, nearly all research with them is done on replication-deficient viruses, and does not improve their transmissibility, pathogenicity, and does not expand the host range.
Why is it called "gain of function" if there's no gain of function?
> why lots of people are so against it
Hearing "GoF is NOT GoF" just makes me suspicious instinctively, that's all - no bad intention.
> why lots of people are so against it
Hearing "GoF is NOT GoF" just makes me suspicious instinctively, that's all - no bad intention.
This is a nomenclature issue. But as a non-involved person, the key function of a virus is distribution/virulance. Gain of Function means increasing the effectiveness of the key function. So making a virus spread more, making an immune cell more effective against pathogens, making a retina cell more sensitive to light.
Gaining An Additional Function is not the same thing, although the confusion is understandable.
Gaining An Additional Function is not the same thing, although the confusion is understandable.
Understood, thanks for nicely explaining it instead of downvoting ;)
They used AAV, which is a virus that doesn't cause disease.
https://en.wikipedia.org/wiki/Adeno-associated_virus
AAV9 can pass the blood-brain barrier (already), it says there.
https://en.wikipedia.org/wiki/Adeno-associated_virus
AAV9 can pass the blood-brain barrier (already), it says there.
I assume, without reading the paper or being an expert, that they use the virus as a vector for their genetic payload, while also removing the reproduction instructions from it. Similar to the astrazeneca vaccines for covid19.
The virus is like that, but naturally occuring:
https://en.wikipedia.org/wiki/Helper_dependent_virus
"The most widely known dependovirus is adeno-associated virus (AAV)"
It's "replication-deficient", a "satellite virus": it requires help (from a different virus) to replicate.
(I don't know this stuff either, I'm just summarizing Wikipedia at you.)
https://en.wikipedia.org/wiki/Helper_dependent_virus
"The most widely known dependovirus is adeno-associated virus (AAV)"
It's "replication-deficient", a "satellite virus": it requires help (from a different virus) to replicate.
(I don't know this stuff either, I'm just summarizing Wikipedia at you.)
Fun fact: The AAVR (AAV receptor) is itself a glycoprotein (carrying the precise type of glycosylation they are trying to repair with the “gene therapy”). Haven’t read up what replacement gene dose ended up being, but entirely within realms of possibility that this could influence which cells get corrected.
So that's, what, a protein on the outside of the cell that lets the virus in, like its own particular catflap? And you're saying this portal is made of mucus, and mucus is what they want to repair, and therefore ... nope, can't piece the conclusion together, sorry. "Could infuence", as in?
Catflap is a surprisingly apt analogy. In this case it is an endocytosis receptor, that selects cargo for uptake. Differs from virus to virus of course, but I could see changes in the sugars on these proteins altering behaviour. Mucus/mucins are basically proteins very heavily modified with sugars, so you have this common system that is adapted to do different things.
(endocytosis, into-cell-doing.)
Stanford explainer, https://news.ycombinator.com/item?id=43233003
> What if a critical piece of the puzzle of brain aging has been hiding in plain sight? While neuroscience has long focused on proteins and DNA, a team of Stanford researchers dared to shift their gaze to sugars – specifically the complex sugar chains that cover all our cells like chain mail.. Shi’s project was the first to investigate how age affects its sugary armor – the glycocalyx.. “Modulating glycans has a major effect on the brain – both negatively in aging, when these sugars are lost, and positively, when they are restored,” Shi says. “This opens an entirely new avenue for treating brain aging and related diseases.”
> What if a critical piece of the puzzle of brain aging has been hiding in plain sight? While neuroscience has long focused on proteins and DNA, a team of Stanford researchers dared to shift their gaze to sugars – specifically the complex sugar chains that cover all our cells like chain mail.. Shi’s project was the first to investigate how age affects its sugary armor – the glycocalyx.. “Modulating glycans has a major effect on the brain – both negatively in aging, when these sugars are lost, and positively, when they are restored,” Shi says. “This opens an entirely new avenue for treating brain aging and related diseases.”
Some are noting that this is "in mice", but a recently approved new drug for schizophrenia suggests that a connection between mucins and brain function in humans is more than speculative: https://en.wikipedia.org/wiki/Xanomeline/trospium_chloride
Brand name Cobenfy, this drug is a combination of a muscarinic agonist and a muscarinic antagonist. Notably its therapeutic component was initially developed as an alzheimer's treatment, and IIRC showed positive results in the few trials that were performed in the 90's before the drug was abandoned due to side effects (until now).
Brand name Cobenfy, this drug is a combination of a muscarinic agonist and a muscarinic antagonist. Notably its therapeutic component was initially developed as an alzheimer's treatment, and IIRC showed positive results in the few trials that were performed in the 90's before the drug was abandoned due to side effects (until now).
Humans have several Mucins genes, each affecting a different part of the body. For example, MUC2 effects the intestines. Many of these mucin enyzmes need copper and calcium. Basically, it is mucus.
These re also glycosylated proteins, which means proteins with sugar in layman terms.
There is no need for gene editing. We have some clues. N-acetylcysteine (NAC) is a mucolytic agent with known effects on mucus viscosity and clearance.More here:
https://stanmed.stanford.edu/neurotransmission-connection-mu...
These re also glycosylated proteins, which means proteins with sugar in layman terms.
There is no need for gene editing. We have some clues. N-acetylcysteine (NAC) is a mucolytic agent with known effects on mucus viscosity and clearance.More here:
https://stanmed.stanford.edu/neurotransmission-connection-mu...
https://pubmed.ncbi.nlm.nih.gov/35975308/
How could NAC help here, if it reduces mucus?
How could NAC help here, if it reduces mucus?
Mucins aren't enzymes (as far as we know!), and the gut mucins are a bit different from those found on the endothelium, largely because they have different functions. The gut (and generally mucous epithelial) mucus is there for (amongst other things) clearing and maintaining a microbiome. Endothelial glycocalyx probably has some other mucin proteins, but also likely lots of mucin-like proteins, and the set of functions of these are much less clear.
The enzyme MUC(1-whatever) makes mucin.
https://www.uniprot.org/uniprotkb?query=mucin&facets=model_o...
https://www.uniprot.org/uniprotkb?query=mucin&facets=model_o...
I think what you mean is the MUC1-20 (ish, numbering is a bit sloppy but hopefully we can clean it up in near future) genes encode for mucins, that are synthesised on a ribosome, threaded into ER, shuffled off into the Golgi and then enzymatically modified by the enzymes encoded by the genes GALNT2, 7 & 10 (at least).
There are a further 20-30 ish enzymes that can modify the mucins as they are traversing the Golgi, and depending on the cell type, it can get packaged into vesicles (alongside calcium) for secretion.
So, they meet a lot of enzymes along the way, but harbour no catalytic activity themselves (as far as we know!).
There are a further 20-30 ish enzymes that can modify the mucins as they are traversing the Golgi, and depending on the cell type, it can get packaged into vesicles (alongside calcium) for secretion.
So, they meet a lot of enzymes along the way, but harbour no catalytic activity themselves (as far as we know!).
...in mice.
We have to start somewhere.
True but "in mice" in the title would save a lot of time.
I would settle for a non-click bait title.
Surprising how many times this exact comment is posted on HN these days.
Arent all human treatments tested on mice first?
Arent all human treatments tested on mice first?
it's not surprising when you consider the title says "the brain" and not "mice brains"
journalists are ruining our understanding of reality by sensationally misleading people with headlines in search of engagement.
journalists are ruining our understanding of reality by sensationally misleading people with headlines in search of engagement.
https://news.ycombinator.com/item?id=43237205
> a recently approved new drug for schizophrenia suggests that a connection between mucins and brain function in humans is more than speculative
> a recently approved new drug for schizophrenia suggests that a connection between mucins and brain function in humans is more than speculative
Thought-terminating Cliche.
What can we eat/do to boost this barrier?
This is basically the first thing asked by the layman when these types of observations emerge.
The replies will almost certainly be regurgitated into a misleading article, which in turn will kick off a damaging trend.
The replies will almost certainly be regurgitated into a misleading article, which in turn will kick off a damaging trend.
Isn't it time for a serious conversation about the wonderful health benefits of ivermectin? (:
It's effective against ticks, fleas and mites (cause scabies) and more. Easy to apply (pour on skin/fur at back of neck). Get dosage right: instructions are on the box/container.
My cat has a much less scratchy life thanks to ivermectin.
My cat has a much less scratchy life thanks to ivermectin.
Should ivermectin be removed from this list?
https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_Me...
https://en.wikipedia.org/wiki/WHO_Model_List_of_Essential_Me...
While you are right about the misleading articles that will likely come from this, we do need to pay attention to what we eat so it is a reasonable question and one that should be investigated.
Eat chlorophyll and spirulina to boost brain slime!
We don’t know is the answer. However, if you were coral, then I would suggest increasing the amount of symbiotic algae, which stimulates mucin secretion (probably a nutrient boost).
A brain normally doesn’t receive enough sunlight for this strategy to work for humans.
A brain normally doesn’t receive enough sunlight for this strategy to work for humans.
A few decades from now, in the biohacker/modder community: "Recap your noggin with our reinforced-glass-ceramic dome!".
Algae omegas possibly?
Mount LEDs inside the skull, got it.
Or replace bone with glass, ending up like those famous crystal skulls from Mexico. But algae might then bloom and grow in uncontrolled fashion. You'd need plancton then, and maybe krill or even fish too - enter skull aquariums.
Ancient medicine solves that problem
https://news.ycombinator.com/item?id=43196488
https://news.ycombinator.com/item?id=43196488
More time in the sun ? :)
It's a fair and good question.
From "Endothelial Glycocalyx Preservation — Impact of Nutrition and Lifestyle" (2023) [1]:
Vitamin D; omega-3 supplementation; dietary sulfur (onion, garlic, leek, kale, broccoli, cauliflower, cabbage...); intermittent fasting
(edited for formatting)
[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC10255458/
From "Endothelial Glycocalyx Preservation — Impact of Nutrition and Lifestyle" (2023) [1]:
Vitamin D; omega-3 supplementation; dietary sulfur (onion, garlic, leek, kale, broccoli, cauliflower, cabbage...); intermittent fasting
(edited for formatting)
[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC10255458/
Sulfur? Would NAC help?
Prebiotics like Akkermansia help improve the mucin layer in the colon. Lower amounts of these beneficial bacteria actually contribute to gut health. The weird part is Akkermansia actually eats the mucin layer. You would think that would cause a less dense mucous layer, but the presence of Akkermansia actually causes goblet cells in your gut produce more mucin which strengthens the mucous layer. We also know that gut health can and does affect the nervous system.
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Does the spelling of the word "ageing" look strange to anyone else? I looked it up and it appears to be acceptable, but why not "pageing", "cageing" etc?
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It kind of surprises me that such a low fold-change in core1 synthase yields such a huge change in glycocalyx. Everything we know about this enzyme says it is an absolute rocket on substrates, so I can’t really see this process being enzyme-limited. There might be other (mouse specific) things going on here that this is scratching the surface on.