9 ms·

Cleaning up the aging brain: Scientists restore brain's trash disposal system

204 points by jdmark 2y ago

hyrix 2y ago
In mice
- alephnerd 2y ago
  Mice are in the same clade as primates, and share around 95-99% of the same genome as primates. We're all part of the Euarchontoglires clade
  - cyberax 2y ago
    The problem is that primates are pretty far removed from mice. And our sheer weight difference often makes is a decisive factor. This is especially true for cancer, brain, and inflammation research. Mice just don't make good models for that.
    - alephnerd 2y ago
      > that primates are pretty far removed from mice They are a good initial test for viability because of the overwhelming genetic similarity. This is why mice and rodents are used to test initial viability before then moving on to theraputics development. You can read some sources if you want [0][1][2] [0] - https://www.jax.org/why-the-mouse/excellent-models https://www.jax.org/why-the-mouse/excellent-models [1] - https://www.cam.ac.uk/research/research-at-cambridge/animal-research/what-types-of-animal-do-we-use/mice https://www.cam.ac.uk/research/research-at-cambridge/animal-... [2] - https://www.genome.gov/10001345/importance-of-mouse-genome https://www.genome.gov/10001345/importance-of-mouse-genome
      - cyberax 2y ago
        > This is why mice and rodents are used to test initial viability before then moving on to theraputics development. They are used because they're the _only_ way to test drugs early in development. Animal cruelty laws make it nearly impossible to use non-murine species for initial drug tests. Additionally, mice are easy to breed and to keep, and there's a great variety of specialized genetic lines.
        alephnerd 2y ago
        Absolutely, yet the underlying similarity between our genomes makes it good enough for most cases, plus the Rodent genome has been sequenced and tested for decades now. Idk why you are trying to die on this hill. I've provided decently authoritative sources (The Jackson Institute, Cambridge University, and the NIH) Unless you have a PhD in Systems Biology or Genomics, I'm going to trust them over you. Edit: an actual OG in the field of genomics just commented - listen/chat with him, not me.
        cyberax 2y ago
        For most cases, yes. Antibiotics discovery? Sure, mice are awesome. But mice make really bad models for anything to do with brain, aging, inflammation, and cancer. That's why comments "in mice" are appropriate in these areas. And it's not at all controversial, here are my citations: https://www.pnas.org/doi/full/10.1073/pnas.1222878110 https://www.pnas.org/doi/full/10.1073/pnas.1222878110 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615039/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615039/ Mice studies are not useless, for sure. But they're almost always are not directly translatable to humans.
        signatoremo 2y ago
        As a layman, why should I trust your citation over studies that highlight the advantages of using mice in aging research? - [0] > But mice make really bad models for anything to do with brain, aging, inflammation, and cancer If mice is really bad for research in the fields you mentioned, why do scientists around the world continue to use it? Wouldn’t they know it’s a dead end? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074346/#:~:text=Mice%20are%20an%20ideal%20mammalian,lifespan%20and%20age%2Drelated%20diseases https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074346/#:~:tex....
    - robwwilliams 2y ago
      Not sure why you think weight is such a key variable. Might make sense if you had focused in bone mineral density—although mice have been extremely useful to study osteoblast and osteoclast biology. Mice gave us a very solid understanding of cancer genetics. Cancer was initially thought of as an almost purely environmental disease. Thanks to “in mice” we learned that genetic susceptibility is a major factor. Transplantation biology and immunology have profited enormously from mouse models—-and more “recently” everything from monoclonal antibodies to CAR-T cells. And when you say “brain” who could been a dozen different things. I can assure you that mouse models are highly useful and translationally relevant to many neurological, behavioral, developmental, and physiological studies of the mammalian brain.
      - cyberax 2y ago
        > Not sure why you think weight is such a key variable. I worked in cancer research-adjacent area (on computational biology). The problem with mice was that cancers in mice necessarily contain fewer cells than human cancers. So a lot of treatments can simply clear these cancers completely, without giving them a chance to evolve resistance. Yes, you can try to compensate for that, but it just is not reliable. In addition, mice are notoriously naturally susceptible to cancer. So their cancers, counter-intuitively, are often less evolved as a result. > And when you say “brain” who could been a dozen different things. I basically mean "degenerative brain diseases", very much including aging.
  - hombre_fatal 2y ago
    Yet none of that matters because only a tiny fraction of interventions make it from rat models to humans.
    - robwwilliams 2y ago
      Ditto from Phase 1 to Phase 3. Side effects always an issue. One could say only half in jest that humans are not particularly good models for humans. Exceedingly expensive and all kind of environmental and compliance confounders. At least when using rodent you can control the environmental factors in a randomized controller “clinic” trials. Compliance not so hard to ensure.
manmal 2y ago
This mechanism sounds like it could have a strong nootropic effect for everyone not having totally ideal sleep. Whenever I sleep badly, or not long enough for some days in a row, my cognitive performance deteriorates rather quickly. Supposedly, the glymphatic system‘s work has a major role to play in this. Melatonin also has been found to have a stimulating effect on the glymphatic system, though we need better trials on that.
- JonChesterfield 2y ago
  Look up creatine as a candidate treatment for sleep deprivation.
  - washadjeffmad 2y ago
    Creatine plus exercise. I add 1.5 tsp to my morning tea, plus 1/5 tsp NAD and 1/2 tsp of L-theanine, and I've doubled my workout and no longer have DOMS. It's like I'm a teenager again. I tried it because I'd been getting 4-5 hours of broken sleep due to peripheral neuropathy from a congenital spinal disorder for the past four or five years, and I finally feel like I'm healing. It's wild being able to fall asleep and stay asleep.
    - grugagag 2y ago
      Do you only take it in the days you exercise? Does it have any side effects?
      - esperent 2y ago
        Creatine is one of the very few supplements that seems to have only upsides and few if any side effects (except the basically obligatory "minor stomach upsets for some people" ). You can take it every day at any time of day, the effects take a few weeks to build up. The main downside is that the effects are small - most of the research is in strength and endurance training and it seems like at most there's a 5-10% increase in lifting endurance (IIRC, it's been a while since I researched this). It's one of a very few supplements that I personally feel should be generally taken by most people (unless you eat a lot of red meat). The others are omega 3 (unless you eat fish several times a week) and possibly magnesium as the western diet tends to be low in that. If you want to read more about effects of creatine on the brain this is a good paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916590/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916590/ The consensus seems to be that supplementation of creatine is less clearly linked to increases in the brain than it is for muscle (although there have only been limited studies done), however, if you've ever suffered from depression, sleep deprivation or other neurological issues it's likely to be beneficial. For people without those issues, there's less evidence yet, but they would still get the benefit of more energy overall if not specifically more cognitive energy.
ggm 2y ago
Are there non drug methods which could restore or assist lymph pumping functions in the head-neck region? Should we all be doing some kind of rotation/lift/squeeze cycle on our cervical spine region?
- OutOfHere 2y ago
  Nafaik, but anything that gives you two extra hours of sleep should help. Also, intense exercise should over time help heal it in part. And as far as drug methods go, a 2-3 month course of memantine could be worth exploring for anyone who doesn't have to drive or operate machinery for the first month.
- thordenmark 2y ago
  Exercise, good food, and good sleep. Pretty much the universal panacea.
  - thordenmark 2y ago
    Sounds easy, but difficult in practice. Especially for those of us chained to a desk all day.
  - hi-v-rocknroll 2y ago
    For disabled and elderly people, these aren't always possible.
    - BobaFloutist 2y ago
      Appropriate exercise is all the more important for disabled and elderly people.
  - OutOfHere 2y ago
    Mild to moderate exercise won't fix it, but intense exercise, e.g. running or similar, carries hope. Good sleep will slow the damage, but after a certain age, e.g. 80, it may not work.
DoreenMichele 2y ago
"Unlike the cardiovascular system which has one big pump, the heart, fluid in the lymphatic system is instead transported by a network of tiny pumps," Not entirely accurate. https://news.ycombinator.com/item?id=25427090 https://news.ycombinator.com/item?id=25427090
- manmal 2y ago
  Since you seem knowledgeable, what do you think of the idea of blocks in lymph, eg through scar tissue or infections, which might need extra massage? Is there something to this?
pedalpete 2y ago
This study in aging adults measured amyloid in blood with phase-targeted auditory stimulation, the technology we've been developing at affectablesleep.com - it's not exactly the same as measuring the glymphatic process, but might be related.
guywithahat 2y ago
If we combine this research with the anti-aging research of Dr. David Sinclair, mice will soon overtake humans in both intelligence and lifespan. Thus making “the hitchhikers guide to the galaxy” reality
- ineedaj0b 2y ago
  we could probably do this in people rn but we'd kill quite a few till we nailed down the dosing.
- tastyfreeze 2y ago
  I was thinking the Rats if NIMH. They need a bit more than long life and intelligence for the pandimensional beings posing as mice.
- waihtis 2y ago
  not that it means anything definitive, but Sinclair has been somewhat of a turbulent figure due to "overreaching claims" in the broader life extension research space: https://www.nmn.com/news/disgraced-david-sinclair-resigns-from-top-aging-academy https://www.nmn.com/news/disgraced-david-sinclair-resigns-fr...
  - adammarples 2y ago
    "The Academy for Health and Lifespan Research is a non-profit organization, composed of about 60 aging scientists." Made me lol
- tucosan 2y ago
  People still haven't caught up to the fact that Sinclair is a fraud it seems.
  - guywithahat 2y ago
    He’s not a fraud; he has, without a doubt, figured out ways to make mice live longer.
aszantu 2y ago
would explain why head massages are feeling extatic, external massage of those lymphangions maybe?
EVa5I7bHFq9mnYK 2y ago
Wonder if dexamethasone has similar effect - felt much younger when it was prescribed to me for brain swelling.
- hinkley 2y ago
  It’s difficult to get objective measures of how something makes you feel when you already feel bad. About half of my best food experiences came after a stressful physical experience. I know that food wasn’t as amazing as my brain was telling me it was, but I still enjoyed the experience. The other people in that Dairy Queen were absolutely not having the transcendental experience my friend and I were enjoying. “Brain swelling” sounds like it would put a lot of things into a new perspective.
  - EVa5I7bHFq9mnYK 2y ago
    My measure was - definitely could get more work done in a day compared to any day in the previous 10 years. Dexamethasone prescribed for swelling probably means it also works on removing fluids from the brain, similar to the drug described in the article. Not that I recommend it for anyone, the drug has terrible side effects.
    - hinkley 2y ago
      So it’s like a diuretic for the brain?
      - EVa5I7bHFq9mnYK 2y ago
        Maybe, IANAD

204 points by jdmark 2y ago

hyrix 2y ago

In mice

alephnerd 2y ago
Mice are in the same clade as primates, and share around 95-99% of the same genome as primates. We're all part of the Euarchontoglires clade
- cyberax 2y ago
  The problem is that primates are pretty far removed from mice. And our sheer weight difference often makes is a decisive factor. This is especially true for cancer, brain, and inflammation research. Mice just don't make good models for that.
  - alephnerd 2y ago
    > that primates are pretty far removed from mice They are a good initial test for viability because of the overwhelming genetic similarity. This is why mice and rodents are used to test initial viability before then moving on to theraputics development. You can read some sources if you want [0][1][2] [0] - https://www.jax.org/why-the-mouse/excellent-models https://www.jax.org/why-the-mouse/excellent-models [1] - https://www.cam.ac.uk/research/research-at-cambridge/animal-research/what-types-of-animal-do-we-use/mice https://www.cam.ac.uk/research/research-at-cambridge/animal-... [2] - https://www.genome.gov/10001345/importance-of-mouse-genome https://www.genome.gov/10001345/importance-of-mouse-genome
    - cyberax 2y ago
      > This is why mice and rodents are used to test initial viability before then moving on to theraputics development. They are used because they're the _only_ way to test drugs early in development. Animal cruelty laws make it nearly impossible to use non-murine species for initial drug tests. Additionally, mice are easy to breed and to keep, and there's a great variety of specialized genetic lines.
      - alephnerd 2y ago
        Absolutely, yet the underlying similarity between our genomes makes it good enough for most cases, plus the Rodent genome has been sequenced and tested for decades now. Idk why you are trying to die on this hill. I've provided decently authoritative sources (The Jackson Institute, Cambridge University, and the NIH) Unless you have a PhD in Systems Biology or Genomics, I'm going to trust them over you. Edit: an actual OG in the field of genomics just commented - listen/chat with him, not me.
        cyberax 2y ago
        For most cases, yes. Antibiotics discovery? Sure, mice are awesome. But mice make really bad models for anything to do with brain, aging, inflammation, and cancer. That's why comments "in mice" are appropriate in these areas. And it's not at all controversial, here are my citations: https://www.pnas.org/doi/full/10.1073/pnas.1222878110 https://www.pnas.org/doi/full/10.1073/pnas.1222878110 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615039/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615039/ Mice studies are not useless, for sure. But they're almost always are not directly translatable to humans.
        signatoremo 2y ago
        As a layman, why should I trust your citation over studies that highlight the advantages of using mice in aging research? - [0] > But mice make really bad models for anything to do with brain, aging, inflammation, and cancer If mice is really bad for research in the fields you mentioned, why do scientists around the world continue to use it? Wouldn’t they know it’s a dead end? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074346/#:~:text=Mice%20are%20an%20ideal%20mammalian,lifespan%20and%20age%2Drelated%20diseases https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074346/#:~:tex....
  - robwwilliams 2y ago
    Not sure why you think weight is such a key variable. Might make sense if you had focused in bone mineral density—although mice have been extremely useful to study osteoblast and osteoclast biology. Mice gave us a very solid understanding of cancer genetics. Cancer was initially thought of as an almost purely environmental disease. Thanks to “in mice” we learned that genetic susceptibility is a major factor. Transplantation biology and immunology have profited enormously from mouse models—-and more “recently” everything from monoclonal antibodies to CAR-T cells. And when you say “brain” who could been a dozen different things. I can assure you that mouse models are highly useful and translationally relevant to many neurological, behavioral, developmental, and physiological studies of the mammalian brain.
    - cyberax 2y ago
      > Not sure why you think weight is such a key variable. I worked in cancer research-adjacent area (on computational biology). The problem with mice was that cancers in mice necessarily contain fewer cells than human cancers. So a lot of treatments can simply clear these cancers completely, without giving them a chance to evolve resistance. Yes, you can try to compensate for that, but it just is not reliable. In addition, mice are notoriously naturally susceptible to cancer. So their cancers, counter-intuitively, are often less evolved as a result. > And when you say “brain” who could been a dozen different things. I basically mean "degenerative brain diseases", very much including aging.
- hombre_fatal 2y ago
  Yet none of that matters because only a tiny fraction of interventions make it from rat models to humans.
  - robwwilliams 2y ago
    Ditto from Phase 1 to Phase 3. Side effects always an issue. One could say only half in jest that humans are not particularly good models for humans. Exceedingly expensive and all kind of environmental and compliance confounders. At least when using rodent you can control the environmental factors in a randomized controller “clinic” trials. Compliance not so hard to ensure.

manmal 2y ago

This mechanism sounds like it could have a strong nootropic effect for everyone not having totally ideal sleep. Whenever I sleep badly, or not long enough for some days in a row, my cognitive performance deteriorates rather quickly. Supposedly, the glymphatic system‘s work has a major role to play in this. Melatonin also has been found to have a stimulating effect on the glymphatic system, though we need better trials on that.

JonChesterfield 2y ago
Look up creatine as a candidate treatment for sleep deprivation.
- washadjeffmad 2y ago
  Creatine plus exercise. I add 1.5 tsp to my morning tea, plus 1/5 tsp NAD and 1/2 tsp of L-theanine, and I've doubled my workout and no longer have DOMS. It's like I'm a teenager again. I tried it because I'd been getting 4-5 hours of broken sleep due to peripheral neuropathy from a congenital spinal disorder for the past four or five years, and I finally feel like I'm healing. It's wild being able to fall asleep and stay asleep.
  - grugagag 2y ago
    Do you only take it in the days you exercise? Does it have any side effects?
    - esperent 2y ago
      Creatine is one of the very few supplements that seems to have only upsides and few if any side effects (except the basically obligatory "minor stomach upsets for some people" ). You can take it every day at any time of day, the effects take a few weeks to build up. The main downside is that the effects are small - most of the research is in strength and endurance training and it seems like at most there's a 5-10% increase in lifting endurance (IIRC, it's been a while since I researched this). It's one of a very few supplements that I personally feel should be generally taken by most people (unless you eat a lot of red meat). The others are omega 3 (unless you eat fish several times a week) and possibly magnesium as the western diet tends to be low in that. If you want to read more about effects of creatine on the brain this is a good paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916590/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916590/ The consensus seems to be that supplementation of creatine is less clearly linked to increases in the brain than it is for muscle (although there have only been limited studies done), however, if you've ever suffered from depression, sleep deprivation or other neurological issues it's likely to be beneficial. For people without those issues, there's less evidence yet, but they would still get the benefit of more energy overall if not specifically more cognitive energy.

ggm 2y ago

Are there non drug methods which could restore or assist lymph pumping functions in the head-neck region? Should we all be doing some kind of rotation/lift/squeeze cycle on our cervical spine region?

OutOfHere 2y ago
Nafaik, but anything that gives you two extra hours of sleep should help. Also, intense exercise should over time help heal it in part. And as far as drug methods go, a 2-3 month course of memantine could be worth exploring for anyone who doesn't have to drive or operate machinery for the first month.
thordenmark 2y ago
Exercise, good food, and good sleep. Pretty much the universal panacea.
- thordenmark 2y ago
  Sounds easy, but difficult in practice. Especially for those of us chained to a desk all day.
- hi-v-rocknroll 2y ago
  For disabled and elderly people, these aren't always possible.
  - BobaFloutist 2y ago
    Appropriate exercise is all the more important for disabled and elderly people.
- OutOfHere 2y ago
  Mild to moderate exercise won't fix it, but intense exercise, e.g. running or similar, carries hope. Good sleep will slow the damage, but after a certain age, e.g. 80, it may not work.

DoreenMichele 2y ago

"Unlike the cardiovascular system which has one big pump, the heart, fluid in the lymphatic system is instead transported by a network of tiny pumps," Not entirely accurate. https://news.ycombinator.com/item?id=25427090 https://news.ycombinator.com/item?id=25427090

manmal 2y ago
Since you seem knowledgeable, what do you think of the idea of blocks in lymph, eg through scar tissue or infections, which might need extra massage? Is there something to this?

pedalpete 2y ago

This study in aging adults measured amyloid in blood with phase-targeted auditory stimulation, the technology we've been developing at affectablesleep.com - it's not exactly the same as measuring the glymphatic process, but might be related.

guywithahat 2y ago

If we combine this research with the anti-aging research of Dr. David Sinclair, mice will soon overtake humans in both intelligence and lifespan. Thus making “the hitchhikers guide to the galaxy” reality

ineedaj0b 2y ago
we could probably do this in people rn but we'd kill quite a few till we nailed down the dosing.
tastyfreeze 2y ago
I was thinking the Rats if NIMH. They need a bit more than long life and intelligence for the pandimensional beings posing as mice.
waihtis 2y ago
not that it means anything definitive, but Sinclair has been somewhat of a turbulent figure due to "overreaching claims" in the broader life extension research space: https://www.nmn.com/news/disgraced-david-sinclair-resigns-from-top-aging-academy https://www.nmn.com/news/disgraced-david-sinclair-resigns-fr...
- adammarples 2y ago
  "The Academy for Health and Lifespan Research is a non-profit organization, composed of about 60 aging scientists." Made me lol
tucosan 2y ago
People still haven't caught up to the fact that Sinclair is a fraud it seems.
- guywithahat 2y ago
  He’s not a fraud; he has, without a doubt, figured out ways to make mice live longer.

aszantu 2y ago

would explain why head massages are feeling extatic, external massage of those lymphangions maybe?

EVa5I7bHFq9mnYK 2y ago

Wonder if dexamethasone has similar effect - felt much younger when it was prescribed to me for brain swelling.

hinkley 2y ago
It’s difficult to get objective measures of how something makes you feel when you already feel bad. About half of my best food experiences came after a stressful physical experience. I know that food wasn’t as amazing as my brain was telling me it was, but I still enjoyed the experience. The other people in that Dairy Queen were absolutely not having the transcendental experience my friend and I were enjoying. “Brain swelling” sounds like it would put a lot of things into a new perspective.
- EVa5I7bHFq9mnYK 2y ago
  My measure was - definitely could get more work done in a day compared to any day in the previous 10 years. Dexamethasone prescribed for swelling probably means it also works on removing fluids from the brain, similar to the drug described in the article. Not that I recommend it for anyone, the drug has terrible side effects.
  - hinkley 2y ago
    So it’s like a diuretic for the brain?
    - EVa5I7bHFq9mnYK 2y ago
      Maybe, IANAD