6 ms·

Anyone know what could cause these types of protein imbalances?

Aurornis 3y ago
That is the question. These are correlated to dementia risk, but that doesn’t mean they’re directly involved causing dementia. They could be a related effect of the root cause(s) of dementia. There are many examples in medicine where we’ve attempted to directly modify measurable markers like this without fixing the underlying disease. They could be useful clues for discovering the root cause, though!
- carbocation 3y ago
  Bingo. More explicitly, there is no strong reason to think that the proteins from the correlational analysis are causal for dementia. The proteins from the Mendelian randomization also don't have to be (can be in a pleiotropic pathway) but there is at least reason to think that they could be causal.
- mcdonje 3y ago
  If these are correlated, then not every treatment for them would necessarily be as effective against dementia. However, if the cause of the protein imbalances is something people can take steps to prevent, then doing so would logically have a greater than zero chance of mitigating dementia risk.
  - Aurornis 3y ago
    > However, if the cause of the protein imbalances is something people can take steps to prevent, then doing so would logically have a greater than zero chance of mitigating dementia risk. Or correcting the protein imbalance could interfere with an important feedback loop that we don't yet understand, which could possibly make the situation worse. Or maybe the protein imbalances are involved in counteracting the issue that causes dementia, and that's why they're elevated. This is a common theme in biological systems. A good example would be cortisol, which has become known as the "stress hormone". Many people assume that lowering cortisol must therefore be a good thing, but if you were to indiscriminately lower cortisol during periods of stress you'd end up in a far worse condition than you were before. Cortisol is part of your body's reaction to stress and part of the system that responds to it, so artificially lowering it can interfere with your stress response process.
    - mcdonje 3y ago
      Good points. Thank you.
    - nonethewiser 3y ago
      It makes me think of running a fever. Its easy to think of fevers as bad but I imagine it would be a lot worse to simply stop the fever (if that were even possible).
      - smolder 3y ago
        > (if that were even possible) Indeed it is. Tylenol, for instance, is marketed as a fever reducer.
        nonethewiser 3y ago
        Well perhaps this proves my intuition wrong. Is it OK to reduce a fever then? But how so if its purpose is to kill off something worse?
        smolder 3y ago
        IANAD, so someone please correct me, but I think there's some truth that treating a mild fever will just interfere with what the immune system is doing, to its detriment. On the other hand, very high fevers in themselves are quite dangerous and so being able to lower someone's temperature is a benefit.
pella 3y ago
(Guinea Pig) : diet, gut microbiota, ... ( ?? ) "The Effects of Different Diets on Guinea Pig Health, Hair Morphology and Blood Protein Concentration" ~ "Guinea pigs (Cavia porcellus) have biological similarities to humans, which make them a suitable animal model in multiple fields of research. " https://lsmu.lt/cris/handle/20.500.12512/115773 https://lsmu.lt/cris/handle/20.500.12512/115773
dsign 3y ago
I learned a lot about aging by watching this Minecraft video[^1] and building the kelp farm. That farm stops working after some (long) time, given the way that kelp grows in Minecraft. If Avomance had done the math beforehand, he would have discovered that he needs a costly full row of observers for the farm to work forever. Biological systems are not designed, but evolved, and evolution ends up selecting systems (which we call "organisms" or "individuals") which are good enough for it to be reproductively successful. In practice that means "low-maintenance" and "energy-efficient". Functional errors and their organism-wide effects slowly accumulate, and although our biology has everything material it needs to fix each and every error[^2], its healing program/intelligence is far from perfect. [^1]: https://www.youtube.com/watch?v=Sf9I3YORSzM https://www.youtube.com/watch?v=Sf9I3YORSzM [^2]: Compare this with a car, for example. If your lights go bust, the car won't grow a new one; you need to change them. But biological organisms have a lot of self-healing capability.
stefantalpalaru 3y ago
[dead]
1MachineElf 3y ago
The HN submission Could leak in blood-brain barrier cause poor memory? (2021) may provide a clue: https://news.ycombinator.com/item?id=26520453 https://news.ycombinator.com/item?id=26520453 >People with ApoE4 have a hard time getting rid of amyloid beta peptide in their brains, which causes an accumulation of plaque. With healthy aging, the pumps in the blood-brain barrier work less efficiently in getting rid of the amyloid beta peptide. The pumps work even less well in people with Alzheimer’s disease. >Recent work suggests that the leak in the blood-brain barrier that occurs with Alzheimer’s may be due to an age-related loss of pericytes. Astrocytes, by contrast, seem to be overactive. Recent work suggests that preserving pericyte function by giving the factors that they secrete or even transplanting them could lead to a healthier blood-brain barrier. >Other findings raise the question of whether the brain’s source of nutrition and its grip on control of the immune and endocrine systems could deteriorate with aging. Another finding raises the possibility that the rate at which many drugs are taken up by the brain may explain why older folks sometimes have different sensitivities to drugs than their children or grandchildren. Pair that with this part of OP: >This regulation is important in preventing proteins from going rogue and clumping together, which is what happens to the amyloid and tau proteins in the brains of people with Alzheimer’s disease, the most common cause of dementia. I'm just a layman, but it sounds like BBB health is a major factor for regulating this in the brain. In some individuals, including those with identified genetic biomarkers for increased Alzheimer's risk, the BBB ages faster, leading to decreased regulation of protein/peptides. So learning more about how to improve BBB health could eventually help people maintain a healthy brain longer. Avoiding excessive alcohol seems to be an important factor for BBB health, according to this 2021 study performed on mice: https://pubmed.ncbi.nlm.nih.gov/33516661/ https://pubmed.ncbi.nlm.nih.gov/33516661/ ; also this research published in 2022: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204474/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204474/ OP refers to "amyloid and tau proteins" while the 2021 article I referenced refers to "amyloid beta peptide" - at this point, I'm really not sure how precisely these terms are being used. Are they interchangeable in this context, or is there an important nuance that I'm missing?
FollowingTheDao 3y ago
Nonsteroidal anti-inflammatory drugs increase GDF15 which was one of the key markers in the study
- garganzol 3y ago
  But NSAIDs do not worsen dementia. Quite the contrary, the symptoms improve due to lowered inflammation. So, as other posters suggested, those proteins can be the effect markers but not the root cause indicators.
  - FollowingTheDao 3y ago
    What? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690966/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690966/ I’m not saying that it isthe root cause at all either, I’m saying they’re a marker as well. I’m saying there a marker as well, possibly from NSAIDS.
    - garganzol 3y ago
      Elderly people have quite a few incident effects related to their age. The most prominent one - the decrease of mitochondrial function, which leads to a significant loss of ATP yield, which in turn is a huge risk factor of acquiring a dementia by itself. If someone is given aspirin under those conditions, they may experience a worsening because aspirin provokes the release of cytochrome C from mitochondria, thus inducing apoptosis (cell death). This is a well-known effect [0] which may lead to encephalopathy under harsh conditions [1] (in reality regardless of age). At the same time, if someone is being administered aspirin in parallel to a correction of the declining mitochondrial function, the effect is the opposite: marginal cells may still die due to apoptosis, but newer cells will be created to take their functions thanks to the increased neurogenesis as the direct result of a restored anabolism. At the same time, anti-inflammatory effects of NSAID help to suppress a low-grade inflammation in vessels' endothelium. The result is: improved blood flow which in turn helps to restore mitochondrial function even further; the loss of marginal tissues similar to autophagy, improved neurogenesis; and sometimes - dementia reversal. BTW, this is why the results of using NSAIDs are different for younger and older cohorts - younger people have fewer chances of acquiring a compromised mitochondrial function. However, mito problems may occur even in young age due to genetics, environmental conditions, toxins, post-bacterial or post-viral effects caused by oxidative stress. So, this should be kept in mind as NSAIDs may indeed worsen the condition causing damages similar to Reye's syndrome unless they are administered together with a mito protocol. Another important point is that different NSAIDs have different effects. Aspirin is a relatively well-regarded medication, while others may be associated with an increased risk of a heart attack or stroke - which may significantly increase the chances of acquiring a dementia, but in a different way. [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1508093/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1508093/ [1] https://pubmed.ncbi.nlm.nih.gov/17147458/#:~:text=Reye's%20syndrome%20is%20a%20serious,teenagers%20%3C18%20years%20of%20age https://pubmed.ncbi.nlm.nih.gov/17147458/#:~:text=Reye's%20s....
petercooper 3y ago
This is unscientific anecdata, but my dad had celiac disease. After a few years, he got "bored" of it and refused to go along with the diet. Within a couple of years, he got vascular dementia (at a relatively young age) and ended up having a brain haemorrhage. The studies are pretty early stage on finding connections between celiac disease and brain damage but the TGM6 protein, common in people with gluten related sensitivities, has been implicated. So, and this is all spitballing for now, I think diet, and inflammation in particular, could prove to be a big deal. At least, I believe it's not following the diet that "got him", as it were.
- aszantu 3y ago
  I agree, I fall into depression after I eat anything seed based
bitwize 3y ago
Probably the usual suspects: inflammation, gut bacteria, the American diet.

That is the question. These are correlated to dementia risk, but that doesn’t mean they’re directly involved causing dementia. They could be a related effect of the root cause(s) of dementia. There are many examples in medicine where we’ve attempted to directly modify measurable markers like this without fixing the underlying disease. They could be useful clues for discovering the root cause, though!

carbocation 3y ago
Bingo. More explicitly, there is no strong reason to think that the proteins from the correlational analysis are causal for dementia. The proteins from the Mendelian randomization also don't have to be (can be in a pleiotropic pathway) but there is at least reason to think that they could be causal.
mcdonje 3y ago
If these are correlated, then not every treatment for them would necessarily be as effective against dementia. However, if the cause of the protein imbalances is something people can take steps to prevent, then doing so would logically have a greater than zero chance of mitigating dementia risk.
- Aurornis 3y ago
  > However, if the cause of the protein imbalances is something people can take steps to prevent, then doing so would logically have a greater than zero chance of mitigating dementia risk. Or correcting the protein imbalance could interfere with an important feedback loop that we don't yet understand, which could possibly make the situation worse. Or maybe the protein imbalances are involved in counteracting the issue that causes dementia, and that's why they're elevated. This is a common theme in biological systems. A good example would be cortisol, which has become known as the "stress hormone". Many people assume that lowering cortisol must therefore be a good thing, but if you were to indiscriminately lower cortisol during periods of stress you'd end up in a far worse condition than you were before. Cortisol is part of your body's reaction to stress and part of the system that responds to it, so artificially lowering it can interfere with your stress response process.
  - mcdonje 3y ago
    Good points. Thank you.
  - nonethewiser 3y ago
    It makes me think of running a fever. Its easy to think of fevers as bad but I imagine it would be a lot worse to simply stop the fever (if that were even possible).
    - smolder 3y ago
      > (if that were even possible) Indeed it is. Tylenol, for instance, is marketed as a fever reducer.
      - nonethewiser 3y ago
        Well perhaps this proves my intuition wrong. Is it OK to reduce a fever then? But how so if its purpose is to kill off something worse?
        smolder 3y ago
        IANAD, so someone please correct me, but I think there's some truth that treating a mild fever will just interfere with what the immune system is doing, to its detriment. On the other hand, very high fevers in themselves are quite dangerous and so being able to lower someone's temperature is a benefit.

pella 3y ago

(Guinea Pig) : diet, gut microbiota, ... ( ?? ) "The Effects of Different Diets on Guinea Pig Health, Hair Morphology and Blood Protein Concentration" ~ "Guinea pigs (Cavia porcellus) have biological similarities to humans, which make them a suitable animal model in multiple fields of research. " https://lsmu.lt/cris/handle/20.500.12512/115773 https://lsmu.lt/cris/handle/20.500.12512/115773

dsign 3y ago

I learned a lot about aging by watching this Minecraft video[^1] and building the kelp farm. That farm stops working after some (long) time, given the way that kelp grows in Minecraft. If Avomance had done the math beforehand, he would have discovered that he needs a costly full row of observers for the farm to work forever. Biological systems are not designed, but evolved, and evolution ends up selecting systems (which we call "organisms" or "individuals") which are good enough for it to be reproductively successful. In practice that means "low-maintenance" and "energy-efficient". Functional errors and their organism-wide effects slowly accumulate, and although our biology has everything material it needs to fix each and every error[^2], its healing program/intelligence is far from perfect. [^1]: https://www.youtube.com/watch?v=Sf9I3YORSzM https://www.youtube.com/watch?v=Sf9I3YORSzM [^2]: Compare this with a car, for example. If your lights go bust, the car won't grow a new one; you need to change them. But biological organisms have a lot of self-healing capability.

stefantalpalaru 3y ago

[dead]

1MachineElf 3y ago

The HN submission Could leak in blood-brain barrier cause poor memory? (2021) may provide a clue: https://news.ycombinator.com/item?id=26520453 https://news.ycombinator.com/item?id=26520453 >People with ApoE4 have a hard time getting rid of amyloid beta peptide in their brains, which causes an accumulation of plaque. With healthy aging, the pumps in the blood-brain barrier work less efficiently in getting rid of the amyloid beta peptide. The pumps work even less well in people with Alzheimer’s disease. >Recent work suggests that the leak in the blood-brain barrier that occurs with Alzheimer’s may be due to an age-related loss of pericytes. Astrocytes, by contrast, seem to be overactive. Recent work suggests that preserving pericyte function by giving the factors that they secrete or even transplanting them could lead to a healthier blood-brain barrier. >Other findings raise the question of whether the brain’s source of nutrition and its grip on control of the immune and endocrine systems could deteriorate with aging. Another finding raises the possibility that the rate at which many drugs are taken up by the brain may explain why older folks sometimes have different sensitivities to drugs than their children or grandchildren. Pair that with this part of OP: >This regulation is important in preventing proteins from going rogue and clumping together, which is what happens to the amyloid and tau proteins in the brains of people with Alzheimer’s disease, the most common cause of dementia. I'm just a layman, but it sounds like BBB health is a major factor for regulating this in the brain. In some individuals, including those with identified genetic biomarkers for increased Alzheimer's risk, the BBB ages faster, leading to decreased regulation of protein/peptides. So learning more about how to improve BBB health could eventually help people maintain a healthy brain longer. Avoiding excessive alcohol seems to be an important factor for BBB health, according to this 2021 study performed on mice: https://pubmed.ncbi.nlm.nih.gov/33516661/ https://pubmed.ncbi.nlm.nih.gov/33516661/ ; also this research published in 2022: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204474/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9204474/ OP refers to "amyloid and tau proteins" while the 2021 article I referenced refers to "amyloid beta peptide" - at this point, I'm really not sure how precisely these terms are being used. Are they interchangeable in this context, or is there an important nuance that I'm missing?

FollowingTheDao 3y ago

Nonsteroidal anti-inflammatory drugs increase GDF15 which was one of the key markers in the study

garganzol 3y ago
But NSAIDs do not worsen dementia. Quite the contrary, the symptoms improve due to lowered inflammation. So, as other posters suggested, those proteins can be the effect markers but not the root cause indicators.
- FollowingTheDao 3y ago
  What? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690966/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690966/ I’m not saying that it isthe root cause at all either, I’m saying they’re a marker as well. I’m saying there a marker as well, possibly from NSAIDS.
  - garganzol 3y ago
    Elderly people have quite a few incident effects related to their age. The most prominent one - the decrease of mitochondrial function, which leads to a significant loss of ATP yield, which in turn is a huge risk factor of acquiring a dementia by itself. If someone is given aspirin under those conditions, they may experience a worsening because aspirin provokes the release of cytochrome C from mitochondria, thus inducing apoptosis (cell death). This is a well-known effect [0] which may lead to encephalopathy under harsh conditions [1] (in reality regardless of age). At the same time, if someone is being administered aspirin in parallel to a correction of the declining mitochondrial function, the effect is the opposite: marginal cells may still die due to apoptosis, but newer cells will be created to take their functions thanks to the increased neurogenesis as the direct result of a restored anabolism. At the same time, anti-inflammatory effects of NSAID help to suppress a low-grade inflammation in vessels' endothelium. The result is: improved blood flow which in turn helps to restore mitochondrial function even further; the loss of marginal tissues similar to autophagy, improved neurogenesis; and sometimes - dementia reversal. BTW, this is why the results of using NSAIDs are different for younger and older cohorts - younger people have fewer chances of acquiring a compromised mitochondrial function. However, mito problems may occur even in young age due to genetics, environmental conditions, toxins, post-bacterial or post-viral effects caused by oxidative stress. So, this should be kept in mind as NSAIDs may indeed worsen the condition causing damages similar to Reye's syndrome unless they are administered together with a mito protocol. Another important point is that different NSAIDs have different effects. Aspirin is a relatively well-regarded medication, while others may be associated with an increased risk of a heart attack or stroke - which may significantly increase the chances of acquiring a dementia, but in a different way. [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1508093/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1508093/ [1] https://pubmed.ncbi.nlm.nih.gov/17147458/#:~:text=Reye's%20syndrome%20is%20a%20serious,teenagers%20%3C18%20years%20of%20age https://pubmed.ncbi.nlm.nih.gov/17147458/#:~:text=Reye's%20s....

petercooper 3y ago

This is unscientific anecdata, but my dad had celiac disease. After a few years, he got "bored" of it and refused to go along with the diet. Within a couple of years, he got vascular dementia (at a relatively young age) and ended up having a brain haemorrhage. The studies are pretty early stage on finding connections between celiac disease and brain damage but the TGM6 protein, common in people with gluten related sensitivities, has been implicated. So, and this is all spitballing for now, I think diet, and inflammation in particular, could prove to be a big deal. At least, I believe it's not following the diet that "got him", as it were.

aszantu 3y ago
I agree, I fall into depression after I eat anything seed based

bitwize 3y ago

Probably the usual suspects: inflammation, gut bacteria, the American diet.