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> It inhibits complex 1, the leading enzyme in a chain of reactions that convert food to energy in cellular organelles called mitochondria. So they upside is t

> It inhibits complex 1, the leading enzyme in a chain of reactions that convert food to energy in cellular organelles called mitochondria. So they upside is that it probably significantly reduces your risk of both cancer and type 2 diabetes, which you're >100x more likely to die from than Parkinson's. There are even longevity bloggers, like Peter Attia, who advocate that everyone should be taking mitochondrial complex 1 inhibitors.

enkid 3y ago
Is there any evidence it actually reduces those risks, or is it speculation?
- voisin 3y ago
  Mitochondrial disfunction is the basis for a huge number of cancers. See “Tripping over the Truth: The Metabolic Theory of Cancer”[0] for a good history of it. [0] https://www.goodreads.com/book/show/23496164 https://www.goodreads.com/book/show/23496164
  - MrBuddyCasino 3y ago
    Ray Peat liked this comment.
- Alex3917 3y ago
  Go on Google Scholar and read through the research on Metformin. Metformin has a complex mechanism of action, acting is as a Mitochondrial Complex 1 inhibitor in some cases but not others. But the consensus seems to be that it reduces cancer risk by about 30%, relating to its capacity as a Mitochondrial Complex 1 inhibitor. Also, if watch Jerry McLaughlin's YouTube talks about pawpaws and cancer, he summarizes the research that mainly focuses on the mechanisms of action of annonaceous acetogenins in fighting cancer -- these are also Mitochondrial Complex 1 inhbitors, similar to Metformin but much stronger. Basically these chemicals cause a buildup of radical oxides in your mitochondria, which reduce their efficiency. If your mitochondria have too many radical oxides, or have them for two long, then your mitochondria will die. And if enough mitochondria in any given cell die, their host cells will also obviously die. This is what causes progressive supranuclear palsy, which is what this article is probably (incorrectly) referring to as Parkinson's. But because the metabolic needs of cancer cells are higher than the metabolic needs of non-cancer cells, there may be a certain dose of these chemicals that is high enough to inhibit cancer but low enough that it doesn't cause palsy. Further, the way that cancer cells often develop resistance to chemotherapy drugs is by using ATP to pump out the drugs once they have entered the cells. These mitochondrial complex 1 inhibitors can prevent these protein pumps from working by making the mitochondria less efficient, and therefor effectively prevent cancer cells from developing certain types of resistance to chemotherapy drugs. Basically if you go through Google Scholar and read the research on pawpaws, rotenone, graviola, and Metformin, it's all more or less the same stuff. John Clifton's book Your Fourth Choice is also a fun book you can get on Amazon and read in an hour or two. It does a good job summarizing the academic research on annonaceous acetogenins. (I bought it because I collect books on North American Pawpaws, not because I was in the market for an experimental cancer treatment.)
dist-epoch 3y ago
> everyone should be taking mitochondrial complex 1 inhibitors These processes have billions of years of evolution behind them and are highly conserved. People shouldn't mess with them until there are huge studies, and not in the context of cancer therapy. Just because something helps with cancer, like mitochondrial complex 1 inhibitors (or radiation) doesn't mean we should all do it. Remember all the talk about how we should all eat lots of anti-oxidants to prevent cancer? It turns out it's more complicated than that, and an anti-oxidant rich diet can actually increase cancer risk.
- Alex3917 3y ago
  > Remember all the talk about how we should all eat lots of anti-oxidants to prevent cancer? It turns out it's more complicated than that, and an anti-oxidant rich diet can actually increase cancer risk. Which is probably because Mitochondrial Complex 1 inhibitors work by producing radical oxides in the mitochondria. I definitely agree with you that it's inherently very risky to mess around with them, but I also don't think it's at all obvious that being exposed to them will increase your all-cause mortality. It may even reduce it. We just don't know.
  - lazide 3y ago
    I think their point was - don’t do something daily with potentially powerful but unclear effects until we have some evidence on it’s long term safety. Unless there is a pressing, specific need (like cancer that may be worth the risk). Which seems reasonable?
    - Alex3917 3y ago
      Which I agree with. I'm definitely not advocating that people take this stuff. Only pointing out that it's not completely obvious that it's harmful.
      - lazide 3y ago
        Sure, but no one will take cyanide every day (they can’t). Folks were around Asbestos for decades before we figured out it was cancer causing. There are some areas where being conservative can be a wise decision. It could pay off though. That’s always the gamble, right?
Tade0 3y ago
The chemical in question was originally banned due to its carcinogenic properties.
throwaway2037 3y ago
As I understand, Parkinson's does not kill you. NHS UK says: <<Parkinson's disease does not directly cause people to die>> Also: <<But with advances in treatment, most people with Parkinson's disease now have a normal or near-normal life expectancy.>> Ref: https://www.nhs.uk/conditions/parkinsons-disease/ https://www.nhs.uk/conditions/parkinsons-disease/
- exchemist 3y ago
  This is often said, but I don't think it should paint too rosy a picture, it's still a massively debilitating disease. My father (diagnosed just after 50) lived nearly 30 years with it (died 78 - I guess that's normal life expectancy, but the last decade of his life he had a pretty bad quality of life). He is unusual in that his death cert just says Parkinson's Disease as cause of death, and I wondered at the time whether the consultant was making a point that PD can be the thing that kills you after all. He really didn't have much else wrong with him except that, once the drugs stopped working he couldn't swallow, talk or walk - he lost a ton of weight and the dementia side of it (which is far less discussed) meant any kind of communication was basically impossible. Not sure what my point is - but "you don't die of it" is a bit of an oversimplification.
  - throwaway2037 3y ago
    That is incredible. To live 27-28 years after diagnosis is a modern medical miracle. That said, I am highly sympathetic to the points that you made. Essentially, he became a vegetable: <<any kind of communication was basically impossible>> Did you ever discuss end-of-life options with him before the disease progressed so far? I have a close relative with PD. I am terrified of the last years, but no idea how to raise the issue of end-of-life options. My family's culture is pretty much "try to live forever" instead of "try to live well". Are there any Swiss/Belgians/Dutchies here with experience on planned end-of-life options? Those three countries are exceptionally liberal on that matter.
- Alex3917 3y ago
  The form of atypical Parkinson's caused by mitochondrial complex 1 inhibitors (progresessive supranuclear palsy) is not treatable, at least with normal Parkinson's drugs. My wild speculative guess is that many of the soldiers in this article have a mild-enough form of PSP that it's being misdiagnosed as Parkinson's.

enkid 3y ago

Is there any evidence it actually reduces those risks, or is it speculation?

voisin 3y ago
Mitochondrial disfunction is the basis for a huge number of cancers. See “Tripping over the Truth: The Metabolic Theory of Cancer”[0] for a good history of it. [0] https://www.goodreads.com/book/show/23496164 https://www.goodreads.com/book/show/23496164
- MrBuddyCasino 3y ago
  Ray Peat liked this comment.
Alex3917 3y ago
Go on Google Scholar and read through the research on Metformin. Metformin has a complex mechanism of action, acting is as a Mitochondrial Complex 1 inhibitor in some cases but not others. But the consensus seems to be that it reduces cancer risk by about 30%, relating to its capacity as a Mitochondrial Complex 1 inhibitor. Also, if watch Jerry McLaughlin's YouTube talks about pawpaws and cancer, he summarizes the research that mainly focuses on the mechanisms of action of annonaceous acetogenins in fighting cancer -- these are also Mitochondrial Complex 1 inhbitors, similar to Metformin but much stronger. Basically these chemicals cause a buildup of radical oxides in your mitochondria, which reduce their efficiency. If your mitochondria have too many radical oxides, or have them for two long, then your mitochondria will die. And if enough mitochondria in any given cell die, their host cells will also obviously die. This is what causes progressive supranuclear palsy, which is what this article is probably (incorrectly) referring to as Parkinson's. But because the metabolic needs of cancer cells are higher than the metabolic needs of non-cancer cells, there may be a certain dose of these chemicals that is high enough to inhibit cancer but low enough that it doesn't cause palsy. Further, the way that cancer cells often develop resistance to chemotherapy drugs is by using ATP to pump out the drugs once they have entered the cells. These mitochondrial complex 1 inhibitors can prevent these protein pumps from working by making the mitochondria less efficient, and therefor effectively prevent cancer cells from developing certain types of resistance to chemotherapy drugs. Basically if you go through Google Scholar and read the research on pawpaws, rotenone, graviola, and Metformin, it's all more or less the same stuff. John Clifton's book Your Fourth Choice is also a fun book you can get on Amazon and read in an hour or two. It does a good job summarizing the academic research on annonaceous acetogenins. (I bought it because I collect books on North American Pawpaws, not because I was in the market for an experimental cancer treatment.)

dist-epoch 3y ago

> everyone should be taking mitochondrial complex 1 inhibitors These processes have billions of years of evolution behind them and are highly conserved. People shouldn't mess with them until there are huge studies, and not in the context of cancer therapy. Just because something helps with cancer, like mitochondrial complex 1 inhibitors (or radiation) doesn't mean we should all do it. Remember all the talk about how we should all eat lots of anti-oxidants to prevent cancer? It turns out it's more complicated than that, and an anti-oxidant rich diet can actually increase cancer risk.

Alex3917 3y ago
> Remember all the talk about how we should all eat lots of anti-oxidants to prevent cancer? It turns out it's more complicated than that, and an anti-oxidant rich diet can actually increase cancer risk. Which is probably because Mitochondrial Complex 1 inhibitors work by producing radical oxides in the mitochondria. I definitely agree with you that it's inherently very risky to mess around with them, but I also don't think it's at all obvious that being exposed to them will increase your all-cause mortality. It may even reduce it. We just don't know.
- lazide 3y ago
  I think their point was - don’t do something daily with potentially powerful but unclear effects until we have some evidence on it’s long term safety. Unless there is a pressing, specific need (like cancer that may be worth the risk). Which seems reasonable?
  - Alex3917 3y ago
    Which I agree with. I'm definitely not advocating that people take this stuff. Only pointing out that it's not completely obvious that it's harmful.
    - lazide 3y ago
      Sure, but no one will take cyanide every day (they can’t). Folks were around Asbestos for decades before we figured out it was cancer causing. There are some areas where being conservative can be a wise decision. It could pay off though. That’s always the gamble, right?

Tade0 3y ago

The chemical in question was originally banned due to its carcinogenic properties.

throwaway2037 3y ago

As I understand, Parkinson's does not kill you. NHS UK says: <<Parkinson's disease does not directly cause people to die>> Also: <<But with advances in treatment, most people with Parkinson's disease now have a normal or near-normal life expectancy.>> Ref: https://www.nhs.uk/conditions/parkinsons-disease/ https://www.nhs.uk/conditions/parkinsons-disease/

exchemist 3y ago
This is often said, but I don't think it should paint too rosy a picture, it's still a massively debilitating disease. My father (diagnosed just after 50) lived nearly 30 years with it (died 78 - I guess that's normal life expectancy, but the last decade of his life he had a pretty bad quality of life). He is unusual in that his death cert just says Parkinson's Disease as cause of death, and I wondered at the time whether the consultant was making a point that PD can be the thing that kills you after all. He really didn't have much else wrong with him except that, once the drugs stopped working he couldn't swallow, talk or walk - he lost a ton of weight and the dementia side of it (which is far less discussed) meant any kind of communication was basically impossible. Not sure what my point is - but "you don't die of it" is a bit of an oversimplification.
- throwaway2037 3y ago
  That is incredible. To live 27-28 years after diagnosis is a modern medical miracle. That said, I am highly sympathetic to the points that you made. Essentially, he became a vegetable: <<any kind of communication was basically impossible>> Did you ever discuss end-of-life options with him before the disease progressed so far? I have a close relative with PD. I am terrified of the last years, but no idea how to raise the issue of end-of-life options. My family's culture is pretty much "try to live forever" instead of "try to live well". Are there any Swiss/Belgians/Dutchies here with experience on planned end-of-life options? Those three countries are exceptionally liberal on that matter.
Alex3917 3y ago
The form of atypical Parkinson's caused by mitochondrial complex 1 inhibitors (progresessive supranuclear palsy) is not treatable, at least with normal Parkinson's drugs. My wild speculative guess is that many of the soldiers in this article have a mild-enough form of PSP that it's being misdiagnosed as Parkinson's.