Current guesses (borrowed from several articles, papers, and studies). I'm seeing a pattern. Comments?

[JAS9]

Over the last few months, I've been noticing some trends, and as I spent another nearly sleepless night reading and watching videos, some of the pieces seem to be fitting together. In short, it seems that more and more theories and studies are focusing on mitochondria. In particular, a "biochemical defect" of Complex 1. "What's that?" you ask.

"Complex 1 is found in cell structures called mitochondria, which convert the energy from food into a form that cells can use. Complex 1 is the first of five mitochondrial complexes that carry out a multi-step process called oxidative phosphorylation, through which cells derive much of their energy." *

"... These results indicated a specific defect of Complex 1 activity in the substantia nigra of patients with Parkinson’s disease. This biochemical defect is the same as that produced in animal models of parkinsonism by 1-methyl-4-phenyl- I ,2,3,6-tetrahydropyridine (MPTP) and adds further support to the proposition that [some cases of] Parkinson’s disease may be due to an environmental toxin with actions similar to those of MPTP." **

It's not just nerve cells in the substantial nigra that have this defect; there are neurons in the "gut brain" that do, too. This may explain how something from the outside environment could affect our substantia nigra: when we eat, drink, or breathe in MPTP (I'll just use MPTP as a stand-in for many possible attackers), it infects the "gut brain" and from there it is carried up the vegas nerve, which attaches to our main brain close to the substantia nigra.

So what happens to a neuron that becomes infected? The brain's immune system should be triggered to fight the infection. I won't get into this in detail, but the end result is PD; dead or badly damaged neurons that are not repaired, recycled, or replaced. Why? Remember; everything takes energy, and without functioning mitochondria, these cells have none. They can't even "self eat" (autophagy) because even that takes energy. So they become senescent cells if they survive at all. The MPTP (attacker) is evidently not gone, or at least its damage continues to spread. Could this be because the senescent cells spew something? Can we trigger autophagy to recycle and replace them?

Now we are finally ready to ask: "What can be done about this?" I was surprised to learn of a study in 2018 that might be pointing to a partial answer. They reported fairly substantial and consistent improvements in PD symptoms for PWP who switched to a very high-fat, low-carb keto diet. It hasn't been widely adopted yet, because a long-term keto diet would be very difficult to sustain by PWP. There was also an unnerving side effect; many of the PWP who switched to the keto diet experienced a significant worsening of their tremors. They faded after a few weeks.

This study also doesn't report on what happened when the subjects switched back to their pre-study diets. Did the subjects revert back to pre-study PD symptoms? If so, did it take time or did they just come rushing back? (I'll look into this more to see if they ever did a follow-up report on that.)

Keto worked (at least to some degree) probably because a keto diet doesn't require a mitochondria's Complex 1 in order to make energy (ketones). However, this (probably) didn't repair the damaged mitochondria. I've asked around a bit, and the few I've found who have tried this have reported that, yes it has lessened their PD symptoms, but their PD continues to progress. Why, and can we do something to repair or replace these mitochondria or the cells they're in? Does anyone know of ways to do this? Fisetin? Time+ (from Nuchido), NMN? Serrapeptase? Rapamycin? 30-day water fast? All of this and more?

This study's results are very interesting, though, because it suggests that we now *might* know what to fix in order to find real answers. They seem to have legitimately had improvements, short-lived or not. That has to give us some clues!

_______________ References

* => medlineplus.gov/genetics/co....

** => d1wqtxts1xzle7.cloudfront.n...

*** => youtu.be/O2yJAqRP0Y8(Not working as expected?)

[PDTom]

symbyxbiome.com/pages/light...

[park_bear]

Links to the study run by Dr. Matthew Phillips:

pubmed.ncbi.nlm.nih.gov/300...

researchgate.net/profile/Ma...

The control group which was a low-fat diet actually did slightly better on UPDRS part III than the keto group - see image.

Study results UPDRS scores

[JAS9 in reply to park_bear]

Thanks, Park. I relied too much on his presentation in which he pointed to a 41% improvement in baseline Part 1 scores. I'm already off on a tangent; trying to see if there's any treatment for "Mitochondrial complex I deficiency". It seems to be a genetic mutation issue, so probably not relevant.

[park_bear in reply to JAS9]

Plenty of evidence that aberrant alpha synuclein is responsible for mitochondrial dysfunction:

journals.biologists.com/dmm...

sciencedirect.com/science/a...

onlinelibrary.wiley.com/doi...

[JAS9 in reply to park_bear]

I'm taking a somewhat different approach from what's been normal for me. I don't think that there's just one, two, or three things to clear up and then PD will be cured. Rather, I believe that there are many issues that need to be addressed (and each of those may require several interventions before we'll see any significant improvement). So, yes, the clumps of alpha-synuclein may well be responsible for some of the mitochondrial dysfunction, but even so it's very possible that if all of the misfolded alpha-synuclein disappeared there would still be problems with the mitochondria. I say this because, even in those w/o PD, as they age, the mitochondria begin to have trouble doing their job(s). This "multi-target" approach is being used more and more (Dr. Nichola Conlon of nuchido.com and Professor Dale Bredesen apollohealthco.com/bredesen...

So, I might use something like Serrapeptase to clear out the alpha-synuclein (and other old proteins). Then use Nuchido's Time+ which is itself a multi-targeting product to fix some problems with the mitochondria's recycling of NAD. At the same time, I might do a 5-day water fast and take Fisetin (a strong senolytic to get rid of senescent cells). If that's not enough, I'll keep looking. Anyway, that's my current theory. I figure that, at the very least, I should get an energy boost from all of this, and I can use that energy to exercise more, which I know helps for sure.

[LAJ12345 in reply to JAS9]

I agree with your new approach. I don’t know if you saw the links I put to the Ari Whitten videos on energy blueprint. If you haven’t seen any of his stuff I think you would be interested as it is explaining lack of energy and aging exactly as you say. I would love to do his course myself but for the cost 😩

theenergyblueprint.com/ener...

[JAS9 in reply to LAJ12345]

Thanks! I'll check it out. Here's a link to a Dr. Nichola Conlon interview : youtube.com/watch?https://y...(Not working as expected?)

[LAJ12345 in reply to JAS9]

Thanks!

[Hidden in reply to JAS9]

I agree with so much of what you stated. Dr. Bredesen says “32 holes in the roof” I agree with the message that it is extremely complex and there is not one target. To clear AS you might want to look in to Ambroxol, Montelukast or Trehalose. There are multiple posts on those.

You might find mitochondrial uncoupling an interesting rabbit hole. Understanding that is my new goal.

And, the epigenetic component of our PD.

I believe that epigenetics is at least a factor in our disease manifestation and progression.

And how does fasting affect epigenetics?

Glutamate Excitotoxicity is yet another factor.

Too much iron accumulated.

Researching all this is overwhelming but I’m determined.

[SilentEchoes in reply to park_bear]

We need to ask why. Why is a-synuclein aberrant, what is the trigger? A-synuclein is the effect, not the cause.

[park_bear in reply to SilentEchoes]

Toxic exposures. Permethrin is one.

healthunlocked.com/cure-par...

[chartist]

Jas9,

You are looking for a way to improve mitochondrial complex 1 activity. Melatonin does this and significantly more in PwP.

Reduced levels of melatonin in the mitochondria leads to mitochondrial damage via increased ROS and RNS levels and damage to the cells that those mitochondria exist in. Adding high dose melatonin (HDM) significantly improves Complex 1 activity and helps protect the mitochondria via reduced levels of ROS and RNS. The HDM helps return the increased oxidative stress levels to levels similar to healthy controls.

ncbi.nlm.nih.gov/pmc/articl...

Here is a relevant quote from the study :

>>> ' At baseline, the activity of mitochondrial complex I and the respiratory control ratio were significantly lower in PD patients than in the healthy control group (Figures 2(a) and 2(b), respectively). Compared with the placebo group, the melatonin group showed significant increases of both parameters after 3 months and reached values similar to the healthy control group. ' <<<

Art

[JAS9 in reply to chartist]

Thanks, Art! This is great! What dose do you take? 25 mg melatonin at noon and 30 minutes before bedtime? Any brand better than the others? Any other tips?

[chartist in reply to JAS9]

In that study in PwP to get those effects they used two 25 mg doses per day for a total of 50 mg/day. I take more than double that amount at 120 +mg total per night. Not everyone can tolerate melatonin in which case you can consider one or more of the 5 other methods I have described for increasing melatonin with no side effects. Here is a link to that, but you will have to scroll through the replies to find the last three ways to naturally increase melatonin significantly without side effects that some people have reported from supplementing melatonin.

healthunlocked.com/cure-par...

And possibly this one using red light therapy (RLT) to increase melatonin :

healthunlocked.com/cure-par...

Art