The way this is presented, one would think that pre-existing B12 levels being high were a risk for PD, but if you happen to be taking some supplements, that didn’t worsen things - which mechanistically is interesting and a bit counter-intuitive. However, supplementation isn’t always the same thing as lifestyle or other genetics resulting in a higher level.
I very much appreciate the laser focus on PD … and overall, I think exercise, including things with a lot of balance and aerobic activity (pickleball for us elders), some weight training, 40 hz devices and GLP-1s are among the the things to highly consider (I know there are more).
But in conjunction with this, if one has a Homocysteine of 35 … I’d still treat it - but for other reasons, just not in the delusion that this will impact PD.
Neurodegeneration will remain a tough nut to crack.
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I wonder if SS 31 / Elamipretide would help with this?
I keep getting delayed in my experiment with this peptide, been quite busy the past couple of weeks
https://www.sciencedirect.com/science/article/pii/S0753332225002501
Contemporary insights into elamipretide’s mitochondrial mechanism of action and therapeutic effects
Highlights
• Mitochondria electron transport system (ETS) produces essential cellular energy.
• ETS is located on cardiolipin (CL)-rich cristae of inner mitochondrial (MITO) membrane.
• In disease, elamipretide binds to CL, improving MITO structure, function and dynamics.
• In animals, elamipretide improves MITO function in cardiac and skeletal myopathies.
• In humans, elamipretide improves symptoms of Barth syndrome myopathy
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adssx
#912
There’s zero evidence that homocysteine-lowering interventions help with anything other than stroke. ZERO: What are your homocysteine levels? What have you done to reduce it? Why isn't it part of PhenoAge or aging.ai clocks? - #156 by adssx
So homocysteine is probably a sign (consequence) of something else going wrong (hard to know what!), but treating it won’t bring benefits.
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Homocysteine’s interference with the NO chain via ROS is more than enough reason to crush it.
It isn’t just a signal of bad stuff; it is bad stuff.
adssx
#914
So how do you explain that Mendelian randomization studies don’t find any causal effect for any diseases other than stroke? And how do you explain that homocysteine-lowering RCTs failed for most conditions? Is there strong evidence (RCT + MR) in favor of homocysteine lowering interventions for anything other than stroke? I’m not talking about longitudinal association studies.
A_User
#915
Serum B12 isn’t specific enough for B12 deficiency and the effects might be non-linear and MR is not good for detecting non-linear effects (i.e a threshold where risk increases, like where the percentile that causes deficiency has negative effects, maybe 1-10th percentile lowest B12 – the rest above no effect).
I searched for methylmalonic acid (but the authors didn’t mention B12):
A non-linear correlation was observed between MMA and AD-specific death and PD-specific mortality. The presence of MMA Q4 was linked to increased death rates among AD patients (HR = 6.39, 95%CI: 1.19–35.24, P = 0.03) after controlling for potential confounders in a multivariable weighted Cox regression model. In PD patients, the MMA Q4 (Q4: HR: 5.51, 95 % CI: 1.26–24, P = 0.02) was also related to increased mortality. The results of survival analysis indicated that the poorer prognoses were observed in AD and PD patients with MMA Q4
https://www.cell.com/heliyon/fulltext/S2405-8440(24)05388-X
adssx
#916
Yes B12 deficiency is bad. Any deficiency is. It is also possible that the current threshold for deficiency is a bit too low. But once/if you’re above that threshold, the evidence for B12 supplementation seems to me very weak. It’s at best association studies. And even some association studies found detrimental effects: Parkinson's disease - #909 by adssx
I would love to be proven wrong.
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adssx
#917
Also, B12 supplementation might be beneficial in people with PD already on levodopa due to some effects of levodopa, see:
And:
https://www.prd-journal.com/article/S1353-8020(23)00080-9/abstract
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I don’t really care to tell you the truth. I just want add much NO and endothelial protection as possible. I don’t see how you could argue against it. Absence of evidence is not evidence of absence I guess, at least for me.
adssx
#919
Then you should consider joining another online community because the goal here is to learn together and find the truth. If you just want to affirm things without spending time reviewing the evidence, go to TikTok.
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No doubt we should look for truth, but sometimes you just have to take the available evidence and make a leap of faith. We all may be dead until something is known for certain. This is a Rapamycin forum, isn’t it? Despite the lack of long term human trials, we have taken that logical leap.
adssx
#921
Of course, we all make decisions under uncertainty. The evidence in favor of B12 supplementation in people without B12 deficiency to prevent PD is just not there.
@adssx 's point is that people should evidence their argument rather than “make a leap of faith”.
B6, 9 and 12 are interesting in lots of ways. However, B6 particularly has a u shaped curve because of self-inhibition, B9 personally I think the normal range may be actually below optimal values.
B12 I don’t think have evidence for oversupplementation.
I never said there was any benefit for PD. All my post were off-topic. Maybe that’s where the misunderstanding came from.
adssx
#924
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Keeping glucose low strikes me as a good strategy. Avoid glucose spikes.
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adssx
#926
SGLT2i are also mild brain-penetrant mTOR inhibitors (indirectly?):
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adssx
#927
Combination therapies: a change in approach for Parkinson’s research
Therefore, we aim to encourage researchers to think about, and test, drug combinations earlier in the drug discovery process; Cure Parkinson’s are championing the testing of combination therapies with the hope of increasing the odds of identifying disease-modifying therapies with urgency.
To kick start this change, Cure Parkinson’s will be opening a £2 million funding call in October 2025 to encourage the testing of combination therapies for Parkinson’s.
@John_Hemming: which combinations would you like to see tested? Citrate + melatonin + K2 I guess?
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That would be a good start, but these things have important aspects relating to dosing and timing of dose. I don’t think CP would want to try 1g of melatonin at night, for example, or even 100mg.
It is one really which requires individual experimentation with potentially quite substantial doses
Well, that really opens up possibilities. In particular, combining drugs where one or both individually may have failed, because the combination is a whole new effect - we’ve seen this over and over again, like the mice lifespan studies I discussed recently - metformin alone failed but in combo with rapa worked, or simvastatin and ramipril both failed individually, but gave a good 9% extension combined.
There were several very promising drugs which we had high hopes for PD for mechanistic reasons, but which sadly and disappointingly failed trials. Combining them might give them a new lease on life. I think that’s a very exciting possibility. We might be giving up on some drugs too soon!
