Mitochondrial damage before Parkinson's - Cure Parkinson's
Mitochondrial damage before Parkinson's
"These findings support 'the hypothesis that mtDNA dysfunction is a primary cause of neurodegeneration' rather than a consequence of nerve damage, the researchers wrote."
And we know that GlyNAC corrects mitochondrial dysfunction in 24 weeks...
2 + 2 =
what is the dose? Have you any recommendations?
The study used 100 mg/kg/day of glycine, and 100 mg/kg/day of NAC, probably spread across the day.
academic.oup.com/biomedgero...
"GlyNAC supplementation began to rapidly improve these defects in 2-weeks, but a longer duration of 16-weeks was needed to correct these defects. Interestingly, acetate oxidation did not differ between unsupplemented YA and OA. It did not change after GlyNAC supplementation. This suggests that tricarboxylic-acid cycle integrity is not compromised in OA. Because optimal and efficient functioning of cellular processes and organs depends on an uninterrupted energy supply, mitochondrial dysfunction could result in cellular, tissue, organ, and whole-body adaptations and dysfunction commonly found in aging (15–20). By correcting mitochondrial dysfunction, GlyNAC supplementation could play a critical role to reverse age-associated declines and improve health in aging humans."
Are you trying this? If so please share your gly/nac source please?
I have Vitacost NAC 600mg capsule in the cupboard. Waiting for Glycine 1000mg capsule from Bulk Supplements. Once it is delivered, I plan to take as follows:
Week 1 - one capsule each 2 hrs post lunch
Week 2 - one capsule glycine 2 capsule NAC
Titrate weekly till 3000mg/day of each, then titrate upwards every two to three weeks till 6000mg/day is reached.
I am 75kg, but I will not cross 6000mg/day just to keep under the study doses.
Once the capsule are exhausted I plan to switch over to powder.
At some point I plan to include R-ALA, but not sure if it makes sense
I would suggest starting light on the ALA - our experience was indigestion with this
Thank you 🙏
When you say "100 mg/kg/day" is that middle "kg" saying "per kilogram of body weight"?
I've been taking 100mg / kg of glycine and NAC for over a year. My mitochondrial dysfunction is certainly not corrected,...yet. Can manage 2 to 4 hours of activity a day before exhausted. But hey, if it takes 10 years or so to develop PD, maybe any 'cure' will take that long!
How would you know that? Maybe it is corrected but the damage is extensive?
I took "correcting" to mean " made better". But there's no control to know how I'd be without it, maybe I'd be a lot worse.
Melatonin helps restore mitochondrial function in people with PD while returning elevated oxidative stress levels to healthy control levels in 3 months in PwP :
ncbi.nlm.nih.gov/pmc/articl...
Here are some relevant quotes from the human 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. '
' The results of our double-blind, cross-over trial suggest the existence of an active, persistent oxidative stress status in PD that is linked to lower mitochondrial complex I activity in platelets. These data are in consonance with previously reported data in platelets [21, 22], muscle biopsy [23], and substantia nigra [24]. Free radicals are by-products of the mitochondrial respiratory chain and at low concentrations are involved in homeostasis and normal cell signaling. However, increased generation of reactive oxygen species is linked to PD and complex I is one of the main sites of electron leakage to oxygen which leads to the production of the superoxide anion [1, 25]. '
' Consistent with this proposal, melatonin treatment prevented the loss of the integrity and function of the striatal mitochondria in a chronic model of PD by preserving the normal levels of ATP and mitochondrial respiration [26, 42], and the loss of the mitochondrial membrane potential that may trigger the activation of the permeability transition pore [43]. Furthermore, melatonin significantly decreased neuronal death and mitochondrial fragmentation in an in vitro model of PD [44, 45]. Interestingly, it has been proposed that melatonin physically interacts with complex I at its amphipathic ramp close to the site of electron leakage: the iron-sulfur cluster N2 [46], reverses the decrease in mitochondrial complex 1 activity that is induced by toxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [47], and upregulates the expression levels of subunits 1, 3 [48] ND1, ND2, ND4, and ND4L of complex I [49]. '
' Taken together, our data showed that melatonin supplementation recovers mitochondrial function and diminishes oxidative stress. Thus, this indolamine could play a role as an adjuvant in the treatment of PD. '
With age, melatonin levels decline and even more so in people with PD. Melatonin is naturally produced directly in the mitochondria and can rapidly neutralize ROS and RNS radicals before they significantly damage the mitochondria. Melatonin helps protect the mitochondria allowing efficient ATP production and keeps the mitochondria functioning properly, but with declining melatonin levels with age and even more so with PD, there comes a tipping point where melatonin levels decline and are no longer able to continue this process efficiently and effectively, thus allowing mitochondrial damage, decreased ATP production and ultimately cellular damage.
Art
Thank you for this paper on Melatonin. I am considering adding it for my HWP. My memory of the supplement is there are regular and long acting versions, usually for 1 to 10 mg so 25+25 sounds high, but that was what was used in the study and it said it was well tolerated. Any suggestions or n how to begin?
You can do 2 x 10mg noon and 3 x 10mg before bed. Start with 1 at bedtime and increase over a few weeks.
chartist I am confused about the 3% absorption of oral Melatonin, and how that would relate to the 50mg study mentioned above...
Jay,
I can only speculate on that point. Melatonin taken orally is going to the gut, but this does not mean it is going to reach a high serum level. We already know that gut dysbiosis is a definite and relevant problem in multiple disease states including PD. It has also been established that melatonin helps to maintain gut homeostasis as discussed here :
ncbi.nlm.nih.gov/pmc/articl...
Here are a couple of relevant quotes from the article :
' Recent studies described the presence of MT in the cells of the gastrointestinal tract (GIT) [12] as well as in every compartment (lumen, mucosa, and muscularis) and segment, from the esophagus to the rectum of the GIT [13,14,15]. MT functions in the gut are not completely elucidated, but available data support its role in immunity, gastrointestinal (GI) secretion, and intestinal motility [16]. '
' Melatonin and intestinal bacteria appear to have an intricate functional interrelationship. As discussed below, microorganisms can modulate the synthesis of melatonin in the GIT; conversely, MT is linked to the proper composition and dynamic of the gut microbiota. Together, they form a complex system that acts on multiple levels to maintain the homeostasis of the host. '
' Recent scientific evidence reveals that MT and the colonic bacterial populations act synergistically and maintain GI and systemic homeostasis through their multiple actions on immunity, oxidative stress, circadian rhythm, and other functions that remain to be elucidated. These findings may be of particular relevance in the context of the increasing number of studies that show an association between dysbiosis and an array of conditions (e.g., IBDs, chronodisruption-associated dysbiosis, obesity, and neuropsychiatric disorders) (Figure 4), most of them with an unclear pathogenesis still. Although the causal relationship between gut microbiota imbalance and these diseases has not been defined yet, therapeutic agents capable of re-balancing the intestinal milieu hold great promise for improving these conditions. Considering all the gathered studies and presented results, this review hypothesizes that MT might be one of such agents, having the advantage of acting through multiple pathways. '
Given the above information, I continue to take oral melatonin as well as topically applied melatonin lotion which appears to have significantly better bioavailability than oral melatonin. I wrote about melatonin lotion here :
healthunlocked.com/cure-par...
Oral melatonin can only reach the skin in limited amounts and offers limited amounts to the blood circulation and brain. On the other hand, melatonin lotion traverses the skin easily and then reaches the blood and ultimately the brain with little if any going to the gut.
Art
I like the idea of the lotion
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