The idea that Parkinson's Disease (PD) is an accelerated form of brain aging has been around for quite a long time. However, as with aging more generally any hypothesis as to the mechanisms behind Parkinson's needs to explain all the known research data.
I have been discussing PD with a number of people over the past few months. The results from research indicate that Parkinsons is not primarily caused by genetic factors. That is because there are studies where individual twins get Parkinsons, whilst their twin does not. I was wondering, therefore, what might be an alternative cause.
This paper is one that substantiates the argument that normally the brain does not age as fast as the rest of the body.
What we need to look at is what might cause this to happen. If we start with the assumption from my previous posts that aging results from the mutation of mitochondrial DNA (mtDNA) then we need to find something that prevents the mutation of mtDNA in the brain that does not operate elsewhere. That is easy to find. It is the existance of Cerebro Spinal Fluid CSF. When people go to sleep the blood pressure goes down and CSF becomes more available to the brain. Within CSF there is a high concentration of melatonin and melatonin protects mtDNA from damage. The pineal gland generates melatonin as part of the daily circadian cycle and injects some of that directly into the CSF. Hence we know why the brain is more protected from mtDNA damage (aging) than the rest of the body. The question then is why people with PD find that their brain is less protected.
It is also quite clear that there is evidence that the level of melatonin in the third ventricle of people with PD is lower than people who don't have PD.
The table below is from this article Significance of High Levels of Endogenous Melatonin in Mammalian Cerebrospinal Fluid and in the Central Nervous System
What is not immediately obvious from this table is that the last line (Leston et Al) is from Patients with PD. It demonstrates a much lower level of melatonin in the third ventricle.
There are two possible causes for this:
a) A higher proportion goes into serum than in non-PD patients
b) Less melatonin is generated.
It does not immediately matter although in rectifying this may lie part of the solution to PD. What matters is that brain cells are getting less melatonin than in non-PD people. Hence their mitochondrial DNA has less protection. This to me seems to be the cause of the accelerated brain aging that is seen with PD.
nb the penultimate line is Traumatic Brain Injury.
Other possibly relevant research
Mitochondrial DNA damage triggers spread of Parkinson’s disease-like pathology In the field of neurodegenerative diseases, especially sporadic Parkinson’s disease (sPD) with dementia (sPDD), the question of how the disease starts and spreads in the brain remains central. While prion-like proteins have been designated as a culprit, recent studies suggest the involvement of additional factors. We found that oxidative stress, damaged DNA binding, cytosolic DNA sensing, and Toll-Like Receptor (TLR)4/9 activation pathways are strongly associated with the sPDD transcriptome, which has dysregulated type I Interferon (IFN) signaling. In sPD patients, we confirmed deletions of mitochondrial (mt)DNA in the medial frontal gyrus, suggesting a potential role of damaged mtDNA in the disease pathophysiology. To explore its contribution to pathology, we used spontaneous models of sPDD caused by deletion of type I IFN signaling (Ifnb–/–/Ifnar–/– mice). We found that the lack of neuronal IFNβ/IFNAR leads to oxidization, mutation, and deletion in mtDNA, which is subsequently released outside the neurons. Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. Furthermore, it caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an “infectious-like” manner. We also discovered that the mechanism through which damaged mtDNA causes pathology in healthy neurons is independent of Cyclic GMP-AMP synthase and IFNβ/IFNAR, but rather involves the dual activation of TLR9/4 pathways, resulting in increased oxidative stress and neuronal cell death, respectively. Our proteomic analysis of extracellular vesicles containing damaged mtDNA identified the TLR4 activator, Ribosomal Protein S3 as a key protein involved in recognizing and extruding damaged mtDNA. These findings might shed light on new molecular pathways through which damaged mtDNA initiates and spreads PD-like disease, potentially opening new avenues for therapeutic interventions or disease monitoring.
Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson’s disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, and iron chelators, have failed in disease-modification clinical trials. In this review, we summarize the cellular determinants of mitochondrial dysfunction, including impairment of electron transport chain complex 1, increased oxidative stress, disturbed mitochondrial quality control mechanisms, and cellular bioenergetic deficiency. In addition, we outline mitochondrial pathways to neurodegeneration in the current context of PD pathogenesis, and review past and current treatment strategies in an attempt to better understand why translational efforts thus far have been unsuccessful.
Edit 27/2/25
Obviously night time levels of melatonin are higher. ChatGPT gives a level of between 500 and 3,000 pg/ml.
There has been quite a bit of burbling in the medical profession about serum levels of melatonin that result from supplementation. Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults and Chronic Administration of Melatonin: Physiological and Clinical Considerations are both papers that look at this.
Summarising the research, however, if people take something like 0.1 to 0.5mg then the peak serum level is in the normal range. If people take 4mg the peak serum level is around 4000 pg/ml. There is a problem, however, which is that normally during the night the brain is exposed to something like 3,000 pg/ml and during the day looking at the above table something like 300 pg/ml. Hence if the priority is to replicate the brain's exposure to melatonin then a single dose providing a peak 4000 pg/ml comes nowhere close to the 3,000 mean figure as the half life is around 30 mins. It is obviously hard to know what is going on in the CSF during the night, but replicating physiological figures for melatonin in the brain requires superphysiological figures for the serum.
There are rightly held concerns as to what effects melatonin may have in higher levels in serum and that is not entirely clear. It does appear to hold back puberty (in my view by preventing mtDNA damage). It may increase levels of some molecules such as SHBG. However, if the objective is to concentrate on improving and protecting brain cells having superphysiological levels of melatonin looks right.
Edit: 13/3/25
Circadian secretion pattern of melatonin in Parkinson's disease is a paper I found after writing the above. This paper looks only at serum levels of melatonin, but it finds that the pattern of melatonin peak in serum peaks earlier in people with PD. That fits with the normal pattern of melatonin secretion being that a material amount first goes into the CSF and then comes out of CSF into serum. Hence people with PD where the melatonin goes into serum rather than CSF will have an earlier peak.
Looking for that paper I found Circadian Melatonin Rhythm and Excessive Daytime Sleepiness in Parkinson Disease. This paper found basically less melatonin. That, of course, would have similar effects.
There is also Serum melatonin is an alternative index of Parkinson's disease severity. This may seem counterintuitive, but if then pineal's melatonin production is constant then serum levels being higher means that less melatonin is available for the brain. Hence you would expect serum levels to indicate severity for a normal pineal production.
I have been discussing PD with a number of people over the past few months. The results from research indicate that Parkinsons is not primarily caused by genetic factors. That is because there are studies where individual twins get Parkinsons, whilst their twin does not. I was wondering, therefore, what might be an alternative cause.
This paper is one that substantiates the argument that normally the brain does not age as fast as the rest of the body.
What we need to look at is what might cause this to happen. If we start with the assumption from my previous posts that aging results from the mutation of mitochondrial DNA (mtDNA) then we need to find something that prevents the mutation of mtDNA in the brain that does not operate elsewhere. That is easy to find. It is the existance of Cerebro Spinal Fluid CSF. When people go to sleep the blood pressure goes down and CSF becomes more available to the brain. Within CSF there is a high concentration of melatonin and melatonin protects mtDNA from damage. The pineal gland generates melatonin as part of the daily circadian cycle and injects some of that directly into the CSF. Hence we know why the brain is more protected from mtDNA damage (aging) than the rest of the body. The question then is why people with PD find that their brain is less protected.
It is also quite clear that there is evidence that the level of melatonin in the third ventricle of people with PD is lower than people who don't have PD.
The table below is from this article Significance of High Levels of Endogenous Melatonin in Mammalian Cerebrospinal Fluid and in the Central Nervous System
Summary of the Presumed Physiological Concentrations of Melatonin in Human CSF
| Reference | Year | Melatonin (pg/ml) | |||||
|---|---|---|---|---|---|---|---|
| Collection Time | Collection Site | Ages (Yr) | Method | Melatonin Form | |||
| Rousseau et al. [54] | 1999 | 08:00-09:00h | Lumbar cistern | 25.3 ± 4.5 | RIA | Free | 32.5 ± 25.5 |
| Rousseau et al. [54] | 1999 | 08:00-09:00h | Lumbar cistern | 25.3 ± 4.5 | RIA | Free | 32.5 ± 25.5 |
| Rousseau et al. [54] | 1999 | 08:00-09:00h | Lumbar cistern | 25.3 ± 4.5 | RIA | Free | 32.5 ± 25.5 |
| Liu et al.[31] | 1999 | 1-12 h after death | Ventricular | 76 ± 1.4 | RIA | Free | 273 ± 47 |
| Rizzo et al. [53] | 2002 | Night | Lumbar cistern | N/A | HPLC | Free + bound | 28.6 ± 7.0 |
| Rizzo et al. [53] | 2002 | Night | Lumbar cistern | N/A | HPLC | Free + bound | 28.6 ± 7.0 |
| Zhou et al. [72] | 2003 | 1-12 h after death | Ventricule | 76 ± 2 | RIA | Free | 280 ± 64 |
| Longatti et al.[34] | 2004 | Day time | Third ventricule | N/A | N/A | Free | 542 |
| Longatti et al. [35] | 2007 | Day time | Third ventricule | 60.3 ± 17.9 | HPLC | Free + bound | 442 ± 45 |
| Seifman et al. [34] | 2008 | 09:00h | ventricule | 30-74 | ELISA | Free | 1.47 ± 0.35 |
| Leston et al.[30] | 2010 | 08:10-11:10 h | Third ventricule | 26-68 | RIA | Free | 8.69 ± 2.75 |
What is not immediately obvious from this table is that the last line (Leston et Al) is from Patients with PD. It demonstrates a much lower level of melatonin in the third ventricle.
There are two possible causes for this:
a) A higher proportion goes into serum than in non-PD patients
b) Less melatonin is generated.
It does not immediately matter although in rectifying this may lie part of the solution to PD. What matters is that brain cells are getting less melatonin than in non-PD people. Hence their mitochondrial DNA has less protection. This to me seems to be the cause of the accelerated brain aging that is seen with PD.
nb the penultimate line is Traumatic Brain Injury.
Other possibly relevant research
Mitochondrial DNA damage triggers spread of Parkinson’s disease-like pathology In the field of neurodegenerative diseases, especially sporadic Parkinson’s disease (sPD) with dementia (sPDD), the question of how the disease starts and spreads in the brain remains central. While prion-like proteins have been designated as a culprit, recent studies suggest the involvement of additional factors. We found that oxidative stress, damaged DNA binding, cytosolic DNA sensing, and Toll-Like Receptor (TLR)4/9 activation pathways are strongly associated with the sPDD transcriptome, which has dysregulated type I Interferon (IFN) signaling. In sPD patients, we confirmed deletions of mitochondrial (mt)DNA in the medial frontal gyrus, suggesting a potential role of damaged mtDNA in the disease pathophysiology. To explore its contribution to pathology, we used spontaneous models of sPDD caused by deletion of type I IFN signaling (Ifnb–/–/Ifnar–/– mice). We found that the lack of neuronal IFNβ/IFNAR leads to oxidization, mutation, and deletion in mtDNA, which is subsequently released outside the neurons. Injecting damaged mtDNA into mouse brain induced PDD-like behavioral symptoms, including neuropsychiatric, motor, and cognitive impairments. Furthermore, it caused neurodegeneration in brain regions distant from the injection site, suggesting that damaged mtDNA triggers spread of PDD characteristics in an “infectious-like” manner. We also discovered that the mechanism through which damaged mtDNA causes pathology in healthy neurons is independent of Cyclic GMP-AMP synthase and IFNβ/IFNAR, but rather involves the dual activation of TLR9/4 pathways, resulting in increased oxidative stress and neuronal cell death, respectively. Our proteomic analysis of extracellular vesicles containing damaged mtDNA identified the TLR4 activator, Ribosomal Protein S3 as a key protein involved in recognizing and extruding damaged mtDNA. These findings might shed light on new molecular pathways through which damaged mtDNA initiates and spreads PD-like disease, potentially opening new avenues for therapeutic interventions or disease monitoring.
Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson’s disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, and iron chelators, have failed in disease-modification clinical trials. In this review, we summarize the cellular determinants of mitochondrial dysfunction, including impairment of electron transport chain complex 1, increased oxidative stress, disturbed mitochondrial quality control mechanisms, and cellular bioenergetic deficiency. In addition, we outline mitochondrial pathways to neurodegeneration in the current context of PD pathogenesis, and review past and current treatment strategies in an attempt to better understand why translational efforts thus far have been unsuccessful.
Edit 27/2/25
Obviously night time levels of melatonin are higher. ChatGPT gives a level of between 500 and 3,000 pg/ml.
There has been quite a bit of burbling in the medical profession about serum levels of melatonin that result from supplementation. Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults and Chronic Administration of Melatonin: Physiological and Clinical Considerations are both papers that look at this.
Summarising the research, however, if people take something like 0.1 to 0.5mg then the peak serum level is in the normal range. If people take 4mg the peak serum level is around 4000 pg/ml. There is a problem, however, which is that normally during the night the brain is exposed to something like 3,000 pg/ml and during the day looking at the above table something like 300 pg/ml. Hence if the priority is to replicate the brain's exposure to melatonin then a single dose providing a peak 4000 pg/ml comes nowhere close to the 3,000 mean figure as the half life is around 30 mins. It is obviously hard to know what is going on in the CSF during the night, but replicating physiological figures for melatonin in the brain requires superphysiological figures for the serum.
There are rightly held concerns as to what effects melatonin may have in higher levels in serum and that is not entirely clear. It does appear to hold back puberty (in my view by preventing mtDNA damage). It may increase levels of some molecules such as SHBG. However, if the objective is to concentrate on improving and protecting brain cells having superphysiological levels of melatonin looks right.
Edit: 13/3/25
Circadian secretion pattern of melatonin in Parkinson's disease is a paper I found after writing the above. This paper looks only at serum levels of melatonin, but it finds that the pattern of melatonin peak in serum peaks earlier in people with PD. That fits with the normal pattern of melatonin secretion being that a material amount first goes into the CSF and then comes out of CSF into serum. Hence people with PD where the melatonin goes into serum rather than CSF will have an earlier peak.
Looking for that paper I found Circadian Melatonin Rhythm and Excessive Daytime Sleepiness in Parkinson Disease. This paper found basically less melatonin. That, of course, would have similar effects.
There is also Serum melatonin is an alternative index of Parkinson's disease severity. This may seem counterintuitive, but if then pineal's melatonin production is constant then serum levels being higher means that less melatonin is available for the brain. Hence you would expect serum levels to indicate severity for a normal pineal production.
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