Patients with PD exhibited an alteration in the levels of the clock genes - What time should you like your Broccoli Tea?

[Bolt_Upright]

Art shared a link to this Melatonin document the other day: Effect of melatonin administration on the PER1 and BMAL1 clock genes in patients with Parkinson’s disease sciencedirect.com/science/a...

This caught my eye: "Patients with PD exhibited an alteration in the levels of the clock genes: MEL increased the levels of BMAL1, but the PER1 levels remained unchanged."

"At the molecular level, expression of the BMAL1 and PER1 clock genes regulates this cycle through negative feedback. The BMAL1 forms a heterodimer with CLOCK, which allows for transcription of the PER1, PER2, CRY1, and CRY2 genes when binding to its E-box, and therefore the translation to their respective proteins: PER and CRY form a dimer, which, when phosphorylated, can enter the nucleus and inhibit the transcription of BMAL and CLOCK [4]. The PER1 has a wide oscillation, and BMAL1 is the central regulator of the biological clock in the SCN. In patients with PD, expression of the clock genes is altered [5,6]."

THIS IS WHERE I TAKE A LEFT TURN INTO SULFORAPHANE LAND:

NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in Mus musculus 2018 ncbi.nlm.nih.gov/labs/pmc/a... "We show here that chemical activation of NRF2 modifies circadian gene expression and rhythmicity, with phenotypes similar to genetic NRF2 activation. Loss of Nrf2 function in mouse fibroblasts, hepatocytes and liver also altered circadian rhythms, suggesting that NRF2 stoichiometry and/or timing of expression are important to timekeeping in some cells. Consistent with this concept, activation of NRF2 at a circadian time corresponding to the peak generation of endogenous oxidative signals resulted in NRF2-dependent reinforcement of circadian amplitude." (ANYBODY ELSE NOTICE THEY MENTIONED THE TIMING OF ACTIVATING THE NRF2?)

Clock Protein Bmal1 and Nrf2 Cooperatively Control Aging or Oxidative Response and Redox Homeostasis by Regulating Rhythmic Expression of Prdx6 2020 ncbi.nlm.nih.gov/labs/pmc/a... "we report for the first time that in lens/LECs, Nrf2, and its target genes, including Prdx6 expression and activities, are regulated by clock protein Bmal1, similar to other cell types and genes described previously [5]. We found Prdx6 to be a circadian protein that has rhythmic expression, which can be related to oxidative load and cellular requirements. Knockdown experimentation with Bmal1 results in increased ROS accumulation and reduced levels of antioxidant genes, along with their regulator Nrf2. Gain- and loss-of-function studies showed Bmal1 to be a major component for activation of Nrf2/Prdx6-mediated cellular protection."

Sulforaphane reactivates cellular antioxidant defense by inducing Nrf2/ARE/Prdx6 activity during aging and oxidative stress 2017 ncbi.nlm.nih.gov/labs/pmc/a... "A Nrf2 activator, Sulforaphane (SFN), augmented Prdx6, catalase and GSTπ expression in dose-dependent fashion, and halted Nrf2 dysregulation of these antioxidants. SFN reinforced Nrf2/DNA binding and increased promoter activities by enhancing expression and facilitating Nrf2 translocalization in nucleus. Conversely, promoter mutated at ARE site did not respond to SFN, validating the SFN-mediated restoration of Nrf2/ARE signaling. Furthermore, SFN rescued cells from UVB-induced toxicity in dose-dependent fashion, which was consistent with SFN’s dose-dependent activation of Nrf2/ARE interaction. Importantly, knockdown of Prdx6 revealed that Prdx6 expression was prerequisite for SFN-mediated cytoprotection. Collectively, our results suggest that loss of Prdx6 caused by dysregulation of ARE/Nrf2 can be attenuated through a SFN, to combat diseases associated with aging."

The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis 2014 genesdev.cshlp.org/content/... "Daily changes in the environment (cycles in light/darkness, feeding, rest–activity, and temperature fluctuations) inevitably expose the mammalian cells and tissues to periodic challenges, including oxidative insults from environmental toxins/pollutants and endogenously produced reactive metabolites as products of respiration (Patel et al. 2014)." AND "Current therapy that aims to slow down the progression of fibrotic diseases is often ineffective (Liu and Gaston Pravia 2009); our study implicates the need for considering circadian timing mechanisms, including timed drug administration (chronopharmacology) (Levi and Schibler 2007)."

I guess they have always said "timing is everything".

[Bolt_Upright]

Circadian Time: By convention, circadian time 0 (CT 0) is defined as the initiation of activity in a diurnal organism. Likewise, CT 12 is defined as the initiation of activity in a nocturnal organism.

[SallySue2 in reply to Bolt_Upright]

In layman’s language, please!!

[Bolt_Upright in reply to SallySue2]

Apologies Sally.

- I take sulforaphane every other day to boost NRF2 and reset a bunch of genes. I do this using broccoli sprout tea.

- I am learning that some of the gene NRF2 resets are clock genes. And that clock genes are messed up in PwP.

- AND I am learning that sulforaphane may successfully reset these clock genes, AND I think I am learning that the timing of the sulforaphane, in relationship to the circadian clock, is important to the effectiveness of the sulforaphane to reset these clock genes.

Okay, that is as far as I got. I have the question: What is the best time of day to take sulforaphane to reset the clock genes?

I don't have the answer. I am trying to figure it out with my high school educated brain.

[SallySue2 in reply to Bolt_Upright]

Thank you for your response!!! I’m a grad of Michigan State and not one word of your post made sense lol

[Bolt_Upright in reply to SallySue2]

This is the key point I am working on: "Consistent with this concept, activation of NRF2 at a circadian time corresponding to the peak generation of endogenous oxidative signals resulted in NRF2-dependent reinforcement of circadian amplitude."

"activation of NRF2 at a circadian time corresponding to the peak generation of endogenous oxidative signals"

"circadian time corresponding to the peak generation of endogenous oxidative signals"

I think you are helping us get closer! The question is becoming clearer.

[SallySue2 in reply to Bolt_Upright]

I guess I don’t have a doctorette so this makes no sense to me . Sorry. But if you understand… that’s all that matters!!

[KERRINGTON in reply to Bolt_Upright]

Can you share the broccoli tea recipe please ! Thanks

[Bolt_Upright in reply to KERRINGTON]

There are safety concerns with Sulforaphane. Please do your research.

Personally, I am using Koyah freeze dried broccoli sprouts. You can read about them here:

healthunlocked.com/cure-par...

The recipe is the 11th reply in the thread.

You will want white or yellow raw mustard seeds. I use this: amazon.com/gp/product/B00LX...

This is the thermometer I use. It is awesome! amazon.com/gp/product/B07YF...

Good luck.

[enjoy2013 in reply to Bolt_Upright]

May I ask, what do you mean it is awesome? Is it tasty? Did your symptoms disappear?I'd add that you can contact papers' authors by email to ask for clarification. I even to ask them to share with you the full text. They might be happy to.

[Bolt_Upright in reply to enjoy2013]

I said that thermometer was awesome. It is my first meat thermometer. It is cheap, it is digital, when you pull the probe out it turns on by itself, you push a little button and the display lights up, it is fast, it is waterproof so easy to rinse off, when you fold the probe back it turns off, and it has a magnet on the back so I leave it stuck to the fan hood over my stove. I love it.

I have not been diagnosed with PD. I have REM Sleep Behavior Disorder, which I am trying to prevent from turning into PD. Based on my tracking, my RBD has not gone away, but it is milder (but I do a lot of things).

And good point. I do contact authors of papers when needed. They often reply and are almost always very nice. I have started to reach out to get the answer on the best time to take sulforaphane to reinforce the circadian clock.

Thanks! Reach out any time if you would like to brainstorm.

[Bolt_Upright]

Circadian clock

Circadian

[Bolt_Upright]

More circadian

Circadian

[wriga]

Bolt, you have lifted the lid on a real can of worms here. The synchronized interactions between ROS levels, natural Nrf2 activation and markers of the circadian cycle are quite remarkable. The paper by Wible & al. is full of information but is totally indigestible. They quote in the abstract: "activation of Nrf2 at a circadian time corresponding to the peak generation of endogenous oxidative signals resulted in Nrf2-dependent reinforcement of circadian amplitude"

However, I cannot find in the text just when this "corresponding circadian time " is for humans. Where they just quoting a principle?

Another parameter to take into account is the degree of Nrf2 activation. "Overexpression of Nrf2 resulted in a reduced circadian amplitude and period length similar to the Keap1-/- cell line.

This is not surprising since overexpression of Nrf2 will generate antioxidant enzymes whose half-life is a few days, so considerably longer than the circadian cycle.

Overexpression of Nrf2 may therefore be good as a short-term measure to knock out oxidative stress, but by saturating the system with antioxidant enzymes, may also cause loss of the circadian cycle if continued for too long or at too high a level. This would increase daytime sleepiness and cause poor night time sleep.

We therefore need to find the right magnitude for which Nrf2 can be increased and just when to synchronise this with the natural circadian increase in Nrf2 to reinforce the circadian amplitude, whilst tackling oxidative stress more vigorously.

An additional problem is the lag between ingesting an activator of Nrf2 and its peak effect on Nrf2.

Once again we are faced with the problem of finding just the right dose. It's the Goldilocks dilemma. Not too little, not too much, ah, just right. But with the added condition; Not too soon, not too late, ah just the right time.

If you find just the right time, let me know.

[Bolt_Upright in reply to wriga]

Thanks wriga! I'm so glad it was not just me that found that paper indigestible.

Like you, I saw the quote "activation of Nrf2 at a circadian time corresponding to the peak generation of endogenous oxidative signals resulted in Nrf2-dependent reinforcement of circadian amplitude" in the abstract, and then I searched the document for more detail. Not only did I not find more detail, I found nothing about that topic at all.

On a different note: What if you could time your sulforaphane boost, and then an hour or two later negate the sulforaphane boost? Reduce the half-life?

[chartist in reply to wriga]

Albert,

Since melatonin is known to significantly activate Nrf2 and melatonin generally peaks in the area of 1 am to 4 am (in healthy people) and melatonin helps the body to maintain multiple circadian rhythms and melatonin promotes REM sleep and the body does significant repair work during REM sleep and daylight shunts pineal gland secretion of melatonin along with a reduction of activation of Nrf2, these seem like important clues in trying to replicate what the body has done very well naturally to hold PD in check when we were much younger and producing significantly more melatonin. With the very significant age related decline of melatonin and SCFAs, which increase melatonin in the gut , these all seem like clues to try and pinpoint that optimal timeframe you are in search of.

When you also consider the relationship of SCFAs with the regulation of Nrf2 and consider the age related decline of SCFAs, these seem like further clues worth considering in trying to gain the answers you seek.

Art

[wriga]

As far as I know, you cannot do that. Once you start the boost, it's irreversible, it runs its course. What does seem to be relevant to our case is that day and night time sleepiness are both non-motor symptoms. And at the low doses of the broccoli seed tea experiment, both were improved. The good responders were therefore unlikely to have been in the state of Nrf2 overexpression. In my experience, higher dosing does lead to poor sleep.

We should therefore also experiment with varying the timing of the dose.

It would be useful to know at what time thr natural circadian peak in Nrf2 occurs.

[Bolt_Upright in reply to wriga]

Well... for a rat the peak seems to be between 0 and 4: Mechanism of circadian regulation of the NRF2/ARE pathway in renal ischemia‑reperfusion

europepmc.org/backend/ptpmc...

The peak of NRF2 protein expression was between ZT0 and ZT4, with a trough between ZT12 and ZT16

So... if I was a rat, and I have been called one, and if ZT0 = 6 AM, then I probably want to have my broccoli sprout tea between 7 and 8 in the morning.

"A standard marker of time that is based upon the free-running period of an oscillation or rhythm. By convention, circadian time 0 (CT 0) is defined as the initiation of activity in a diurnal organism. Likewise, CT 12 is defined as the initiation of activity in a nocturnal organism."

NRF2 vs Circadian Clock

[Bolt_Upright in reply to Bolt_Upright]

But I can see Art's timing idea also. It looks like NRF2 bottoms out when the sun goes down, then starts climbing. MAYBE sundown would be the perfect time to goose the NRF2?

So we have narrowed it down to between 6 AM and 6 PM

[Bolt_Upright in reply to Bolt_Upright]

But rats are nocturnal! That flips the script.

[Bolt_Upright in reply to Bolt_Upright]

I guess the way they measure NRF2 at different times of day is based on disecting animals. That makes human data hard to come by. But I found this study with over 12,000 corpses, pnas.org/content/110/24/9950, and they had a valuable nugget:"The phasing of known circadian genes was consistent with data derived from other diurnal mammals."

We don't need human data. Just diurnal mammal data.

[Bolt_Upright in reply to Bolt_Upright]

mdpi.com/2073-4409/9/8/1861...

In conclusion, we identified, for the first time, that circadian clock protein Bmal1, along with Nrf2, cooperatively and simultaneously regulated Prdx6 transcription, as well as that both were essential for optimal expression of Prdx6 in LECs. We showed a link between Bmal1-Nrf2-antioxidant genes, specifically Prdx6, and their levels of expression in controlling ROS homeostasis (Figure 10). Additionally, we found that the cellular abundance of Bmal1 was prerequisite for elevating antioxidant defense to protect cells against aging or oxidative stress. Mechanistically, we discovered that Bmal1 physically and functionally bound to its responsive element in the Prdx6 promoter to regulate its transcription. We surmised that, like the Prdx6 gene, other antioxidant genes are also regulated. Our most significant finding was that Bmal1 regulated oxidative pathways in mouse LECs/lenses in vivo by regulating and resetting rhythmic expression of an antioxidant pathway to maintain lens homeostasis. However, further studies will be required to understand how clock is involved in the regulation of Nrf2-mediated antioxidant activity. Such research may open new opportunities for developing therapies in the treatment of diseases related to dysregulation of Bmal1, Nrf2, and antioxidants/Prdx6 in aging or oxidative stress.

[Bolt_Upright in reply to Bolt_Upright]

The wrinkling of time: Aging, inflammation, oxidative stress, and the circadian clock in neurodegeneration 2020 sciencedirect.com/science/a...

This document is the codex we have been looking for. The answers can be found through it (I think). It covers an amazing number of familiar concepts, all tied to the circadian clock.

[Bolt_Upright in reply to Bolt_Upright]

And this is also the codex!

Genomics of circadian rhythms in health and disease

genomemedicine.biomedcentra...

[wriga]

Hi Bolt,

I'm replying to you (and your other post today) here to try to keep the information in one place .

I have scanned the web, identified a lot of articles on this subject and printed out more than 30 that I'm slowly trying to understand. The subject is complicated for several reasons.

1) we 1 have a dominant central clock in the brain and subsidiary peripheral clocks in all organs and cells. These are all trying to work in a synchronized way.

2) Experiments on living humans or animals imply that the whole system is used. These are not many of these available. In vitro studies on specific cells and genetically modified cell lines are more common and more detailed, but real time input from the central clock is then severed. I simply do not know how much credibility we can give to the the conclusions of such studies.

3) Most studies are done on rodents which are nocturnal. In a simplified way you can just inverse the night/day periods for activity/sleep, but there's a complication in that light is the primary driver for the circadian cycle in humans via D1 dopamine receptors in specific cells in the retina especially sensitive to blue light during the active period which suppress the production of melatonin. This is not the case for nocturnal animals. Just investing the day/night timeline is too simple.

More to come....

[wriga in reply to wriga]

The potential impact of the circadian rhythm on PD is really quite remarkable. A whole bunch of things with relevance to PD seem to modulate the circadian rhythm or be affected by it.

What follows is based on my current understanding of the subject which is quite basic and certainly false in some areas. I reserve the right to change my mind on practically everything.

As far as I can work out, Nrf2 synthesis in neurons is driven by circadian clocks to match the circadian fluctuations in the production of reactive oxygen species during active and sleep phases. On that basis, Nrf2 peaks in the early morning for humans. Experiments on Nrf2 knock out mice (they don't have the Nrf2 gene) also show that the circadian clock needs Nrf2, but at the same time, overexpression of Nrf2 flattens the dynamic range of CR. This means that too little or too much Nrf2 are bad. We need just the right amount at just the right time. in return, dopamine modulates the circadian rhythm in the brain, partly through dopamine in the light-sensitive amacrine cells and through the influence of D1 receptors on PER2 expression.

Furthermore the amplitude of the circadian rhythm is compromised in Parkinson's patients, possibly through the reduction of dopamine in these light-sensitive cells and this is observed as a large reduction in the amplitude of the melatonin circadian cycle compared to non-PDs of the same age. This of course impacts the sleep cycle. It also indicates that the CR in PwPs is fragile and may be easily modified or disrupted.

Tyrosine hydroxylase (TH) also peaks in the beginning of the active phase which means that the rate-limiting enzyme in dopamine synthesis is directly matched to the circadian rhythm.

What strikes me in all this is that every pathway or process that might be involved in causing PD through oxidative stress and/or mitochondrial dysfunction (my favourite hypothesis) or in modifying disease progression by combatting these processes seem to be impacted by the circadian rhythm and vice versa

Consequently, any therapy to upregulate Nrf2 should take into account and possibly be synchronised to match the natural Nrf2 CR. Synchronised activation of Nrf2 will most likely amplify the circadian rhythm and maintain the waveform and phase, whereas out-of-phase activation will most likely interfere with the existing waveform, modify or shift the phase and could negatively impact the perceived response of Nrf2 to oxidative stress by adversely affecting the active/sleep cycle.

By chance I have been taking the broccoli seed tea in the morning, but maybe not early enough to match the natural Nrf2 cycle given the delays involved in the process.

If all this is true then we will have to rethink the whole issue of upregulating Nrf2 by broccoli seed tea or sprouts both in terms of timing and dose. Precise timing is likely to have an impact. This raises the question of the impact of slower absorption processes from broccoli sprouts for example. Spreading out the increase in Nrf2 over a wide timescale by absorption through GI will likely create a bumpy out-of-phase effect. We also have to consider the half-lives of the antioxidant enzymes, some of which are more than 12 hours.

I don't think we will get a clear enough understanding of this subject to make informed decisions without input from specialists. A couple of the authors of the paper cited by Bolt are also colleagues of Prof Jed Fahey. I have emailed him to see if we can get some clarification from them.

[Bolt_Upright in reply to wriga]

Brilliant wrigga. The only thing I might quibble with is "This means that too little or too much Nrf2 are bad". I would think too much is bad. Too little would just not be optimum.

You also raised another question when mentioning how the preparation time throws off your ability to hit a mark in time:

How can we pre-make the sulforaphane drink? If I could make it and keep it in a bottle I could have a shot every morning at the same time.

I read an article where they made a sulforaphane drink and used it in a trial. I need to find that article.

[wriga in reply to Bolt_Upright]

Hi Bolt,When is say too little is bad, I mean the absolute value, not just that produced by external action.

Your question about preparation in advance of ingestion is a good one. Jed Fahey insists that sulforaphane in aqueous solution is unstable, but I don't have information on the rate of decomposition. Maybe you can find it in one of publications.

I'm just reading a publication about sleep dysfunction in early stage PD patients. The profile for Melatonin is reduced and that for Cortisol is increased but there is no phase shift.

CR Clock gene expression is a mess in PwPs.

The forward driver of CR is flat in PwPs, whereas it peaks strongly at 12 midnight (0h00) in non-PD people.

On the other hand, the negative drivers, Per2 and RevErba have higher night time amplitude, higher at 3am and lower at 9am compared to healthy people.

dx.doi.org/10.1001/jamaneur...

[Bolt_Upright in reply to wriga]

I thought we were getting close but the deeper you dig the darker it gets.

"One possible explanation for altered Bmal1 expression in PD is that dopamine is capable of regulating BMAL1/CLOCK heterodimer activity,31 meaning that dopamine deficiency might directly affect this central component of the molecular clock. Alternatively, damage to the SCN itself could be responsible for clock gene dysregulation. However, the precise nature and extent of circadian rhythm disruption in PD needs to be investigated further because sleep may be crucial in the clearance of degradation products of neural activity that accumulate during wakefulness,32 and circadian disruption may accelerate PD-related pathology."

On the sulforaphane beverage, I was thinking of boiling it for the 5 minutes but not adding the mustard. Then in the morning heating up a little water, adding a shot of my mixture, and adding a pinch of mustard. Then giving it 10 minutes before drinking it.

[Bolt_Upright in reply to wriga]

Hi wrigga, I reached out to the person who did the rat study showing peak NRF2 between ZT0 and ZT4 and learned some stuff:

1: They have not explored the circadian rhythm of human Nrf2.

2: Their view is that humans have great individual differences. Many factors will affect the circadian rhythm of humans including light and diet. So it may be too difficult to explore the rhythm expression of human Nrf2. And the protein expression in different tissues is also different. For instance there are also great differences in the rhythmic expression of Nrf2 gene between hippocampus and kidney.

3: In therir previous research, a total of ≥10 days prior to experimentation, the animals were housed in a strict 12-h light/dark cycle [The light time is 7 a.m.–7 p.m. (zeitgeber time (ZT) 0-ZT12), and the dark time is 7 p.m.–7 a.m. (ZT12-ZT24)].

Point 3 tells me that the whole ZT0 to ZT4 window is not an absolute, but is a reference from an artificially controlled start light point.

More to come.

[chartist in reply to wriga]

Albert,

Just a thought.

What if it turns out that the timing and rate of delivery and control of Nrf2 are too difficult to be controlled by us such as might be the case with H2S? A little at just the right time, place and amount can be quite beneficial to our health, but too little or at the wrong time and it is ineffective. Too much and it can then be toxic. There is a sweet spot and time for proper and effective delivery and the body can perform this precise balancing act, but maybe we can not.

When we were younger, the body was still able to perform this balancing act effectively, but with age and disease progression, not so much.

The gut biome, via the interplay of short chain fatty acids, melatonin and maintenance of gut integrity are a main controlling feature for Nrf2 and when we were younger, our bodies made more of both that helped to maintain gut integrity and PD was held in check or progression was at a very slow rate, but with the age related decline of SCFAs and melatonin resulting in loss of gut integrity and an increase in gut permeability as well as the slow advancement of the disease progress which further decreased availability of SCFAs and melatonin and now decreased control of Nrf2 activity, allowing the disease to progress much more freely and at an advanced rate.

FMT hints that repair of the gut microbiome which includes increased SCFAs and melatonin production as well as increased and better controlled Nrf2 activity can potentially improve PD symptoms. Perhaps increasing SCFA producing bacteria to increase SCFAs themselves, which in turn increase melatonin production and melatonin receptors as well as improve the gut barrier function via improving the mucosal barrier, epithelial integrity and tight junction integrity, ultimately allowing increased control and activity of Nrf2 as well as decreased inflammation and oxidative stress. To say that a little differently, try and reset the gut microbiome to a place where it was better able to maintain control of PD.

The following study illustrates how SCFAs exert control over Nrf2 for multiple areas of the body including neurons :

ncbi.nlm.nih.gov/labs/pmc/a...

It doesn't seem possible for us to manually do what SCFAs are doing. It seems that the body is such a complicated and intricate life form that even activities that seem straightforward and simple can be very complex with multiple checks and balances that we can not easily replicate.

We know that SCFAs, melatonin, melatonin receptors and Nrf2 activation and control are reduced with age and further reduced with the disease. Replenishing the SCFAs as well as the bacteria that produce them seem like a worthwhile avenue of exploration for PD and a multitude of other diseases and health conditions. I think the needed knowledge base may already be there, but integration of that data is a bit light.

Art

[Bolt_Upright in reply to chartist]

Well done Art!

In a synchronicity, I've spent much of the evening debating keeping Mannitol in my stack. But Mannitol does seem to boost Butyrate and Propionate production, tandfonline.com/doi/pdf/10...., so that is a point in Mannitol's favor for sure.

[Bolt_Upright in reply to Bolt_Upright]

But then there is this. I may need another path to boost SCFAs:

Dietary sorbitol and mannitol: food content and distinct absorption patterns between healthy individuals and patients with irritable bowel syndrome pubmed.ncbi.nlm.nih.gov/239...

"Conclusions: Increased and discordant absorption of mannitol and sorbitol occurs in patients with IBS compared to that in healthy controls. Polyols induced gastrointestinal symptoms in patients with IBS independently of their absorptive patterns, suggesting that the dietary restriction of polyols may be efficacious."

Having IBS slightly raises a person's risk of getting PD. 44% increase in risk nature.com/articles/s41531-...

More than constipation - bowel symptoms in Parkinson's disease and their connection to gut microbiota pubmed.ncbi.nlm.nih.gov/288...

"Results: Symptoms that were IBS-like were significantly more prevalent in PD patients than in controls (24.3% vs. 5.3%; P = 0.001). Criteria for functional constipation were met by 12.2% of PD patients and 6.7% of controls (P = 0.072). PD patients with IBS-like symptoms had more non-motor symptoms and a lower faecal abundance of Prevotella bacteria than those without IBS-like symptoms."

But just because PD makes it more likely you have IBS, and Mannitol makes it more likely you will get IBS, does that mean you should be so determined not to have IBS that you bypass Mannitol even though it might boost SCFAs?

[chartist in reply to Bolt_Upright]

Bolt,

Declining SCFAs and the bacteria that produce them are something we know are seen with age and even more so in PD and other age related diseases and we also know that they can be increased to levels seen in are younger days through various means. It doesn't require tightly controlled timing or amounts and SCFAs, based on available studies seem to stimulate healthful mechanism throughout the body including melatonin and melatonin receptors as well as Nrf2 activation and control.

Replacing depleted SCFA producing bacteria or stimulating the system to produce more SCFAs seems like something we can do and there are many things that do this, but we don't yet know which are the most potent inducers of SCFAs or SCFA producing bacteria.

Art

[wriga]

Bolt, Art,

The interactions of the circadian rhythm with the Nrf2 cycle is just one example of how we are dealing with a complex system dysfunction.

SCFAs and gut bacteria are another branch of the problem and I think Art may be right,

It may be easier to nudge the Nrf2 cycle in the right direction through improving the gut bacteria profile than by trying to hit it head on which will automatically engage negative feedback loops to counter the movement.

However we should be aware that the cycle exists and activating Nrf2 in a way which opposes the cycle may be counterproductive in terms of the CR cycle even though it may be good to counteract Oxidative stress.

I think it might all depend on the magnitude of each individual dysfunction. If Oxidative stress and mitochondrial dysfunction is running out of control, we have dysfunctional neurons which are losing branches they cannot maintain. Think of this as a tree during a hot summer drought. We have to water it and cool it down whether it's day or night. For neurons this requires directly boosting Nrf2 irrespective of the CR phase.

Once that is done, I believe that we will have functionality working neurons with the physical damage of broken or dead branches (axons). We want to give them the best chance to work optimally and if possible to grow new branches. We want to keep oxidative stress under control which may mean a much more modest activation of Nrf2, and at the same time respect the CR phase.

My feeling is that when oxidative stress and mitochondrial dysfunction are running wild, modifying the SCFA profile may be insufficient to do the job, but could be useful as a maintenance strategy once this problem is resolved.

[Bolt_Upright in reply to wriga]

This whole situation makes me wonder what young people taking sulforaphane are doing to their circadian rhythms and their health.

[Bolt_Upright]

Taurine does a good job at resetting the circadian rhythm! I've been taking it for quite a while now. healthunlocked.com/cure-par...

[Bolt_Upright in reply to Bolt_Upright]

And with Taurine, it does not matter what time you take it: Mice were allowed free access to food and water and maintained a 12 h light–dark cycle at 24 °C and constant humidity in soundproof cages.

Taurine Treatment Modulates Circadian Rhythms in Mice Fed A High Fat Diet 2016 ncbi.nlm.nih.gov/labs/pmc/a...

[Bolt_Upright]

I have been studying the circadian rhythm: Light and diet affect the circadian rhythm. I have learned that light affects the SCN circadian rhythm and diet affects the circadian rhythm of the cells in the body. I have started eating only during the sunlight hours, as I read that eating outside of daylight hours can put your cellular circadian rhythm out of sync with the SCN. I am also getting up at dawn, walking outside in the morning, and wearing blue blocker glasses after sundown.

I still have not determined the best time to take sulforaphane, but I am starting to think sulforaphane won't impact the SCN circadian rhythm.

[Bolt_Upright]

I have been studying the circadian rhythm: Light and diet affect the circadian rhythm. I have learned that light affects the SCN circadian rhythm and diet affects the circadian rhythm of the cells in the body. I have started eating only during the sunlight hours, as I read that eating outside of daylight hours can put your cellular circadian rhythm out of sync with the SCN. I am also getting up at dawn, walking outside in the morning, and wearing blue blocker glasses after sundown.

I have decided to take the Sulforaphane in the morning as the circadian rhythm is on the rise (A) and go back to taking my NAC (plus Taurine) at night as the circadian rhythm is on the decline (B).

circadian rhythm