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Phosphotau Clearance via Fasting?

alzheimers phosphotau tau hyperphosphorylated caloric restriction fast fasting autophagy macroautophagy

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#1 resveratrol_guy

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Posted 25 July 2015 - 03:19 PM


While awaiting tau vaccine, I've considered a number of alternative ways in which to reduce existing phosphotau, in the absence of which it be possible to arrest Alzheimer's disease using current drugs or dietary interventions.

One obvious approach is some form of fasting. While it's well known that caloric restriction (CR) and intermittant fasting (IF) are beneficial to a wide variety of health parameters, they operate very differently in this regard. In particular, whereas CR seems to thwart amyloid and phosphotau deposition, IF appears to allow the brain to function better despite having little effect on such pathology. In other words, IF seems to seems to mimic the ketogenic diet as applied to established AD. But perhaps this is an erroneous conclusion based on differences in caloric consumption between the CR and IF groups in the former linked study: "Mice on the CR diet were provided an amount of food equal to 60% of that consumed by mice in the 3xTgAD [unrestricted control] group (40% caloric restriction). Mice on the IF diet were deprived of food for 24 h every other day." In other words, calorically equivalent CR and IF might be indistinguishable from the perspective of brain plaque; I have no informative data.

In a perfect world, we'd all be on CR in order to enjoy its many benefits on various health parameters, reduced brain plaque deposition being one of many. But CR is hard to follow, and leaves us more susceptible to musculoskeletal injury, excessive bleeding, and unexpected disruptions to eating ability (for example, infectious disease). On the plus side, we know that it upregulates autophagy, which in theory should clear intracellular junk like lipofuscin -- not merely thwart its formation in the first place. OTOH, does it also upregulate macroautophagy, that is, the clearance of extracellular junk by macrophages? Macroautophagy is absolutely necessary in order to clear cis-phosophotau, which is the gasoline that fuels the AD chain reaction.

If this works, then by implication, we don't need to worry much about maintaining CR. Instead, we can simply conduct a protracted water fast in order to maximize macroautophagy, wait for the plaque to clear, and then slowly refeed, perhaps under medical supervision. Obviously we can't clear 100% of the plaque, but what, in fact, would the upper limit be? If it were "enough to be useful", then we could simply fast, say, once a year, instead of partially fasting all the time (which is what CR amounts to, and why it's so frustrating to sustain).

Nevertheless, my default assumption is that macroautophagy isn't affected by CR at all. I mean, why should our microglia suddenly figure out how to clear phosphotau just because we're hungry? I don't think they would, because surviving CR in the wild is all about deeply engrained evolutionary pathways to cope with energy deficits -- not specific epitope targetting of junk proteins which exist outside the realm of cellular metobolism. What we need is a neon sign pinned to the debris piles, flagging them for collection, which in practical terms means that we need the monoclonal antibody in tau vaccine.

There is even some question regarding the use of CR to prevent AD in the first place: While CR might be superior to ketogenic diet for prevention of AD, the father of modern CR, Dr. Roy Walford, warned against its use in individuals suffering from neurodegenerative disease in some specific cases such as ALS. Unfortunately, I can't find his full explanation, which might well not apply to AD; tragically, he died of ALS himself.

So my question is: to what extent is what type of fasting capable of clearing existing extracellular phosphotau, as opposed to merely delaying its accumulation?
 


Edited by resveratrol_guy, 25 July 2015 - 03:24 PM.

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#2 tunt01

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Posted 01 August 2015 - 01:22 PM

The three patterns of eating/fasting that I am aware of which are practiced by actual scientists who study autophagy/CR are:

 

- Ana Marie Cuervo (Einstein Medical).  Eats breakfast, skips lunch and eats dinner.

 

- Mark Mattson (Neuroscientist NIH/NIA).  Eats 1 meal a day (dinner) 5 times a week and 2 times on weekends (lunch/dinner).

 

- Valter Longo (Univ. S. Cali).  Fasts 3-4 days straight at a time.  I'm not sure the frequency (every 6 months etc.)? off the top of my head.

 

I personally eat twice a day within about a 6 hour window (11 AM  and 5 PM).

 

 

I wish I had a more thoughtful answer for you.  But I would imagine it is very hard in these studies to separate the rate of phosphotau formation with improved clearance.


Edited by prophets, 01 August 2015 - 01:34 PM.


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#3 lourdaud

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Posted 01 August 2015 - 03:21 PM


I personally eat twice a day within about a 6 hour window (11 AM  and 5 PM).

 


Do you get low blood sugar before or in between meals when eating like this?



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#4 tunt01

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Posted 01 August 2015 - 04:01 PM

 

Do you get low blood sugar before or in between meals when eating like this?

 

 

No.  If anything, I think I have a problem with excessive gluconeogenesis and slightly elevated glucose, poor fasting glucose levels as seen in some people who practice CR.



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#5 resveratrol_guy

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Posted 02 August 2015 - 03:34 AM

The three patterns of eating/fasting that I am aware of which are practiced by actual scientists who study autophagy/CR are:

 

- Ana Marie Cuervo (Einstein Medical).  Eats breakfast, skips lunch and eats dinner.

 

- Mark Mattson (Neuroscientist NIH/NIA).  Eats 1 meal a day (dinner) 5 times a week and 2 times on weekends (lunch/dinner).

 

- Valter Longo (Univ. S. Cali).  Fasts 3-4 days straight at a time.  I'm not sure the frequency (every 6 months etc.)? off the top of my head.

 

I personally eat twice a day within about a 6 hour window (11 AM  and 5 PM).

 

 

I wish I had a more thoughtful answer for you.  But I would imagine it is very hard in these studies to separate the rate of phosphotau formation with improved clearance.

 

Thank you for that. I wasn't even dreaming of human data. I was just hoping that someone discovered that fasting of any kind enhanced cis-phosphotau clearance. Heck, even a fruitfly study would be informative. I suppose the question could be posed more generally: is there any method within the realm of current technology (i.e. without tau vaccine) whereby humans can enhance microglial activity which targets extraneuronal misfolded tau? Astonishingly, this does seem to occur in rats treated with intranasal NGF (Figure 8E-G). (Nerve "growth" factor is so understated; it's an environmental remediation signalling molecule.) I presume that the mechanism is microglial activation, but it might be something else entirely. But that would be beyond the current technological horizon, as there is no protocol established in humans, let alone long term study data.

 

Hmm... I wonder if we could disassemble cis-phosophotau shortly after transcription using siRNA. Just a thought. This might be easily done in vitro, with actual delivery being the hard part.

 

@loudaud: You don't need to worry about low blood sugar if you're running off ketones, at least, if Dominic D'Agostino is corrent. (Granted, this does not apply to 99% of people.)

 


Edited by resveratrol_guy, 02 August 2015 - 03:52 AM.






Also tagged with one or more of these keywords: alzheimers, phosphotau, tau, hyperphosphorylated, caloric restriction, fast, fasting, autophagy, macroautophagy

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