87 replies to this topic

[pone11]

Antibiotics and fasting

I posted this idea a couple of days ago perhaps in a wrong thread --simply cause that's where conversation came up-- but I am really interested in your opinion about my hypothesis, which has been ripening in my head for the past several years. The idea is that by combining an antibiotic therapy with fasting one can greatly increase the efficiency of fasting as a health improvement method.

This idea was based not so much on studies, even though there is plenty on autophagy and pathogens in cell culture already... The first hint I got was years ago when I noticed that sarcoidosis was cured in Russia with series of long fasts and the same disease was treated with antibiotics in Marshall protocol in the US -?! It intrigued me no end that such vastly different methods could cure what is otherwise touted as an "incurable autoimmune" disease. Also, due to some personal history, I have never had faith in "autoimmune" paradigm, having been the follower of the pathogen etiology of all diseases (aside from obvious poisonings, trauma and genetic mishaps, of course).
 

 

Head over to the Marshall Protocol site and ask the admins there if they have any data on combining pulsed antibiotics with fasting?  It's a great idea.

Edited by pone11, 11 May 2016 - 09:22 AM.

[pone11]

 

And my interest in antimicrobial peptides has nothing to do with Marshal protocol. I know about it since my long interest in antibiotics, but this is the first time I hear about AMPs in conjunction with his protocol -? Is it the latest development? I have not been to his site in a couple of years.

AMPs were a buzzword in immunology several years ago. When I first heard about them, I could not get enough and read everything. They opened up my eyes on what is immunity. And I suggest you study them for what they are, apart from whatever theories. Immunity starts with an eukaryotic cell and AMPs. The same is with metabolism in various diets. If you want to understand it, you start with the metabolism of a fast and then build on it.

 

 

Besides fasting, are you doing anything to stimulate AMP production?

 

Are you sure that this AMP production is independent of the AMPs created by the vitamin D receptor?  Marshall's point is that the bacteria and viruses disable the VDR by occupying sockets that 1,25-dihydroxyvitamin-D would occupy to activate it.  That's how they become long term parasites in the cell, by suppressing AMP production and the innate immune system.

 

One of the diagnostics that Marshall looks at is high levels of 1,25-dihydroxyvit-d, which he feels might be caused by the body upregulating this steroid in order to activate the VDR. But since the bacteria fill the VDR sockets the 1,25 levels stay permanently high.

 

Measuring 1,25 is problematic since it tends to fluctuate a lot.

Edited by pone11, 11 May 2016 - 09:24 AM.

[xEva]

Head over to the Marshall Protocol site and ask the admins there if they have any data on combining pulsed antibiotics with fasting?  It's a great idea.

I was there recently, after many years. They now require to register to read the forums, which used to be mostly open. But years ago I saw that they discourage fasting. They  also discourage supplements. That was years ago. Who knows what the "protocol" consists of now. They started with pulsed antibiotics, but then cancelled them and, last time I checked, relied entirely on benicar and vit D avoidance, though it's hard to say if this new, antibiotic-free method is quite as good as the old.
 
My personal opinion on this is that they would be free from their dieseases in less than a year (instead of many long years!) if only they combined fasting with antibiotics.

 

Besides fasting, are you doing anything to stimulate AMP production?

 

 

This is the first time I hear that fasting simulates antimictobial peptides production. You have a ref for this? 

 

Re the other part of your question, production of AMPs  is triggered by pattern-recognition receptors that sense characteristic microbial proteins, be it a part of bacterial cell wall, a specific bacterial toxin, or something else, that tells of a presence of a microbe.

 

 

Edited by xEva, 11 May 2016 - 04:14 PM.

[pone11]

 

Head over to the Marshall Protocol site and ask the admins there if they have any data on combining pulsed antibiotics with fasting?  It's a great idea.

I was there recently, after many years. They now require to register to read the forums, which used to be mostly open. But years ago I saw that they discourage fasting. They  also discourage supplements. That was years ago. Who knows what the "protocol" consists of now. They started with pulsed antibiotics, but then cancelled them and, last time I checked, relied entirely on benicar and vit D avoidance, though it's hard to say if this new, antibiotic-free method is quite as good as the old.
 
My personal opinion on this is that they would be free from their dieseases in less than a year (instead of many long years!) if only they combined fasting with antibiotics.

 

 

I need help following part of what you are describing.  Do you have any written fasting protocol you are using, or if not could you describe exactly how you are doing it?   How many days or hours are you going on fast?   What do you think of the idea of doing a 16 hour fast every day and trying to eat all meals in an eight-hour window?   That's the Jaminet's approach.

 

Is your thinking around antibiotics being combined with fasting based on your own dramatic recovery from an autoimmune disease, using that combination?  Is there any research for it?

 

Marshall's website is definitely tightly moderated now.   They have very bizarre organization ideas, such as having people with questions about the protocol write all of their different questions into a single thread that is exclusively owned by each individual user.  People are supposed to somehow find your questions by digging through your personal file.   I can't seem to get them to understand that this is just about the worst designed system in the history of discussion sites.   They are definitely unique in how they do everything.

 

I think the Vitamin D avoidance part of their protocol is the most suspect.   His claim that the supplemental form of Vitamin D will immunosuppress the 1,25-dihydroxy form is based on his own computer model, and I have seen others with models that contradict his claim.   I really cannot see trying to lower my vitamin D levels to 12 ng/dL given all of that evidence in studies showing a dramatic lower risk of death with levels > 30 ng/dL.   I don't see how his protocol needs to require this anyway.   The key idea is really to get the vitamin D receptor upregulated and to stop the suppression by pathogens.  He accomplishes that with the Benicar so using that alone seems enough to test his idea.

 

 

This is the first time I hear that fasting simulates antimictobial peptides production. You have a ref for this? 

 

Re the other part of your question, production of AMPs  is triggered by pattern-recognition receptors that sense characteristic microbial proteins, be it a part of bacterial cell wall, a specific bacterial toxin, or something else, that tells of a presence of a microbe.

 

I misunderstood your post.   You already had a discussion earlier in this thread on a part of this issue.   Marshall is claiming that two specific AMPs are activated by the vitamin D receptor.  I was trying to understand your mechanism for AMP creation around eukaryotic cells that seemed totally different than the pathway Marshall is describing.

 

I thought you were trying to say that fasting would somehow accelerate AMP production.    If not, what do you think the mechanism of action is for fasting assisting antibiotics?

 

 

 

Edited by pone11, 12 May 2016 - 01:40 AM.

[xEva]

I need help following part of what you are describing.  Do you have any written fasting protocol you are using, or if not could you describe exactly how you are doing it?   How many days or hours are you going on fast?   What do you think of the idea of doing a 16 hour fast every day and trying to eat all meals in an eight-hour window?   That's the Jaminet's approach.
 
Is your thinking around antibiotics being combined with fasting based on your own dramatic recovery from an autoimmune disease, using that combination?  Is there any research for it?
 
Marshall's website is definitely tightly moderated now.   They have very bizarre organization ideas, such as having people with questions about the protocol write all of their different questions into a single thread that is exclusively owned by each individual user.  People are supposed to somehow find your questions by digging through your personal file.   I can't seem to get them to understand that this is just about the worst designed system in the history of discussion sites.   They are definitely unique in how they do everything.
 
I think the Vitamin D avoidance part of their protocol is the most suspect.   His claim that the supplemental form of Vitamin D will immunosuppress the 1,25-dihydroxy form is based on his own computer model, and I have seen others with models that contradict his claim.   I really cannot see trying to lower my vitamin D levels to 12 ng/dL given all of that evidence in studies showing a dramatic lower risk of death with levels > 30 ng/dL.   I don't see how his protocol needs to require this anyway.   The key idea is really to get the vitamin D receptor upregulated and to stop the suppression by pathogens.  He accomplishes that with the Benicar so using that alone seems enough to test his idea.
 
 
 
I misunderstood your post.   You already had a discussion earlier in this thread on a part of this issue.   Marshall is claiming that two specific AMPs are activated by the vitamin D receptor.  I was trying to understand your mechanism for AMP creation around eukaryotic cells that seemed totally different than the pathway Marshall is describing.
 
I thought you were trying to say that fasting would somehow accelerate AMP production.    If not, what do you think the mechanism of action is for fasting assisting antibiotics?

Maybe you misunderstood Marshal as well -? Maybe he meant that some bugs downregulate AMP production by jamming the vit D receptor -? But no AMPs are produced "just in case".

 

That's the whole point behind "beneficial bacteria". They induce AMPs production by their mere presence and this protects the body in case something really nasty comes along. 

 

There was a study to this effect, several years ago, and with a misleading title, as is often the case. The title said something like 'antibiotics make mice more vulnerable to the infection with'... And what they did was this: They pretreated mice with antibiotics which totally wiped out their flora. Naturally, the gut stopped producing AMPs, since there was no longer stimulus for this. Then they forcefed those poor mice with some nasty bug which invaded and killed more in this group than the controls.The gist of their finding was that the lack of microbes in the gut stops production of AMPs, which in turn eaves the host more vulnerable to an invasion by a pathogen. Instead they misleadingly put the focus on antibiotics. 

 

 

Re fasting and infections, authopagy is the first line of defence against intracellular pathogens and this is what upregulated by fasting. Also, repeated fasting cycles reboot the immune sys. And interesting that long before this become known,  in Russia they treated sarcoidosis with repeated fasts. I believe that doing antibiotics between fasts should be more effective than either method alone. 

 

And no, if you read the thread, I don't have autoimmune conditions and never had, though I was so misdiagnosed, and not just once, before I took the matters in my own hands and got cured with a week-long course of an antibiotic. Since then I rather believe that when they cannot find a pathogen --for whatever reason-- the diagnosis is invariably 'autoimmunity'. But is it, really?

 

His recognition that pathogens are behind most chronic conditions is what I liked about Marshal. This and his use of antibiotics, when he used them. Re vit D -- maybe -? I know it does not apply to me, coz I sorta tried avoiding it, as an experiment, years ago, and in less than two weeks started to feel like crap, which promptly cured me from that folly lol. I think if they had their cohort genotyped for this vit D receptor, it could give his idea more credence (provided they find a correlation with  some SNPs) otherwise, I'm not terribly convinced.

[pone11]

 

I need help following part of what you are describing.  Do you have any written fasting protocol you are using, or if not could you describe exactly how you are doing it?   How many days or hours are you going on fast?   What do you think of the idea of doing a 16 hour fast every day and trying to eat all meals in an eight-hour window?   That's the Jaminet's approach.
... 

...

 

Let's try this again:

 

Do you have any written fasting protocol you are using, or if not could you describe exactly how you are doing it?   How many days or hours are you going on fast?   What do you think of the idea of doing a 16 hour fast every day and trying to eat all meals in an eight-hour window?   That's the Jaminet's approach.

 

The rest of your reply I will respond to within the next few weeks.

Edited by pone11, 14 May 2016 - 02:50 PM.

[Kalliste]

 

 

I need help following part of what you are describing.  Do you have any written fasting protocol you are using, or if not could you describe exactly how you are doing it?   How many days or hours are you going on fast?   What do you think of the idea of doing a 16 hour fast every day and trying to eat all meals in an eight-hour window?   That's the Jaminet's approach.
... 

...

 

Let's try this again:

 

Do you have any written fasting protocol you are using, or if not could you describe exactly how you are doing it?   How many days or hours are you going on fast?   What do you think of the idea of doing a 16 hour fast every day and trying to eat all meals in an eight-hour window?   That's the Jaminet's approach.

 

The rest of your reply I will respond to within the next few weeks.

 

 

16 hours is really not fasting as much as it's "normal time for humans between meals" although that notion is close to heresy in our global 24/7 food bonanza culture.

xEva probably refers to several days of zero or almost zero calories. That has been covered in other threads here.

 

Google for "Valter Longo fasting" for some up to date science, but keep in mind rodent fasting probably can't be translated in effects to humans hour for hour as many pop-science articles seems to imply.

 

For me fasting truly starts after about 24 hours, 36 hours or so if I ate lots of carbs right before starting. Many beneficial effects probably cannot be had with only 16 hours. I do 16 hours pretty often and throw in a five day faste every 3 months. It gets considerably easier once you've done a few and gotten to know the fasting sensation. Orgasms get better, sleep is deep, dreams become vivid, thoughts are clearer, I feel lighter.

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[pone11]

 

 

 

I need help following part of what you are describing.  Do you have any written fasting protocol you are using, or if not could you describe exactly how you are doing it?   How many days or hours are you going on fast?   What do you think of the idea of doing a 16 hour fast every day and trying to eat all meals in an eight-hour window?   That's the Jaminet's approach.
... 

...

 

Let's try this again:

 

Do you have any written fasting protocol you are using, or if not could you describe exactly how you are doing it?   How many days or hours are you going on fast?   What do you think of the idea of doing a 16 hour fast every day and trying to eat all meals in an eight-hour window?   That's the Jaminet's approach.

 

The rest of your reply I will respond to within the next few weeks.

 

 

16 hours is really not fasting as much as it's "normal time for humans between meals" although that notion is close to heresy in our global 24/7 food bonanza culture.

xEva probably refers to several days of zero or almost zero calories. That has been covered in other threads here.

 

Google for "Valter Longo fasting" for some up to date science, but keep in mind rodent fasting probably can't be translated in effects to humans hour for hour as many pop-science articles seems to imply.

 

For me fasting truly starts after about 24 hours, 36 hours or so if I ate lots of carbs right before starting. Many beneficial effects probably cannot be had with only 16 hours. I do 16 hours pretty often and throw in a five day faste every 3 months. It gets considerably easier once you've done a few and gotten to know the fasting sensation. Orgasms get better, sleep is deep, dreams become vivid, thoughts are clearer, I feel lighter.

 

 

16 hours is based on the claim made in some places that an average human exhausts liver glycogen in the window between 12 and 16 hours.  What is not clear is whether autophagy is signaled by low insulin and no protein eaten during the fast alone, or does autophagy rely on some signaling that only occurs when glucose levels also go low.   In my case I have prediabetes and high fasting glucose 105 to 120 up to about hour 18 of a fast.  At that point I feel horrible and my ketones do not rise rapidly.  My glucose does fall to the 90 mg/dL level at around hour 18, so presumably that is the place that glycogen exhausts.

 

If you have any paper citations showing autophagy does not get to therapeutic levels until after hour 16 in a fast, I would love to see those.   I am looking all over for papers that show hour by hour changes in insulin, glucagon, glucose, fatty acids, ketones, cortisol, and growth hormone in the first two or three days of a fast.   You would think that paper would be easy to find.  Most paper with all of these metabolites only provide time graphs with the x axis showing days not hours.  The one with hourly data do not have comprehensive capture of metabolites.

 

All of this is made more complicated because there is no simple biochemical marker we can look at that will signal the body is in autophagy.  Most studies rely on luminescence of lysosomes or other structures and then visual observation of these.  Most of the papers I have seen claim that autophagy is signaled by AMPK.  This system is downregulated by insulin and proteins/amino acids.  It is upregulated by exercise, fasting, and drugs like metformin that apparently downregulate complex 1 of the electron transport chain.   

 

If I talk my doctor into letting me get tested for insulin, glucagon, fatty acids every two hours corresponding to hours 12 through 22 of a fast, I should be able to clearly see the point in time when insulin goes low.   Would low insulin, high free fatty acids, and no feeding of protein induce autophagy, even in presence of high glucose and some remaining liver glycogen?   That's the mystery I want to figure out.

 

Regarding your proposal for a five day fast, be careful with that.   There are good studies in rodents (I agree with you translating that to humans is tough) showing even a three day fast results in a condition where upon re-feeding the body stops autophagy all together, and it can take more than one day for it to start.   I do not know where the same point is for humans, but many who advocate intermittent fasting argue that crossing that magic line will allow any pathogens you kill to just grow back if you fast too long, once you enter the refeeding period.  You want that magic amount of fasting that will enhance autophagy without creating a problem during refeeding.   Why not do a two day fast every other week?

 

So your protocol is - roughly - 16 hour daily fasts, and five days every three months?   What are the effects that you start to see only after 24 hours?   Do you have a sense for when those good effects peak?

 

I was thinking of something like 16 hour daily fasts, and then 24 to 36 hours once a week.  

 

I don't understand why xEva did not share the fast protocol used.   A lot of time was spent in this thread by xEva advocating fasts, and documenting how a pathogen infection was treated.  Wouldn't it be nice to know the actual protocol that all of this discussion is being built on?   

Edited by pone11, 02 June 2016 - 04:37 AM.

[xEva]

16 hours is based on the claim made in some places that an average human exhausts liver glycogen in the window between 12 and 16 hours.  What is not clear is whether autophagy is signaled by low insulin and no protein eaten during the fast alone, or does autophagy rely on some signaling that only occurs when glucose levels also go low.   In my case I have prediabetes and high fasting glucose 105 to 120 up to about hour 18 of a fast.  At that point I feel horrible and my ketones do not rise rapidly.  My glucose does fall to the 90 mg/dL level at around hour 18, so presumably that is the place that glycogen exhausts.

That claim is based on the fact that an average liver holds 100-150 g of glycogen, which is then computed for an average metabolic rate and requirements. But this widely circulating claim does not take into account the last meal, which takes 6 to 8 hrs to digest and assimilate -- at the very least! And until it is assimilated, no liver glycogen is spent.
 
It's easy to know when you run out of liver glycogen, because ketosis starts right there -- and you can't miss it, even if you don't have the strips.  For most people who fast, ketosis starts 36-48h after the last meal. If it was a meager meal low on carbs, one can go into ketosis 24h after the last meal. Interesting that people with cirrhosis of the liver go into ketosis "at the drop of a hat", 'cause their scarred liver can't hold much glycogen.  (that trivia is for you, phone11 )
 
Re your blood sugar levels, this may have to do with diurnal fluctuations. Blood sugar is the highest in the morning and tapers off in the afternoon. Your drop in glucose 18 h after the last meal may simply coincide with this diurnal drop.

 

So yeah, as Cosmicalstorm said, "16h fast" is called eating once a day -- and that's what I usually do anyway. As for "protocols", this is not a thread for that. I have shared some of my fasts (no "protocols" though). You just have to use the search function. 

Edited by xEva, 03 June 2016 - 01:14 AM.

[Kalliste]

Well I got into the weird problem that my web client could not copy and paste into the forum for whatever reason (worked fine with other forums?). Tired of it and print screened my reply, attached as image.

 

 

 

 

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Edited by Cosmicalstorm, 03 June 2016 - 04:46 AM.

[pone11]

 

16 hours is based on the claim made in some places that an average human exhausts liver glycogen in the window between 12 and 16 hours.  What is not clear is whether autophagy is signaled by low insulin and no protein eaten during the fast alone, or does autophagy rely on some signaling that only occurs when glucose levels also go low.   In my case I have prediabetes and high fasting glucose 105 to 120 up to about hour 18 of a fast.  At that point I feel horrible and my ketones do not rise rapidly.  My glucose does fall to the 90 mg/dL level at around hour 18, so presumably that is the place that glycogen exhausts.

That claim is based on the fact that an average liver holds 100-150 g of glycogen, which is then computed for an average metabolic rate and requirements. But this widely circulating claim does not take into account the last meal, which takes 6 to 8 hrs to digest and assimilate -- at the very least! And until it is assimilated, no liver glycogen is spent.
 
It's easy to know when you run out of liver glycogen, because ketosis starts right there -- and you can't miss it, even if you don't have the strips.  For most people who fast, ketosis starts 36-48h after the last meal. If it was a meager meal low on carbs, one can go into ketosis 24h after the last meal. Interesting that people with cirrhosis of the liver go into ketosis "at the drop of a hat", 'cause their scarred liver can't hold much glycogen.  (that trivia is for you, phone11 )
 
Re your blood sugar levels, this may have to do with diurnal fluctuations. Blood sugar is the highest in the morning and tapers off in the afternoon. Your drop in glucose 18 h after the last meal may simply coincide with this diurnal drop.

 

So yeah, as Cosmicalstorm said, "16h fast" is called eating once a day -- and that's what I usually do anyway. As for "protocols", this is not a thread for that. I have shared some of my fasts (no "protocols" though). You just have to use the search function. 

 

 

I found some great mice studies that look at the issue of high fasting blood glucose during a fast.  It turns out that this is actually the gluconeogenesis acting on the free amino acids created by autophagy itself.  Fantastic information in this study:

http://www.ncbi.nlm....les/PMC3149698/

 

The graphs in three of the figures are priceless.  Of course this would need to be calibrated to human beings, but the general behavior of glucose in the fast is extremely surprising and non obvious.  From the graphs, I think that measuring free amino acids in the blood during the fast would give the clearest indication of the start of autophagy.  I had no idea that our cells hid so much garbage to affect amino acid levels in such a profound way.

 

I'm leaning towards 16 to 17 hour daily fast, and I will experiment with a once a week 40 hour fast.  Observe in the mouse study how autophagy alone is able to elevate fasting blood glucose for up to the 40 hours they observed in the study.  

Edited by pone11, 04 June 2016 - 12:16 AM.

[pone11]

Well I got into the weird problem that my web client could not copy and paste into the forum for whatever reason (worked fine with other forums?). Tired of it and print screened my reply, attached as image.

 

I was able to read your screen image and will answer on a few of your points.  Please reference the mouse study on autophagy that I link in my last post.

 

* I am skeptical about feeding fructose and glucose during a fast.  These will provoke an insulin response - albeit a small one - and the triggers to autophagy include low insulin and a lack of dietary amino acid.   All of this could be experimentally confirmed simply by measuring your free amino acids during a fast and then - after autophagy starts and FAA surge - testing a small carb meal and seeing what that does to the FAA levels in the following hours, and compare that behavior against the baseline with no carb feeding.

 

* I will go read Valter Longo Fasting and come back if there are new points to make.  However I have to warn you about fasting as a cancer therapy.  Cancer is in many ways the most difficult disease.  Most cancers are very good at survival in conditions of autophagy!!  I can link you to some Youtube presentations on this where this issue is discussed in subordination to a detailed discussion of autophagy triggers.   A superb anti-cancer strategy would be autophagy together with a pharmaceutical that blocks the autophagy initiator for the specific type of cancer that the patient has.   I don't think the science has mainstreamed this approach yet.

 

* I completely agree with you that periods of starvation must have been commonplace for ancient humans.   In the most recent past, cooking was a big deal, so probably the day had fewer, larger meals, more closely spaced together.  It's only the processed foods and long-term storage of food that requires no cooking that have made it so easy for people to break history and start eating 24x7.   

 

* I will take your hypothesis about starvation and raise it one higher:  what if long fasting periods was the norm for homo sapiens and actually became our primary way to fight difficult intracellular, parasitic bacteria and viruses?  Evolution might not have ever had a reason to give us more robust biochemical defenses against these organisms because fasting and autophagy might have done an excellent job of ridding less robust homo sapiens of these invaders.   Now, in the last 100 years, we remove autophagy and all of a sudden obesity and autoimmune diseases become commonplace.   The correlation is worth studying.

 

* i agree the timelines in rodent studies are suspect.  We need human studies to establish correct baselines.  However am I reading the rodent study correctly that the surge of free amino acids is the biochemical trigger we measure in a blood test to establish that autophagy is in full swing?   The rodent study very elegantly designs an experiment that uses as a comparison to the control group genetically engineered mice that cannot do autophagy.   Look at the surge of free amino acids and gluconeogenesis in just the mice that have autophagy intact.

 

How often should we fast?  I would propose using the free amino acids and level of gluconeogenesis to calibrate the answer.  If your FAA levels fall after N hours in a fast, you are succeeded in cleaning out the intracellular garbage that autophagy targets.  If FAA remains high, autophagy is productive and the fast might be beneficial to extend.

 

Against all of the above, keep in mind that rodent studies show that a one day fast generates profound autophagy, but a three day fast creates a condition where upon refeeding all autophagy stops and is hard to then restart, thus allowing organisms to grow back.  There are good stories about people in concentration camps who get extremely ill upon being released and suddenly refed.   Finding the magic window of benefit, and avoiding the dark edges of this from an overly-long fast, is important.

 

I have been doing 16 hour fasts for two weeks now, and the last few days I am pushing autophagy by doing exercise in the morning a few hours before starting my feeding window at 2pm.  So far this has all felt amazing.  I have been extremely ill for 2.5 years now, and the autophagy overcomes my brain fog in a very profound way.  The refeeding windows allow me to get calories in and I don't have any abnormal weight loss.   I feel some kind of healing going on here - particularly neurologically - that is profound.   I am closer to the beginning of the experiment than the end, but all of this has gotten me keenly interested in autophagy.

Edited by pone11, 04 June 2016 - 12:42 AM.

[pone11]

Well I got into the weird problem that my web client could not copy and paste into the forum for whatever reason (worked fine with other forums?). Tired of it and print screened my reply, attached as image.

 

The Russian fasting book contains almost not citations.   It's hard to know what can be trusted there.

[xEva]

pone11, thank you for posting this mouse study. Very interesting! 

 

Re men and mice, you don't seem to be aware that mice have a very fast metabolic rate. You can look up their heart and respiratory rates for starters. They also lose 10% of their body weight after a 24h fast -- which starts at the moment of the food withdrawal. By the way, this study has an interesting graph of liver glycogen levels. Note that it goes up during the first 3 hrs, which means that it took that long for mice to assimilate their food after it was withdrawn. Only after that did their liver glycogen level begin to descend.  

 

There are a couple of threads here that discuss this difference between human and mouse metabolic rates (by Brett Black, and with references). You may want to look them up.

 

From my reading on this subject in the past years, I saw many studies reporting that mice lose ~20% of their body weightafter a 48h fast and 30% after 3 days. If the ambient temperature is ideal for them (~24C) then mice can fast 3 days. I have not seen studies that would fast them longer than 3 days. Presumably, mice begin to die of starvation after that. Rats can last more than a week, depending on the strain. In comparison, a healthy 70kg human can fast for 2 months before starving. And, by the way, a 70 kg human will take more than a week to lose 7 kg. That's why it is generally believed that a day of fasting for a mouse equals to about a week of fasting for a man (the range is generally given as 1 mouse day equals to 6 to 8 human days of fasting or that mouse metabolic rate is 6 to 8 times faster than human).

 

The other major difference between starving humans and mice is that mice don't develop the level of ketosis seen in man after the adaptation period (10 days on average). At that point, the blood glucose level also rises, but not necessarily due to autophagy. Rather, at that point the brain switches to ketones, at 30% of its requirements, and this lower demand by the brain allows the level of glucose to rise. (read Owen and Cahill circa 1960s-1970s).

 

By the way, did you notice 400 mg/dl  glucose level in mice after glucose administration? This would be raging diabetes for a man. Too bad they did not measure the ketones. Also, they measured the loss of the liver weight (25% after 24h!!! -- can you imagine losing a quarter of your liver after a day of fast -?!) but did not bother to measure the loss of body weight, but probably that is because there is plenty of studies that report this among other data. 

 

Overall, very interesting about the rise of FAAs as an indicator of autophagy. I skimmed this paper just now, but will return to it later to see how this could be applied to a fasting human. 

 

Edited by xEva, 05 June 2016 - 11:59 PM.

[xEva]

So I'm reading this paper again, checking the refs, specifically, when autophagy is induced by starvation.
 
In the beginning they say that glucagon "significantly stimulates autophagic protein degradation". It is well known that levels of glucagon has the inverse relationship to insulin and blood glucose levels. Then they say, "the reduction in insulin plays a principal role in the induction of liver autophagy." This means that there is no need, really, to measure the levels of FAAs. The levels of insulin and/or glucagon should suffice. 
 
One can judge the levels of insulin by the levels of blood glucose. As for glucagon, here is a paper that examines its levels in humans by the day of fasting (THE EFFECTS OF TOTAL STARVATION UPON THE LEVELS OF CIRCULATING GLUCAGON AND INSULIN IN MAN, 1963). There is a graph there, on page 1034, showing the mean glucagon levels on each day (they fasted for 3 days). Here is what they say:
 

Glucagon concentration, which had averaged 292
uL/ugEq per ml before starvation, failed to change
significantly during the first 24 hours; however,
at the end of 48 hours there was a statistically significant
increase in glucagon concentration, which
rose further to a mean level of 893 uL/ugEq per ml
at the end of day 3 of starvation (p < 0.01). 
 

Very interesting is Table II in this human study report. It lists glucose, insulin and glucagon levels in each of their cohort day by day. Note that when glucose is higher than 80 mg/dL, the glucagon level is 0 (in fasted men), which means that autophagy remains at the basal level. You need to get the glucose well below that to trigger glucagon release and for this, you need to deplete your liver glycogen. Again, for most people it takes 36-48 hrs after the last meal, as it is self-reported on the fasting forums. This paper confirms this.
 
So, It is doubtful you get autophagy above the basal level in your 16h "fasts". It is also doubtful that you get there even with the induction of ketosis, at 38-48h after the last meal. This is because, according to the paper you posted, in mice, the enhanced level of autophagy was seen after 24h, i.e. after they have already lost 25% of the liver weight.
 
Judging also by their FFA and triacylglycerol graphs (Fig. 2), it looks like by the 24h mark these mice have depleted their main fat reserves and this is what in turn then triggered autophagy -- iow they began to catabolize their protein only after they have lost most of their disposable fat, which is in line with all animal starvation studies. Protein is precious and fat is disposable. Too bad this paper does not list how much weight and fat the mice lost by 24h. Were they lean or fat mice to begin with? Of course, a fat mouse would take a longer time to get there than a lean mouse, and the same applies to humans. I'd guess they were lean mice, 'cause they had already fasted them for a day, then fed them just for a few hrs before fasting them again for this 40h study. 
 
To me this rather confirms that for a human --and I'm talking about a lean human to start-- it should take a couple of weeks to get to the level of autophagy seen in these mice during the second day of fasting. Of course, this brings another issue, the muscle loss. People want to fast and they want to induce autophagy, but they don't want to lose muscle mass. There is no easy answers here, especially without proper human studies.
 
My conclusion: your "16h fast" does not induce the level of autophagy you dream about, sorry. Again, in my book it is called not a fast, but eating once a day. Nothing to do with fasting.

Edited by xEva, 07 June 2016 - 12:17 AM.

[Kalliste]

 

Well I got into the weird problem that my web client could not copy and paste into the forum for whatever reason (worked fine with other forums?). Tired of it and print screened my reply, attached as image.

 

The Russian fasting book contains almost not citations.   It's hard to know what can be trusted there.

 

 

Take it with a spoonful of salt. But I think it contains an important perspective on fasting.

 

Btw

 

 

Prolonged Nightly Fasting and Breast Cancer Prognosis

Catherine R. Marinac, BA^1,2,3; Sandahl H. Nelson, MS^1,2; Caitlin I. Breen, BS, BA¹; Sheri J. Hartman, PhD^1,3; Loki Natarajan, PhD^1,3; John P. Pierce, PhD^1,3; Shirley W. Flatt, MS¹; Dorothy D. Sears, PhD^1,3,4; Ruth E. Patterson, PhD^1,3

[+] Author Affiliations

JAMA Oncol. Published online March 31, 2016. doi:10.1001/jamaoncol.2016.0164

Text Size: A A A

 

ABSTRACT

ABSTRACT | INTRODUCTION | METHODS | RESULTS | DISCUSSION | CONCLUSIONS | ARTICLE INFORMATION | REFERENCES

 

Importance  Rodent studies demonstrate that prolonged fasting during the sleep phase positively influences carcinogenesis and metabolic processes that are putatively associated with risk and prognosis of breast cancer. To our knowledge, no studies in humans have examined nightly fasting duration and cancer outcomes.

Objective  To investigate whether duration of nightly fasting predicted recurrence and mortality among women with early-stage breast cancer and, if so, whether it was associated with risk factors for poor outcomes, including glucoregulation (hemoglobin A_1c), chronic inflammation (C-reactive protein), obesity, and sleep.

Design, Setting, and Participants  Data were collected from 2413 women with breast cancer but without diabetes mellitus who were aged 27 to 70 years at diagnosis and participated in the prospective Women’s Healthy Eating and Living study between March 1, 1995, and May 3, 2007. Data analysis was conducted from May 18 to October 5, 2015.

Exposures  Nightly fasting duration was estimated from 24-hour dietary recalls collected at baseline, year 1, and year 4.

Main Outcomes and Measures  Clinical outcomes were invasive breast cancer recurrence and new primary breast tumors during a mean of 7.3 years of study follow-up as well as death from breast cancer or any cause during a mean of 11.4 years of surveillance. Baseline sleep duration was self-reported, and archived blood samples were used to assess concentrations of hemoglobin A_1c and C-reactive protein.

Results  The cohort of 2413 women (mean [SD] age, 52.4 [8.9] years) reported a mean (SD) fasting duration of 12.5 (1.7) hours per night. In repeated-measures Cox proportional hazards regression models, fasting less than 13 hours per night (lower 2 tertiles of nightly fasting distribution) was associated with an increase in the risk of breast cancer recurrence compared with fasting 13 or more hours per night (hazard ratio, 1.36; 95% CI, 1.05-1.76). Nightly fasting less than 13 hours was not associated with a statistically significant higher risk of breast cancer mortality (hazard ratio, 1.21; 95% CI, 0.91-1.60) or a statistically significant higher risk of all-cause mortality (hazard ratio, 1.22; 95% CI, 0.95-1.56). In multivariable linear regression models, each 2-hour increase in the nightly fasting duration was associated with significantly lower hemoglobin A_1c levels (β = –0.37; 95% CI, –0.72 to –0.01) and a longer duration of nighttime sleep (β = 0.20; 95% CI, 0.14-0.26).

Conclusions and Relevance  Prolonging the length of the nightly fasting interval may be a simple, nonpharmacologic strategy for reducing the risk of breast cancer recurrence. Improvements in glucoregulation and sleep may be mechanisms linking nightly fasting with breast cancer prognosis.

http://oncology.jama...ticleid=2506710

[gamesguru]

sometimes people produce rogue antibodies (autoimmune disease) in response to pathogens; that can block receptors, commonly cholinergic, or assault certain tissues directly. or sometimes people don't produce one kind of antibody at all and this makes it much easier for one king of virus to flourish. sometimes their immune system is too aggressive or too passive, and both cases allow the virus to spread.

 

Quercetin, Nilotinib, Galangin and Silibinin all induce phagocytosis. and Baicalein interesting inhibits phagocytosis while managing to prevent fibril tangles and amyloid plaques. Rotenone and Ceramide induce mitophagy.

 

many things besides fasting could be helpful

Herpes simplex virus type 1 DNA polymerase requires the mammalian chaperone hsp90 for proper localization to the nucleus.
Burch AD1, Weller SK. (2005)

Many viruses and bacteriophage utilize chaperone systems for DNA replication and viral morphogenesis. We have previously shown that in the herpes simplex virus type 1 (HSV-1)-infected cell nucleus, foci enriched in the Hsp70/Hsp40 chaperone machinery are formed adjacent to viral replication compartments (A. D. Burch and S. K. Weller, J. Virol. 78:7175-7185, 2004). These foci have now been named virus-induced chaperone-enriched (VICE) foci. Since the Hsp90 chaperone machinery is known to engage the Hsp70/Hsp40 system in eukaryotes, the subcellular localization of Hsp90 in HSV-1-infected cells was analyzed. Hsp90 is found within viral replication compartments as well as in the Hsp70/Hsp40-enriched foci. Geldanamycin, an inhibitor of Hsp90, results in decreased HSV-1 yields and blocks viral DNA synthesis. Furthermore, we have found that the viral DNA polymerase is mislocalized to the cytoplasm in both infected and transfected cells in the presence of geldanamycin. Additionally, in the presence of an Hsp90 inhibitor, proteasome-dependent degradation of the viral polymerase was detected by Western blot analysis. These data identify the HSV-1 polymerase as a putative client protein of the Hsp90 chaperone system. Perturbations in this association appear to result in degradation, aberrant folding, and/or intracellular localization of the viral polymerase.

Geldanamycin, a Ligand of Heat Shock Protein 90, Inhibits the Replication of Herpes Simplex Virus Type 1 In Vitro
Yu-Huan Li,1 Pei-Zhen Tao,1,* Yu-Zhen Liu,1 and Jian-Dong Jiang1,2 (2004)

Geldanamycin (GA) is an antibiotic targeting the ADP/ATP binding site of heat shock protein 90 (Hsp90). In screening for anti-herpes simplex virus type 1 (HSV-1) candidates, we found GA active against HSV-1. HSV-1 replication in vitro was significantly inhibited by GA with an 50% inhibitory concentration of 0.093 μM and a concentration that inhibited cellular growth 50% in comparison with the results seen with untreated controls of 350 μM. The therapeutic index of GA was over 3,700 (comparable to the results seen with acyclovir). GA did not inhibit HSV-1 thymidine kinase. Cells infected with HSV-1 demonstrated cell cycle arrest at the G1/S transition; however, treatment with GA resulted in a cell cycle distribution pattern identical to that of untreated cells, indicating a restoration of cell growth in HSV-1-infected cells by GA treatment. Accordingly, HSV-1 DNA synthesis was suppressed in HSV-1+ cells treated with GA. The antiviral mechanism of GA appears to be associated with Hsp90 inactivation and cell cycle restoration, which indicates that GA exhibits broad-spectrum antiviral activity. Indeed, GA exhibited activities in vitro against other viruses, including severe acute respiratory syndrome coronavirus. Since GA inhibits HSV-1 through a cellular mechanism unique among HSV-1 agents, we consider it a new candidate agent for HSV-1.

Antiviral Activity and RNA Polymerase Degradation Following Hsp90 Inhibition in a Range of Negative Strand Viruses
John H. Connor,1,2,* Margie O. McKenzie,2 Griffith D. Parks,3 and Douglas S. Lyles2 (2007)

We have analyzed the effectiveness of Hsp90 inhibitors in blocking the replication of negative-strand RNA viruses. In cells infected with the prototype negative strand virus vesicular stomatitis virus (VSV), inhibiting Hsp90 activity reduced viral replication in cells infected at both high and low multiplicities of infection. This inhibition was observed using two Hsp90 inhibitors geldanamycin and radicicol. Silencing of Hsp90 expression using siRNA also reduced viral replication. Hsp90 inhibition changed the half-life of newly synthesized L protein (the large subunit of the VSV polymerase) from >1 hour to less than 15 minutes without affecting the stability of other VSV proteins. Both the inhibition of viral replication and the destabilization of the viral L protein were seen when either geldanamycin or radicicol was added to cells infected with paramyxoviruses SV5, HPIV-2, HPIV-3, or SV41, or to cells infected with the La Crosse bunyavirus. Based these results we propose that Hsp90 is a host factor that is important for the replication of many negative strand viruses.

Anti-herpes simplex virus activity of moronic acid purified from Rhus javanica in vitro and in vivo.
Kurokawa M1, Basnet P, Ohsugi M, Hozumi T, Kadota S, Namba T, Kawana T, Shiraki K. (1999)

Rhus javanica, a medicinal herb, has been shown to exhibit oral therapeutic anti-herpes simplex virus (HSV) activity in mice. We purified two major anti-HSV compounds, moronic acid and betulonic acid, from the herbal extract by extraction with ethyl acetate at pH 10 followed by chromatographic separations and examined their anti-HSV activity in vitro and in vivo. Moronic acid was quantitatively a major anti-HSV compound in the ethyl acetate-soluble fraction. The effective concentrations for 50% plaque reduction of moronic acid and betulonic acid for wild-type HSV type 1 (HSV-1) were 3.9 and 2.6 microgram/ml, respectively. The therapeutic index of moronic acid (10.3-16.3) was larger than that of betulonic acid (6.2). Susceptibility of acyclovir-phosphonoacetic acid-resistant HSV-1, thymidine kinase-deficient HSV-1, and wild-type HSV type 2 to moronic acid was similar to that of the wild-type HSV-1. When this compound was administered orally to mice infected cutaneously with HSV-1 three times daily, it significantly retarded the development of skin lesions and/or prolonged the mean survival times of infected mice without toxicity compared with the control. Moronic acid suppressed virus yields in the brain more efficiently than those in the skin. This was consistent with the prolongation of mean survival times. Thus, moronic acid was purified as a major anti-HSV compound from the herbal extract of Rhus javanica. Mode of the anti-HSV activity was different from that of ACV. Moronic acid showed oral therapeutic efficacy in HSV-infected mice and possessed novel anti-HSV activity that was consistent with that of the extract.





Anti-herpes simplex virus type-1 flavonoids and a new flavanone from the root of Limonium sinense.
Lin LC1, Kuo YC, Chou CJ. (2000)

From the root of Limonium sinense (Girard) Ktze a new (2R,3S)-3,5,7,4'-tetrahydroxy-3',5'-dimethoxyflavanone was isolated and named isodihydrosyringetin (3), together with nine other known compounds, (-)-epigallocatechin 3-O-gallate (1), samarangenin B (2), myricetin (4), myricetin 3-O-alpha-rhamnopyranoside (5), quercetin 3-O-alpha-rhamnopyranoside (6), (-)-epigallocatechin (7), gallic acid (8), N-trans-caffeoyltyramine (9), and N-trans-feruloyltyramine (10). All of them were examined for their inhibitory effects on herpes simplex virus type-1 (HSV-1) replication in Vero cells. Both compounds 1 and 2 exhibited potent inhibitory activities in HSV-1 replication. Comparison of the IC50 values indicated that compounds 1 and 2 had higher inhibitory activities than the positive control acyclovir (38.6 +/- 2.6 vs. 55.4 +/- 5.3 microM, P < 0.001; 11.4 +/- 0.9 vs. 55.4 +/- 5.3 microM, P < 0.0005). Cytotoxicity was unlikely involved because no cell deaths were observable in the Vero cells following 5 day treatments with compound 1 or 2.

Anti-herpes simplex virus activity of alkaloids isolated from Stephania cepharantha.
Nawawi A1, Ma C, Nakamura N, Hattori M, Kurokawa M, Shiraki K, Kashiwaba N, Ono M. (1999)

By screening water and MeOH extracts of 30 Chinese medicinal plants for their anti-herpes simplex virus (HSV)-1 activity, a MeOH extract of the root tubers of Stephania cepharantha HAYATA showed the most potent activity on the plaque reduction assay with an IC50 value of 18.0 microg/ml. Of 49 alkaloids isolated from the MeOH extract, 17 alkaloids were found to be active against HSV-1, including 13 bisbenzylisoquinoline, 1 protoberberine, 2 morphinane and 1 proaporphine alkaloids, while benzylisoquinoline and hasubanane alkaloids were inactive. Although N-methylcrotsparine was active against HSV-1, as well as HSV-1 thymidine kinase deficient (acyclovir resistant type, HSV-1 TK-) and HSV-2 (IC50 values of 8.3, 7.7 and 6.7 microg/ml, respectively), it was cytotoxic. FK-3000 was found to be the most active against HSV-1, HSV-1 TK- and HSV-2 (IC50 values of 7.8, 9.9 and 8.7 microg/ml) with in vitro therapeutic indices of 90, 71 and 81, respectively. FK-3000 was found to be a promising candidate as an anti-HSV agent against HSV-1, acyclovir (ACV) resistant-type HSV-1 and HSV-2.

An Indole Alkaloid from a Tribal Folklore Inhibits Immediate Early Event in HSV-2 Infected Cells with Therapeutic Efficacy in Vaginally Infected Mice
Paromita Bag, Durbadal Ojha, Hemanta Mukherjee (2013)

Herpes genitalis, caused by HSV-2, is an incurable genital ulcerative disease transmitted by sexual intercourse. The virus establishes life-long latency in sacral root ganglia and reported to have synergistic relationship with HIV-1 transmission. Till date no effective vaccine is available, while the existing therapy frequently yielded drug resistance, toxicity and treatment failure. Thus, there is a pressing need for non-nucleotide antiviral agent from traditional source. Based on ethnomedicinal use we have isolated a compound 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (HM) from the traditional herb Ophiorrhiza nicobarica Balkr, and evaluated its efficacy on isolates of HSV-2 in vitro and in vivo. The cytotoxicity (CC50), effective concentrations (EC50) and the mode of action of HM was determined by MTT, plaque reduction, time-of-addition, immunofluorescence (IFA), Western blot, qRT-PCR, EMSA, supershift and co-immunoprecipitation assays; while the in vivo toxicity and efficacy was evaluated in BALB/c mice. The results revealed that HM possesses significant anti-HSV-2 activity with EC50 of 1.1-2.8 µg/ml, and selectivity index of >20. The time kinetics and IFA demonstrated that HM dose dependently inhibited 50-99% of HSV-2 infection at 1.5-5.0 µg/ml at 2-4 h post-infection. Further, HM was unable to inhibit viral attachment or penetration and had no synergistic interaction with acyclovir. Moreover, Western blot and qRT-PCR assays demonstrated that HM suppressed viral IE gene expression, while the EMSA and co-immunoprecipitation studies showed that HM interfered with the recruitment of LSD-1 by HCF-1. The in vivo studies revealed that HM at its virucidal concentration was nontoxic and reduced virus yield in the brain of HSV-2 infected mice in a concentration dependent manner, compared to vaginal tissues. Thus, our results suggest that HM can serve as a prototype to develop non-nucleotide antiviral lead targeting the viral IE transcription for the management of HSV-2 infections.

The alkaloid 4-methylaaptamine isolated from the sponge Aaptos aaptos impairs Herpes simplex virus type 1 penetration and immediate-early protein synthesis.
Souza TM1, Abrantes JL, de A Epifanio R, Leite Fontes CF, Frugulhetti IC. (2007)

We describe in this paper that the alkaloid 4-methylaaptamine, isolated from the marine sponge Aaptos aaptos, inhibited HSV-1 infection. We initially observed that 4-methylaaptamine inhibited HSV-1 replication in Vero cells in a dose-dependent manner with an EC50 value of 2.4 microM. Moreover, the concentration required to inhibit HSV-1 replication was not cytotoxic, since the CC50 value of 4-methylaaptamine was equal to 72 microM. Next, we found that 4-methylaaptamine sustained antiherpetic activity even when added to HSV-1-infected Vero cells at 4 h after infection, suggesting that this compound inhibits initial events during HSV-1 replication. We observed that 4-methylaaptamine impaired HSV-1 penetration without affecting viral adsorption. In addition, the tested compound could inhibit, in an MOI-dependent manner, the expression of an HSV-1 immediate-early protein, ICP27, thus preventing the inhibition of macromolecular synthesis induced by this virus. Our results warrant further investigation on the pharmacokinetics of 4-methylaaptamine and propose that this alkaloid could be considered as a potential compound for HSV-1 therapy.

In vitro anti-viral activity of the total alkaloids from Tripterygium hypoglaucum against herpes simplex virus type 1.
Ren Z1, Zhang CH, Wang LJ, Cui YX, Qi RB, Yang CR, Zhang YJ, Wei XY, Lu DX, Wang YF. (2010)

Herpes simplex virus type 1 (HSV-1) is a commonly occurring human pathogen worldwide. There is an urgent need to discover and develop new alternative agents for the management of HSV-1 infection. Tripterygium hypoglaucum (level) Hutch (Celastraceae) is a traditional Chinese medicine plant with many pharmacological activities such as anti-inflammation, anti-tumor and antifertility. The usual medicinal part is the roots which contain about a 1% yield of alkaloids. A crude total alkaloids extract was prepared from the roots of T. hypoglaucum amd its antiviral activity against HSV-1 in Vero cells was evaluated by cytopathic effect (CPE) assay, plaque reduction assay and by RT-PCR analysis. The alkaloids extract presented low cytotoxicity (CC(50) = 46.6 μg/mL) and potent CPE inhibition activity, the 50% inhibitory concentration (IC(50)) was 6.5 μg/mL, noticeably lower than that of Acyclovir (15.4 μg /mL). Plaque formation was significantly reduced by the alkaloids extract at concentrations of 6.25 μg/mL to 12.5 μg/mL, the plaque reduction ratio reached 55% to 75 which was 35% higher than that of Acyclovir at the same concentration. RT-PCR analysis showed that, the transcription of two important delayed early genes UL30 and UL39, and a late gene US6 of HSV-1 genome all were suppressed by the alkaloids extract, the expression inhibiting efficacy compared to the control was 74.6% (UL30), 70.9% (UL39) and 62.6% (US6) respectively at the working concentration of 12.5 μg/mL. The above results suggest a potent anti-HSV-1 activity of the alkaloids extract in vitro.

Effects of cytochalasin and alkaloid drugs on the biological expression of herpes simplex virus type 2 DNA ☆
F.E. Farber, R. Eberle (1976)

Pretreatment of rabbit kidney cells with cytochalasins B and D (CB, CD) enhanced herpes simplex virus type 2 (HSV-2) DNA infectivity 3- to 6-fold over values obtained using the standard CaCl2 technique. Cells were pretreated with CB for 4–6 h to achieve infectivity enhancement. A lower concentration of CD, and shorter pretreatment periods, resulted in comparable DNA infectivity. Separate exposure of cells to colchicine, colcemid, or vinblastine increased DNA infectivity 7-, 6-, and 5-fold, respectively, over control values. Additional enhancement was obtained when CD was used together with any one of the aforementioned drugs. Maximal enhancement of HSV-2 DNA infectivity was obtained by pretreating recipient cells with a drug mixture containing colchicine, colcemid, and CD. This treatment maximized infectivity levels 20- to 30-fold over CaCl2 control values.

Effect of alkaloids isolated from Amaryllidaceae on herpes simplex virus
J. Renard-Nozaki (1), T. Kim (1), Y. Imakura (2), M. Kihara (2), S. Kobayashi (2) (1989)

Studies were carried out on the effects of Amaryllidaceae alkaloids and their derivatives upon herpes simplex virus (type 1), the relationship between their structure and antiviral activity and the mechanism of this activity.
All alkaloids used in these experiments were biosynthesized from N-benzylphenethylamine; the apogalanthamine group was synthesized in our laboratory; those which may eventually prove to be antiviral agents had a hexahydroindole ring with two functional hydroxyl groups. Benzazepine compounds were neither cytotoxic nor antiviral, but many structures containing dibenzazocine were toxic at low concentrations.
It was established that the antiviral activity of alkaloids is due to the inhibition of multiplication and not to the direct inactivation of extracellular viruses. The mechanism of the antiviral effect could be partly explained as a blocking of viral DNA polymerase activity.

Tokai J Exp Clin Med. 1981 Jan;6(1):77-83.
Effect of plant alkaloid against the action of herpes simplex type 1 in experimental corneal herpes in rabbits: the effect of an aqueous extract of Coptis japonica Makino against herpes simplex.





Effect of fatty acids on arenavirus replication: inhibition of virus production by lauric acid.
Bartolotta S1, García CC, Candurra NA, Damonte EB. (2001)

To study the functional involvement of cellular membrane properties on arenavirus infection, saturated fatty acids of variable chain length (C10-C18) were evaluated for their inhibitory activity against the multiplication of Junin virus (JUNV). The most active inhibitor was lauric acid (C12), which reduced virus yields of several attenuated and pathogenic strains of JUNV in a dose dependent manner, without affecting cell viability. Fatty acids with shorter or longer chain length had a reduced or negligible anti-JUNV activity. Lauric acid did not inactivate virion infectivity neither interacted with the cell to induce a state refractory to virus infection. From mechanistic studies, it can be concluded that lauric acid inhibited a late maturation stage in the replicative cycle of JUNV. Viral protein synthesis was not affected by the compound, but the expression of glycoproteins in the plasma membrane was diminished. A direct correlation between the inhibition of JUNV production and the stimulation of triacylglycerol cell content was demonstrated, and both lauric-acid induced effects were dependent on the continued presence of the fatty acid. Thus, the decreased insertion of viral glycoproteins into the plasma membrane, apparently due to the increased incorporation of triacylglycerols, seems to cause an inhibition of JUNV maturation and release.

Inactivation of enveloped viruses and killing of cells by fatty acids and monoglycerides. (1987)

Lipids in fresh human milk do not inactivate viruses but become antiviral after storage of the milk for a few days at 4 or 23 degrees C. The appearance of antiviral activity depends on active milk lipases and correlates with the release of free fatty acids in the milk. A number of fatty acids which are normal components of milk lipids were tested against enveloped viruses, i.e., vesicular stomatitis virus, herpes simplex virus, and visna virus, and against a nonenveloped virus, poliovirus. Short-chain and long-chain saturated fatty acids had no or a very small antiviral effect at the highest concentrations tested. Medium-chain saturated and long-chain unsaturated fatty acids, on the other hand, were all highly active against the enveloped viruses, although the fatty acid concentration required for maximum viral inactivation varied by as much as 20-fold. Monoglycerides of these fatty acids were also highly antiviral, in some instances at a concentration 10 times lower than that of the free fatty acids. None of the fatty acids inactivated poliovirus. Antiviral fatty acids were found to affect the viral envelope, causing leakage and at higher concentrations, a complete disintegration of the envelope and the viral particles. They also caused disintegration of the plasma membranes of tissue culture cells resulting in cell lysis and death. The same phenomenon occurred in cell cultures incubated with stored antiviral human milk. The antimicrobial effect of human milk lipids in vitro is therefore most likely caused by disintegration of cellular and viral membranes by fatty acids. Studies are needed to establish whether human milk lipids have an antimicrobial effect in the stomach and intestines of infants and to determine what role, if any, they play in protecting infants against gastrointestinal infections.

Interaction of polyunsaturated fatty acids with animal cells and enveloped viruses.
A Kohn, J Gitelman, and M Inbar (1980)

Essential unsaturated fatty acids such as oleic, linoleic, or arachidonic were incorporated into the phospholipids of animal cells and induced in them a change in the fluidity of their membranes. Exposure of enveloped viruses such as arbo-, myxo-, paramyxo-, or herpesviruses to micromolar concentrations of these fatty acids (which are not toxic to animal cells) caused rapid loss of infectivity of these viruses. Naked viruses such as encephalomyocarditis virus, polio virus or simian virus 40 were not affected by incubation with linoleic acid. The loss of infectivity was attributed to a disruption of the lipoprotein envelope of these virions, as observed in an electron microscope.

[Nate-2004]

A reply to the original post on this thread:

 

What are the reasons for this lack of focus and funding on this important area of research? This is an issue I would love to see discussed further on this site. 

This lack of focus and funding on how pathogens may cause accelerated aging and precipitate disease needs to be addressed.

 

The same reason as all the other areas. The incentives system in science is seriously messed up. Researchers aim for prestige, social approval and acceptance. Going out on the fringe (aging research in this and other areas) or attempting to reproduce and publish results is discouraged and the bad interpretation and reporting by journalists is the least of all the problems.

 

It's an old system that needs serious change. The motives for publishing a paper should be curiosity and interest, not getting into some prestigious journal or getting the approval of peers.  This system along with the patent and copyright system need to end, that kind of protectionism and outright theft (corporate welfare) by publishers distorts and seriously slows everything down in addition to all this mess.

 

Luckily some rebels are fighting back.

 

 

Edited by Nate-2004, 14 June 2016 - 08:23 PM.

[pone11]

 
In the beginning they say that glucagon "significantly stimulates autophagic protein degradation". It is well known that levels of glucagon has the inverse relationship to insulin and blood glucose levels. Then they say, "the reduction in insulin plays a principal role in the induction of liver autophagy." This means that there is no need, really, to measure the levels of FAAs. The levels of insulin and/or glucagon should suffice. 
 
One can judge the levels of insulin by the levels of blood glucose. As for glucagon, here is a paper that examines its levels in humans by the day of fasting (THE EFFECTS OF TOTAL STARVATION UPON THE LEVELS OF CIRCULATING GLUCAGON AND INSULIN IN MAN, 1963). There is a graph there, on page 1034, showing the mean glucagon levels on each day (they fasted for 3 days). Here is what they say:
 

Glucagon concentration, which had averaged 292
uL/ugEq per ml before starvation, failed to change
significantly during the first 24 hours; however,
at the end of 48 hours there was a statistically significant
increase in glucagon concentration, which
rose further to a mean level of 893 uL/ugEq per ml
at the end of day 3 of starvation (p < 0.01). 
 

Very interesting is Table II in this human study report. It lists glucose, insulin and glucagon levels in each of their cohort day by day. Note that when glucose is higher than 80 mg/dL, the glucagon level is 0 (in fasted men), which means that autophagy remains at the basal level. You need to get the glucose well below that to trigger glucagon release and for this, you need to deplete your liver glycogen. Again, for most people it takes 36-48 hrs after the last meal, as it is self-reported on the fasting forums. This paper confirms this.

 

Glucagon may in fact act as a key stimulus to autophagy, but I think it is a misreading of figures 2 and 3 in the rodent study I linked to use glucagon as your marker.  Look at figure 2 and glucagon.  There is no sudden rise there.   There is absolutely nothing in the shape of the glucagon curve that tells us when autophagy starts.  So while it may be a biochemical trigger, it is not the useful clinical marker.   To contrast figure 3 is outstanding.  Every single amino acid they measured - including a simple plasma measurement of free amino acids - DRAMATICALLY rises between hours 19 and 23.  I think in fact that the data underestimates this effect because they are interpolating only two data points.  Had they supplied the missing points in between, I predict that autophagy is like a light switch and would have given a sharp dramatic rise in free amino acids literally within a single hour.   So free amino acids is the useful clinical marker.

 

The above paragraph by itself is very important.   I have been looking for a useful clinical marker to signal the start of autophagy for months.  It has been dead end after dead end.  I think this one is pay dirt.

 

I think your reasoning is not quite right regarding autophagy, glucagon, insulin, and glucose.  In the rodent study, figure 4 clearly shows us a *dramatic rise in glucose* at the moment autophagy turns on, right around hour 23.  This is in the face of falling insulin!!!   I have problems understanding this, but the data is very clear that the rising glucose - from the gluconeogenesis of the amino acid products of autophagy - does NOT stimulate additional insulin.   Could it be that insulin is triggered primarily by glucose entering in through the digestive system, and glucose from gluconeogenesis does not trigger rises in insulin in the same way?

 

 

So, It is doubtful you get autophagy above the basal level in your 16h "fasts". It is also doubtful that you get there even with the induction of ketosis, at 38-48h after the last meal. This is because, according to the paper you posted, in mice, the enhanced level of autophagy was seen after 24h, i.e. after they have already lost 25% of the liver weight.

 
Judging also by their FFA and triacylglycerol graphs (Fig. 2), it looks like by the 24h mark these mice have depleted their main fat reserves and this is what in turn then triggered autophagy -- iow they began to catabolize their protein only after they have lost most of their disposable fat, which is in line with all animal starvation studies. Protein is precious and fat is disposable. Too bad this paper does not list how much weight and fat the mice lost by 24h. Were they lean or fat mice to begin with? Of course, a fat mouse would take a longer time to get there than a lean mouse, and the same applies to humans. I'd guess they were lean mice, 'cause they had already fasted them for a day, then fed them just for a few hrs before fasting them again for this 40h study. 
 
To me this rather confirms that for a human --and I'm talking about a lean human to start-- it should take a couple of weeks to get to the level of autophagy seen in these mice during the second day of fasting. Of course, this brings another issue, the muscle loss. People want to fast and they want to induce autophagy, but they don't want to lose muscle mass. There is no easy answers here, especially without proper human studies.
 
My conclusion: your "16h fast" does not induce the level of autophagy you dream about, sorry. Again, in my book it is called not a fast, but eating once a day. Nothing to do with fasting.

 

I tend to agree with you.  The amount of autophagy I am likely to see after 16 hours is not significant.   However, it's not something I am willing to extrapolate and guess about based on rodents.   As you say, there are differences between the species.

 

So here is the experiment I propose:  as I am fasting, measure free amino acids every four hours, looking for the time when there is a dramatic jump up.   It should not be subtle.  FAA are going to settle into a flat trend and then - boom - there will be a steep rise and then a slow return to the baseline.   Time the end of the fast to be the point when FAA have returned back 80% (approximate) of the way to baseline.

 

There is a related issue here.   At what point does gluconeogenesis start tearing down my skeletal muscle and wasting precious lean mass?  If I believe the mouse study the amount of amino acids from autophagy alone is huge and probably lessens muscle wasting?   But how would I measure this?  

 

The sweet spot here is to get a biochemical marker for the start of autophagy and a separate biochemical marker for the start of muscle wasting, and - in a perfect world - you chase autophagy and end the fast at the point muscle wasting starts.   

 

I would be all over making myself the guinea pig for this, but I need the biochemical markers.

 

I'm thinking there must be a human study somewhere that measure free amino acids in humans several times a day for the first two weeks of a fast?

 

Edited by pone11, 16 June 2016 - 07:46 AM.

[pone11]

 

Quercetin, Nilotinib, Galangin and Silibinin all induce phagocytosis. and Baicalein interesting inhibits phagocytosis while managing to prevent fibril tangles and amyloid plaques. Rotenone and Ceramide induce mitophagy.

 

 

And what is the value of phagocytosis without autophagy?   All you would be doing is collecting cellular garbage that never gets removed from the cell.  Autophagy is the key to cleaning out those phagocytes.   I thought the whole point of diseases like alzheimer's was that phagocytes do collect things but autophagy never works correctly, so the garbage accumulates and plaques develop.  This induces apoptosis, which is effectively the death of neurons.   

 

The whole point of autophagy is to avoid apoptosis / cell death.  It's a cellular rotor rooter to clean out bad organelles, defective proteins, bacteria, and viruses, that might otherwise accumulate and trigger some apoptosis event that kills the cell.

 

Autophagy probably does not attack bacteria and viruses that are stealthy enough to disable innate immunity.   Or does it?  That's one of the open questions for me, whether autophagy might represent a novel and unique way for the body to deal with invaders that otherwise evade innate immunity working on its own.

Edited by pone11, 16 June 2016 - 08:03 AM.

[gamesguru]

the two are related, even with apoptosis. I think HSV keeps multiplying despite sequester vesicles, until apoptosis.

Galangin sensitizes TRAIL-induced apoptosis through down-regulation of anti-apoptotic proteins in renal carcinoma Caki cells.

[Nate-2004]

Just keeping this thread up to date, there's a discussion going on in the NR thread about this now regarding whether NR just feeds into these pathogens.

[SearchHorizon]

I have to agree with the idea that the most significant factor is likely genetic/epigenetic, not microbes. We have not yet identified the major culprit (i.e., identified the specific gene or epigenetic factor) - if we had, we should have been able to extend lifespans of lab mice multifold (e.g., 5x, 3x, etc.).

 

 

[JustGetMeIntoSpace]

I am going to kind of just insert myself into the middle of a long thread here, but I think the point is worth noting.  There is an author - Thomas Levy - who has done a nice job compiling the older but very convincing imo - research into the power of (liposomal and IV) Vitamin C megadosing to control and irradicate viruses.  If you read his book, you'll see that there are abundant case studies from M.D.'s that Vitamin C - at high plasma levels - can control many of these very very nasty viruses that plague mankind right now.  I think it's a shame that it doesn't get more attention.

 

Is there any modern corroboration of this?  Well, there is a study showing Epstein-Barr was nicely decreased, although not totally cured within the study period, but Vitamin C and there is a cancerous tumor shrinking study as well.

 

Now my only caution with all of this is that it works by increasing peroxide levels, but side effects seem to be non-existent, so the theory is that it only increases peroxide at the infection locations.

 

Anyway, viruses are half the battle and Vitamin C appears to be a pretty good tool in one's arsenal whether or not these microbes play a major or minor role in life extension.

[ceridwen]

I thought a large amount of Vitamin C could cause cancer?

[Logic]

Cross referencing:

Chronic Bacterial and Viral Infections in Neurodegenerative and Neurobehavioral Diseases

http://www.longecity...ioral-diseases/

Biofilm breakers and, further down; bacteriophage how to etc.
http://www.longecity...ndpost&p=781392

 

[pamojja]

I thought a large amount of Vitamin C could cause cancer?

 

https://www.ncbi.nlm...les/PMC4388666/

 

Why you thought so?
 

[Logic]

Surprise Discovery Suggests Scientists May Need To Rethink Which Genes Control Aging
 
"...To better understand the role of bacteria in health and disease, National Institutes of Health researchers fed fruit flies antibiotics and monitored the lifetime activity of hundreds of genes that scientists have traditionally thought control aging. To their surprise, the antibiotics not only extended the lives of the flies but also dramatically changed the activity of many of these genes. Their results suggested that only about 30% of the genes traditionally associated with aging set an animal’s internal clock while the rest reflect the body’s response to bacteria..."
https://scitechdaily...-control-aging/

The Paper
https://www.cell.com...14?showall=true