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How Many Hours Before Autophagy Begins in Fasting?

autophagy mtor fasting

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#1 Nate-2004

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Posted 16 May 2017 - 02:13 PM


I've been scouring the internet to find any kind of definitive answer and the only hint I can find is 36 hours in a Jason Fung interview. Does anyone know at which point during a water fast that mTOR is deactivated in response to zero protein and autophagy begins?

 

Also is there anything other than protein that might disrupt this process?



#2 Michael

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Posted 17 May 2017 - 12:08 AM

There's no real answer to this. Autophagy is engaged to varying degrees in varying tissues even over the course of a normal day with an 8 h overnight fast. Here's what it looks like in mouse liver (remember, or know ye, that mice are active in the dark and sleep in the day, so invert the pattern you see here):
 

F1.large.jpg

Figure 1. Rhythmic induction of autophagy in the liver. "Temporal orchestration of circadian autophagy rhythm by C/EBPβ."

 
Mice tend to either max out autophagy at 24 hours of fasting, or slightly increase it, or return to baseline at 48:
 

F4.large.jpg

Figure 7. Quantitative analysis of the formation of GFP-LC3 dots during starvation.  In Vivo Analysis of Autophagy in Response to Nutrient Starvation Using Transgenic Mice Expressing a Fluorescent Autophagosome Marker

 
.. with the caveat that we don't have data for eg. 12 or 36 hours. This is all macroautophagy, by the way: the circadian rhythms of micro- , chaperone-mediated, and mitophagy doubtless all follow a different pattern (see wikipedia if this is gibberish). Per unpublished work by Anna-Maria Cuervo, "regular" 40% daily CR is very effective in boosting CMA, whereas alternate-day fasting has nearly no effect (unpublished, but presented at UABBA 2008).
 
Humans on regular CR exhibit elevated autophagy in muscle after a normal overnight fast, whereas marathoners do not; on the other hand, an acute bout of
"aerobic exercise activates %5Bmuscle%5D autophagic signaling through ULK1 in human skeletal muscle, independently of nutrient background".
 
To get a sense of the human time-course, you'd have to either have transgenic humans expressing fluorescent tags upon expression of key autophagy-induced genes, or have people willing to undergo repeat biopsies over the course of your time period of interest (and be able to take account of the artifactual effects of these injuries).


Edited by Michael, 17 May 2017 - 12:11 AM.

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#3 xEva

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Posted 17 May 2017 - 01:42 AM

Thanks Michael :)  that's very interesting! Thought these mouse data could be of more use to humans if they also showed when their livers ran out of glycogen.  

 

Otherwise this study shows that mice lose 25% of liver mass after 24h: Liver autophagy contributes to the maintenance of blood glucose and amino acid levels, 2011, PMC3149698

 

Clearly, mouse data is not easy to apply to humans. The metabolic rate is vastly different.



#4 Michael

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Posted 17 May 2017 - 03:15 AM

Thanks Michael :)  that's very interesting! Thought these mouse data could be of more use to humans if they also showed when their livers ran out of glycogen.

 
I don't want to read too much into your choice of words, but you seem here to be buying into the notion (widespread in Paleo circles) that autophagy is initiated in the liver and muscle after glycogen is depleted. Rather, autophagic degradation of glycogen granules is itself an important function of autophagy.

 

Clearly, mouse data is not easy to apply to humans. The metabolic rate is vastly different.


Sure, but the rotation of the Earth is the same ;) . I don't disagree that there will be time-course differences due to differences in metabolic rate, residual energy reserves, and other things, but a key driver is the circadian rhythm, and that's 24 hours for (nearly?) every organism on earth.



#5 xEva

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Posted 17 May 2017 - 08:36 AM

 

Thanks Michael :)  that's very interesting! Thought these mouse data could be of more use to humans if they also showed when their livers ran out of glycogen.

 
I don't want to read too much into your choice of words, but you seem here to be buying into the notion (widespread in Paleo circles) that autophagy is initiated in the liver and muscle after glycogen is depleted. Rather, autophagic degradation of glycogen granules is itself an important function of autophagy.

 


 
I'm sure "autophagic degradation of glycogen granules" is not the kind of autophagy that interests Nate here. He wants to know when real! autophagy starts, the one that utilizes all sorts of junk lying around, renews mitochondria, kills intracellular pathogens and makes you young and pretty :) Right, Nate?
 
And it's natural to assume that that kind of autophagy will start well after your last meal is fully utilized and liver glycogen is depleted. That's what mice studies could show -- or not. Though by now there must be  enough data to figure it out, if one really wants to know. 

 
 

 

Clearly, mouse data is not easy to apply to humans. The metabolic rate is vastly different.


Sure, but the rotation of the Earth is the same ;) . I don't disagree that there will be time-course differences due to differences in metabolic rate, residual energy reserves, and other things, but a key driver is the circadian rhythm, and that's 24 hours for (nearly?) every organism on earth.

 

 

 

I don't see why circadian rhythm should be a key driver in a fast that lasts longer than a day. A day for a mouse is very long time. After 2 days of fasting it will be in "profound neuronal authophagy", that's how desperate its brain will be, while an average human is still cruising in the same metabolic mode, not even in ketosis. On the 3rd day a mouse will be on its last leg, while a human is just getting into ketosis. A mouse has already starved to death, while a human is still in the second phase, adapting to starvation. There is no comparison. 

 

And yes, this is expected just from comparing heartbeat (670 vs 72) and respiratory rates (63 vs 12). Also, I'm sure you know, but Nate may not, that a mouse will lose 10% of its body weight in 24h, while a human < 2%, and even then it will be mostly water. Metabolic demand and expenditure in the same time period are vastly different.

 

No one denies the importance of circadian rhythms, and you must be right saying  that they will cause the authophagy level to dip or rise throughout a day accordingly, but it is the progression of the stages of starvation through the days for a mouse and weeks for a human that take precedence here, no?  

 

 

Still no clear answer, ah Nate? :)


Edited by xEva, 17 May 2017 - 08:39 AM.


#6 Michael

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Posted 17 May 2017 - 11:35 AM

 

you seem here to be buying into the notion (widespread in Paleo circles) that autophagy is initiated in the liver and muscle after glycogen is depleted. Rather, autophagic degradation of glycogen granules is itself an important function of autophagy.


I'm sure "autophagic degradation of glycogen granules" is not the kind of autophagy that interests Nate here. He wants to know when real! autophagy starts, the one that utilizes all sorts of junk lying around, renews mitochondria, kills intracellular pathogens and makes you young and pretty :) Right, Nate?
 
And it's natural to assume that that kind of autophagy will start well after your last meal is fully utilized and liver glycogen is depleted. That's what mice studies could show -- or not. Though by now there must be  enough data to figure it out, if one really wants to know.

 
You may think it natural to assume that, but, well, it's not true ;) . Macroautophagy (the kind "that utilizes all sorts of junk lying around") is going on all the time: its "merely" upregulated at different times per circadian rhythm and with fasting. Mitophagy (which renews mitochondria) is a selective process driven primarily by membrane damage to the individual mitochondria, which then actively recruits isolation membranes via PINK1 and Parkin. Sure, it's also secondarily affected by of day and fasting — a study which AFAICS hasn't yet been published formally  reports the time-course of mitophagy in fasting in mice — but it's just not the case that mitophagy or any kind of autophagy doesn't get started until some extended fast period has taken place. And as I noted, Cuervo has found that "regular" 40% daily CR is very effective in boosting CMA in mice, whereas alternate-day fasting has nearly no effect, despite a longer period with no food.
 

 

xEva wrote: Clearly, mouse data is not easy to apply to humans. The metabolic rate is vastly different.

Sure, but the rotation of the Earth is the same ;) . I don't disagree that there will be time-course differences due to differences in metabolic rate, residual energy reserves, and other things, but a key driver is the circadian rhythm, and that's 24 hours for (nearly?) every organism on earth.

 
I don't see why circadian rhythm should be a key driver in a fast that lasts longer than a day. A day for a mouse is very long time.

 


Again, I don't disagree: I've just posted data showing multiple different time-courses of autophagy in different organs over the course of 24 and 48 hours  of fasting in mice (to which your nice in vivo neuronal study adds an additional organ), and "I don't disagree that there will be time-course differences due to differences in metabolic rate, residual energy reserves, and other things." But, again, there is no reason to think that some special, unique autophagic process suddenly goes from zero to one, or "not enough" to "enough," after some extended period of fasting: rather, there is an upregulation of processes that are active constitutively and with diurnal variations (and, in the case of CMA, mitophagy, and to a lesser extent microautophagy, also depending on regulatory factors specific to their selective targets).



#7 Nate-2004

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Posted 17 May 2017 - 01:18 PM

So basically nobody really knows when autophagy begins in humans fasting longer than 24h. It could take 36 hours it could take 120, I didn't know if I should keep going after 72 hrs today or what, but I think I've already made the decision to break it after 72. 



#8 Nate-2004

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Posted 17 May 2017 - 01:28 PM

I'm sure "autophagic degradation of glycogen granules" is not the kind of autophagy that interests Nate here. He wants to know when real! autophagy starts, the one that utilizes all sorts of junk lying around, renews mitochondria, kills intracellular pathogens and makes you young and pretty :) Right, Nate?

 

That's pretty much spot on. I guess there's just no legit answer here.



#9 maxwatt

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Posted 17 May 2017 - 03:17 PM

Asking the question is like asking  "how high is up?"


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#10 xEva

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Posted 17 May 2017 - 03:17 PM

I think there are clues, and they point to an extended time, for a human. Take for example the in vivo study ("profound neuronal authophagy") mentioned above. Why did they have to fast their mice for 48h? I'm guessing, and not without reason, that at 24h the changes were not quite as striking, or maybe even not 'statistically insignificant' -?

 

But there are definite, well defined stages or phases of starvation, and it's possible to tie certain observations to a particular phase. Unfortunately the principle studies on this were done not on mice but on rats, like this one: Fasting-induced rise in locomotor activity in rats coincides with increased protein utilization. It's fairly straightforward to map time through the phases of starvation for each species. Though it would be more precise if we had a mouse study to begin with. Maybe there is such -? Otherwise one would have to prorate the rat data.

 

I would not mind making a time estimate for humans based on a 'phases of starvation' study on a mouse, if it exists, (I'm not inclined to look for one now).

 

 

PS

of course it's funny that they called their study on neuronal autophagy "short-term fasting", 'cause 48h is not short-term for a mouse. It's definitely well into phase II or maybe even phase III already. 



#11 Nate-2004

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Posted 17 May 2017 - 03:22 PM

Asking the question is like asking  "how high is up?"

 

I am inclined to disagree. You'll have to explain this metaphor more to convince me.



#12 Michael

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Posted 17 May 2017 - 04:05 PM

I think there are clues, and they point to an extended time, for a human. Take for example the in vivo study ("profound neuronal authophagy") mentioned above. Why did they have to fast their mice for 48h? I'm guessing, and not without reason, that at 24h the changes were not quite as striking, or maybe even not 'statistically insignificant'

 

If you read the full-text study that you linked, ;) you'll read and see:

 

 

Autophagosomes are detectable in cortical neurons of normal-fed mice, and their abundance and characteristics are markedly altered by short-term food restriction.

... Autophagosomes were readily detectable in cortical neurons of normal-fed mice  ... These vesicles were few in number and small in size (Fig. 2B). Food restriction caused a marked increase in both the number and the size of neuronal autophagosomes in the cell body of cortical neurons; these changes were present after 24 hours of food restriction (Fig. 2A, middle row), and were even more dramatic at 48 hours (Fig. 2A and bottom row). As was observed in the liver (Fig. 1), when compared to autophagosomes in normal-fed mice, those present in the cortical neurons of mice that had been food-restricted for 48 hours showed reduced circularity, with concomitantly increased feret and perimeter (Fig. 2B). Changes in GFP-LC3 signal also were observed in the neuronal cell processes ...

 

kaup_a_10912376_f0002.gif

 

As you can see, there is baseline autophagy in cortical neurons of fed mice, which increases with fasting; most of the induction is present at 24 h, with a more modest further enhancement at 48. And, again, see the figures in my original post for other organs.

 

 

Asking the question is like asking  "how high is up?"

 

I am inclined to disagree. You'll have to explain this metaphor more to convince me.

 

The metaphor is given concrete form in my first two posts. There is no magic point at which autophagy "begins" (let alone a special, fasting-specific form of autophagy): it's on all the time, and enhanced by fasting, at different time courses in different organs. A better question might be "when does autophagy peak after initiating fasting." As I also indicated in my original post, I'm not aware of solid data on the time-course in humans, which would require multiple biopsies or transgenic humans whose cells would light up when autophagic genes were being expressed — or a novel visualization technique that has yet to be invented.


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#13 Nate-2004

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Posted 17 May 2017 - 04:25 PM

Thanks Michael. That makes a lot of sense, as much of that as I could understand at least.



#14 Michael

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Posted 17 May 2017 - 04:28 PM

I'm not aware of solid data on the time-course in humans, which would require multiple biopsies or transgenic humans whose cells would light up when autophagic genes were being expressed — or a novel visualization technique that has yet to be invented.


Ah, here's something in humans! Leave it to college students to have chunks taken out of their healthy young muscles ;) .

 

 

Fasting Increases Human Skeletal Muscle Net Phenylalanine Release and This Is Associated with Decreased mTOR Signaling

Eight healthy male volunteers were studied ... on 2 occasions separated by >1 month: 1) after an overnight fast of 10 hours (control), and 2) after 72 hours of fasting, during which subjects were allowed to drink tap water and to perform normal ambulatory activities, excluding physical exercise. At 0800 h (t = 0) the subjects were admitted to a quiet, thermo-neutral room on both examination days. ... Signaling to protein synthesis and breakdown were assessed in skeletal muscle biopsies obtained during non-insulin and insulin stimulated conditions on both examination days.

Results mTOR phosphorylation was decreased by ∼50% following [72 h] fasting [compared to the control 10 h overnight fast], together with reduced downstream phosphorylation of [mTOR targets] 4EBP1, ULK1 and rpS6. In addition, the insulin stimulated increase in mTOR and rpS6 phosphorylation was significantly reduced after fasting indicating insulin resistance in this part of the signaling pathway. Autophagy initiation is in part regulated by mTOR through ULK1 and fasting increased expression of the autophagic marker LC3B-II by ∼30%. p62 is degraded during autophagy but was increased by ∼10% during fasting making interpretation of autophagic flux problematic.

 

However, they just have those 2 time points: we don't know what the eg. 24 and 48 h induction levels looked like.



#15 Nate-2004

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Posted 17 May 2017 - 04:42 PM

Right that leaves open the question of when it peaked or if it was still going to peak even more after 72h. It's not as impressive as I'd like to see but there are other studies showing that the immune system is completely regenerated after 72h fasts, so we know that at least if it's relevant here.



#16 Nate-2004

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Posted 17 May 2017 - 04:50 PM

I wonder what would happen if I just had the occasional tablespoon of olive oil throughout the day during an extended fast.

 

Here's a study that addresses polyphenols and autophagy, which is what made me think of that. Protein is what signals mTOR to activate, or "phosphorylation" as it was put, so it wouldn't involve any protein, just monounsaturated fats. Maybe some coconut oil too.


Edited by Nate-2004, 17 May 2017 - 04:50 PM.


#17 xEva

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Posted 17 May 2017 - 09:39 PM

Right that leaves open the question of when it peaked or if it was still going to peak even more after 72h. It's not as impressive as I'd like to see but there are other studies showing that the immune system is completely regenerated after 72h fasts, so we know that at least if it's relevant here.

 

in rodents, no?

 

I wonder what would happen if I just had the occasional tablespoon of olive oil throughout the day during an extended fast.

 

Here's a study that addresses polyphenols and autophagy, which is what made me think of that. Protein is what signals mTOR to activate, or "phosphorylation" as it was put, so it wouldn't involve any protein, just monounsaturated fats. Maybe some coconut oil too.

 

why, you're too lean as it is and don't have enough of your own fat to burn?



#18 Nate-2004

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Posted 17 May 2017 - 10:08 PM

 

Right that leaves open the question of when it peaked or if it was still going to peak even more after 72h. It's not as impressive as I'd like to see but there are other studies showing that the immune system is completely regenerated after 72h fasts, so we know that at least if it's relevant here.

 

in rodents, no?

 

I wonder what would happen if I just had the occasional tablespoon of olive oil throughout the day during an extended fast.

 

Here's a study that addresses polyphenols and autophagy, which is what made me think of that. Protein is what signals mTOR to activate, or "phosphorylation" as it was put, so it wouldn't involve any protein, just monounsaturated fats. Maybe some coconut oil too.

 

why, you're too lean as it is and don't have enough of your own fat to burn?

 

 

No, humans. That study he quoted was in humans I think. That's what I was replying to.

 

No, it's not that I don't have my own fat to burn, I have some belly pudge. It's that the past 3 days have been unbearable for the most part. This is why most people don't do this, or at least most people in the U.S.  I want to use an all fat diet that I described above so that I am not so miserable. I was outrageously hungry with brief periods of lucidity and clarity and no emptiness, and a sort of lackadaisical weakness. I don't know why you guys don't feel hunger pangs but I do. They're in the stomach, they are super uncomfortable and it growls and cramps and feels soooo empty till I feed it. Either you're not telling the truth about ever feeling that feeling or you're an outlier whose biology or life experiences were nothing like mine.

 

I've never gone a day without food till now.


Edited by Nate-2004, 17 May 2017 - 10:09 PM.

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#19 sthira

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Posted 17 May 2017 - 11:44 PM

...there are other studies showing that the immune system is completely regenerated after 72h fasts, so we know that at least if it's relevant here.


Could you point me to those (human) studies? Not that I'm doubting you, ok, yes, I'm doubting you. Are you referring to some of Longo's studies?

He's made comments to the pop science writers to this effect -- "fasting completely rejuvenated the immune system" -- and he said the same things in podcasts and in a few public speeches. I can post the studies, press articles and links to youtubes and shit, but somehow I think they've been posted dozens of times here.

Groundhog Day. Y'all see that movie? Boy what a good one.

But my understanding is Longo looked at bone marrow cells, did he investigate immune cells like T cells? Does fasting rejuvenate T cells or the thymus? Can you point me in the right direction? I'm lost. Who doesn't want a completely rejuvenated immune system from not eating food for a week or two?
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#20 Nate-2004

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Posted 18 May 2017 - 01:12 PM

 

...there are other studies showing that the immune system is completely regenerated after 72h fasts, so we know that at least if it's relevant here.


Could you point me to those (human) studies? Not that I'm doubting you, ok, yes, I'm doubting you. Are you referring to some of Longo's studies?

He's made comments to the pop science writers to this effect -- "fasting completely rejuvenated the immune system" -- and he said the same things in podcasts and in a few public speeches. I can post the studies, press articles and links to youtubes and shit, but somehow I think they've been posted dozens of times here.

Groundhog Day. Y'all see that movie? Boy what a good one.

But my understanding is Longo looked at bone marrow cells, did he investigate immune cells like T cells? Does fasting rejuvenate T cells or the thymus? Can you point me in the right direction? I'm lost. Who doesn't want a completely rejuvenated immune system from not eating food for a week or two?

 

 

Let me google that for ya lol https://www.google.c...chrome&ie=UTF-8

 

I read some of the quora answers as well, I don't know if the study one of the answer refers to is the one people are referring to. I assumed it was on humans, not mice. I don't remember which one I saw first or where. You're right it was posted somewhere on this forum and the search function might find it.


Edited by Nate-2004, 18 May 2017 - 01:16 PM.


#21 Michael

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Posted 18 May 2017 - 02:38 PM

 

 

...there are other studies showing that the immune system is completely regenerated after 72h fasts, so we know that at least if it's relevant here.

Could you point me to those (human) studies? Not that I'm doubting you, ok, yes, I'm doubting you. Are you referring to some of Longo's studies?

He's made comments to the pop science writers to this effect -- "fasting completely rejuvenated the immune system" -- and he said the same things in podcasts and in a few public speeches. I can post the studies, press articles and links to youtubes and shit, but somehow I think they've been posted dozens of times here.

But my understanding is Longo looked at bone marrow cells, did he investigate immune cells like T cells? Does fasting rejuvenate T cells or the thymus?

 

Let me google that for ya lol https://www.google.c...chrome&ie=UTF-8

 

... and you'll get a whole whack of exactly the kind of uncritical pop science writing to this effect to which Sthira refers ;) . He's quite correct. Longo's "immune regeneration" studies are only on bone marrow stem cells, not the functional immune system; they offer evidence of regeneration, but none on cell-level rejuvenation;  and the human study showed only a nonsignificant trend towards changes in the lymphoid:myeloid ratio which promptly reverts to baseline shortly after the fast ends.
 


Edited by Michael, 18 May 2017 - 02:42 PM.

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#22 Nate-2004

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Posted 18 May 2017 - 03:57 PM

Wow that's sad. There is just no hope is there. Everything is sensationalist media hype and the rest is pathetic, useless, hopeless drivel.  I am really skeptical now about the whole fasting thing. How much of it is BS? Like, can we really trust Valter Longo's assessments or Jason Fung's claims or Rhonda Patrick's encouraging points? 



#23 xEva

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Posted 18 May 2017 - 05:09 PM

...
... and you'll get a whole whack of exactly the kind of uncritical pop science writing to this effect to which Sthira refers ;) . He's quite correct. Longo's "immune regeneration" studies are only on bone marrow stem cells, not the functional immune system; they offer evidence of regeneration, but none on cell-level rejuvenation;  and the human study showed only a nonsignificant trend towards changes in the lymphoid:myeloid ratio which promptly reverts to baseline shortly after the fast ends.

 

 

Sorry :) but I don't understand what you mean by "cell-level rejuvenation" -? Here the cells of the immune sys are regenerated anew, and new cells are as young as can be (minus telomere length maybe -?) So what do you mean by rejuvenation here? What would be a good indicator of it?



#24 xEva

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Posted 18 May 2017 - 11:29 PM

.. Longo's "immune regeneration" studies are only on bone marrow stem cells, not the functional immune system; they offer evidence of regeneration, but none on cell-level rejuvenation;  and the human study showed only a nonsignificant trend towards changes in the lymphoid:myeloid ratio which promptly reverts to baseline shortly after the fast ends.


It's not "only on bone marrow stem cells". In mice, they also kept track of lymphoid and myeloid cells:

 

 At the end of six cycles of treatment, mice in the PF group [prolonged fasting] also showed normal or close to normal levels of lymphoid cells and normal ratios of lymphoid and myeloid cells (L/M) (Figure 1E, right panel). 

 

Regarding humans and 72h:

 

the results from a phase I clinical trial indicate that 72 but not 24 hr of PF  in combination with chemotherapy were associated with normal lymphocyte counts and maintenance of a normal lineage balance in WBCs (Figure 1F). 

 

If you look at Figure 1F, it does not look "nonsignificant". To the contrary, it looks like 72h fasting protected lymphocytes from destruction by chemo seen in the control group.  

 

 

Also, in mice again, they tied it neatly together:

 

In agreement with the effect of PF on the recovery in WBC numbers and improvement in lymphoid/myeloid ratio, results of fluorescence-activated cell sorting (FACS) analyses for stem cell populations indicated an improved preservation of LT-HSCs and ST-HSCs and the enhanced resistance to the myeloid bias in the PF group after six cycles of CP treatment in mice (Figures 1G and 1H).

 

As for functionality of the immune sys, they transplanted bone marrow cells from the treated mice to the recipient mice and then took measurements at 16 weeks:

 

BM cells collected from mice treated with either CP or PF + CP were transplanted into the recipient mice. The chimerism of donor-derived cells in PB and that in BM was determined 16 weeks after primary BM transplantation. The ratio of lymphocytes to myeloid cells (L/M) in the reconstituted blood was also measured.(Figure 1I).

 

 

Then they studied aged mice and restored their biased ratio to that of young mice:

 

 We therefore investigated if PF cycles can correct this bias in aged mice. Results from 18-month-old mice indicate that eight cycles (!) of PF could reverse the age-dependent myeloid bias in HSC subtypes and reverse the effect of aging on WBC number in whole blood (Figures 2F and 2G), .... Taken together, these results suggest that PF cycles can also stimulate the HSCs in a chemotherapy-independent manner, which leads to a lineage-balanced hematopoietic regeneration.

 

 

Regarding your "lymphoid:myeloid ratio which promptly reverts to baseline shortly after the fast ends" -- where did you see that? Besides, regeneration mainly takes place during the refeeding phase, which is after the fast ends. Maybe you mean that soon after refeeding it went back to the biased baseline? Admittedly, It's a hairy study, I did not see it, but maybe I missed it -? That would be a real bummer, if after all that effort it reverted to baseline.

 

Thanks Michael  :)

 

 

But guys, did you notice that it takes 5 to 8 cycles to revive an aged or damaged immune sys? What makes you think that "not eating food for a week or two"  --just once-- would suffice?

 

 

oh yeah: Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression, 2014


Edited by xEva, 18 May 2017 - 11:38 PM.


#25 Michael

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Posted 19 May 2017 - 02:06 AM

 

.. Longo's "immune regeneration" studies are only on bone marrow stem cells, not the functional immune system; they offer evidence of regeneration, but none on cell-level rejuvenation;  and the human study showed only a nonsignificant trend towards changes in the lymphoid:myeloid ratio which promptly reverts to baseline shortly after the fast ends.


It's not "only on bone marrow stem cells". In mice, they also kept track of lymphoid and myeloid cells:
 

 At the end of six cycles of treatment, mice in the PF group [prolonged fasting] also showed normal or close to normal levels of lymphoid cells and normal ratios of lymphoid and myeloid cells (L/M) (Figure 1E, right panel). 

 
Regarding humans and 72h:
 

the results from a phase I clinical trial indicate that 72 but not 24 hr of PF  in combination with chemotherapy were associated with normal lymphocyte counts and maintenance of a normal lineage balance in WBCs (Figure 1F). 

 
If you look at Figure 1F, it does not look "nonsignificant". To the contrary, it looks like 72h fasting protected lymphocytes from destruction by chemo seen in the control group.
oh yeah: Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression, 2014

 


Youl'll note that I mentioned the effect on the lymphoid:myeloid ratio in my original reply. This refers to population-level shifts in the balance of lymphoid- and myeloid-biased progenitor cells exiting the bone marrow. LT-HSCs and ST-HSCs, of which you also quote below, are also bone marrow progenitor cells.
 
Second, the study you're quoting involves fasting in combination with myeloablative chemotherapy to wipe out the original bone marrow compartment:
 

To assess whether the protection of [Hematopoietic stem and progenitor cells (HSPCs)] improved the hematopoietic recovery, we compared the hematological profiles of [cyclophosphamide (CP)]  and [prolonged fasting (PF)] + CP mice at baseline (before CP treatments, after PF), at nadir (2–4 days after CP) and during the recovery phase (8–10 days after CP) for each cycle of chemotherapy. ... Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients.

 
I don't think that's what Nate is interested in ;) . I was discussing Longo's work in modified fasting in untreated, otherwise-normal humans:
 

In mice, cycles of the FMD promoted an increase of mesenchymal stem and progenitor cells (MSPC; Figure 2). We therefore analyzed linCD184+CD45 MSPCs in the peripheral blood of human FMD subjects (Figure 6J). Although not significant, the percentage of MSPC in the peripheral blood mono-nucleated cell population showed a trend (p = 0.1) to increase from 0.15 ± 0.1 at baseline to 1.06 ± 0.6 at the end of FMD, with a subsequent return to baseline levels after re-feeding (0.27 ± 0.2). A larger randomized trial will be required to determine whether the number of specific populations of stem cells is in fact elevated by the FMD in humans.


 This is after three monthly rounds of modified fasting and refeeding. I'm not aware of any other data on this question in otherwise-normal, otherwise-healthy humans. 
 


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#26 Nate-2004

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Posted 19 May 2017 - 03:05 AM

This video popped up on my YouTube making the same sort of claims regarding the immune system and other claims which I'm not sure about. I assume a lot of this is sensationalist stuff based on yet more mouse studies that haven't really been repeated over and over.

 



#27 xEva

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Posted 19 May 2017 - 03:49 AM

Youl'll note that I mentioned the effect on the lymphoid:myeloid ratio in my original reply. This refers to population-level shifts in the balance of lymphoid- and myeloid-biased progenitor cells exiting the bone marrow. LT-HSCs and ST-HSCs, of which you also quote below, are also bone marrow progenitor cells.

Second, the study you're quoting involves fasting in combination with myeloablative chemotherapy to wipe out the original bone marrow compartment:


yes, in combination with chemo for human subjects. But I think it was unfair for you to ignore their studies of "aged mice", undamaged by chemo -- which was in addition to damaged by chemo mice, just like humans-- which allowed them to draw meaningful parallels. In aged mice they restored their biased by age ratio to that of young mice after 8 cycles of fasting (I quote them above).
 
and the "modified fasting" study you quote also lists complete blood counts of mice in all groups (in supplemental information) -- so it's more than "only bone marrow stem cells".

 

I don't think that's what Nate is interested in ;) . I was discussing Longo's work in modified fasting in untreated, otherwise-normal humans:
 

 This is after three monthly rounds of modified fasting and refeeding. I'm not aware of any other data on this question in otherwise-normal, otherwise-healthy humans.

 

ok found it. This must be what you meant by "reverting to baseline":
 

 Although not significant, the percentage of MSPC in the peripheral blood mono-nucleated cell population showed a trend (p = 0.1) to increase from 0.15 ± 0.1 at baseline to 1.06 ± 0.6 at the end of FMD, with a subsequent return to baseline levels after re-feeding (0.27 ± 0.2).

 

But in humans, there were only 3 cycles of modified diet vs 5-8 fasting cycles in mice -? Maybe it's too early to pooh-pooh them just yet, there is hope:  

 

A larger randomized trial will be required to determine whether the number of specific populations of stem cells is in fact elevated by the FMD in humans.

 

 

 

In the meantime, Nate is quickly turning into a fasting detractor   :laugh:

You Michael were a vocal fasting detractor, years ago. Has your position changed much? or you still believe in superiority of sustained CR?

 

 



#28 xEva

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Posted 19 May 2017 - 04:10 AM

This video popped up on my YouTube making the same sort of claims regarding the immune system and other claims which I'm not sure about. I assume a lot of this is sensationalist stuff based on yet more mouse studies that haven't really been repeated over and over.

 

 

He is lying a bit: prolonged fasting does not touch muscle glycogen stores. Nothing but exercise does. 

 

He is right though about satiated vs hungry states (the best performance, mental or physical, is always in a fasted state) and other things, and  yes, even about the reboot in the immune sys.

 

It's a fact that WBC go down. When the level is restored in refeeding phase, the composition reflects the current needs. True, there is no solid proof in humans yet, but there is empirical evidence: in Russia, in the 1970-80s they were successfully treating sarcoidosis with repeated cycles of prolonged fast (at least 3 cycles of 2-3 weeks each).  



#29 Nate-2004

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Posted 19 May 2017 - 12:53 PM

 

This video popped up on my YouTube making the same sort of claims regarding the immune system and other claims which I'm not sure about. I assume a lot of this is sensationalist stuff based on yet more mouse studies that haven't really been repeated over and over.

 

 

He is lying a bit: prolonged fasting does not touch muscle glycogen stores. Nothing but exercise does. 

 

He is right though about satiated vs hungry states (the best performance, mental or physical, is always in a fasted state) and other things, and  yes, even about the reboot in the immune sys.

 

So if that's the case wouldn't exercise, even a couple of 30 seconds high intensity sprint during a fast speed up ketosis considerably if liver stores are gone in 16 hours?

 

In my experience with the past few days of fasting vs eating and throughout my whole life actually, I have rarely felt I had good mental performance or focus on an empty stomach, for most of the time I'm continuously distracted by thoughts of food and the rumbling, acidic emptiness of my stomach, like it's a black hole trying to consume all my insides.  During those few times when my stomach wasn't torturing me, begging for food, I will say my mental clarity was higher, but my energy was low. I will say though that the moment I broke the 72 hour fast, my brain was done. I went to improv rehearsal that night and I couldn't do a damn thing. He was right about that in the video. 


Edited by Nate-2004, 19 May 2017 - 12:54 PM.


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#30 xEva

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Posted 19 May 2017 - 03:38 PM

So if that's the case wouldn't exercise, even a couple of 30 seconds high intensity sprint during a fast speed up ketosis considerably if liver stores are gone in 16 hours?

 

Not in the least! Muscle glycogen is reserved for muscle itself (and for a good reason!). But during a prolonged fast, muscle glycogen can participate in blood glucose maintenance, though in a very indirect way: exercise leads to lactic acid release, which in liver is then converted to glucose (Cory cycle) and then some of this glucose is picked by by muscle again. That's why exercise feels so good on a fast (subjectively, as if you had a meal).

 

vigorous workouts during the first 2 days of fasting can lead to complete exhaustion of both muscle and liver glycogen -- in muscle due to workouts, in liver just because it's time -- to the point that in the morning of the 3rd day the person can barely move. I know of 2 cases like this and in both they were forced to break the fast.

 
 

In my experience with the past few days of fasting vs eating and throughout my whole life actually, I have rarely felt I had good mental performance or focus on an empty stomach, for most of the time I'm continuously distracted by thoughts of food and the rumbling, acidic emptiness of my stomach, like it's a black hole trying to consume all my insides.  During those few times when my stomach wasn't torturing me, begging for food, I will say my mental clarity was higher, but my energy was low. I will say though that the moment I broke the 72 hour fast, my brain was done. I went to improv rehearsal that night and I couldn't do a damn thing. He was right about that in the video.


Nate, you say yourself that this is a new thing to you. Adaptation to anything new is always hard, especially if one is well past childhood. It takes time and a bit of misery. No way around it.

 

 

Edited by xEva, 19 May 2017 - 04:00 PM.






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