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Has delayed resumption of autophagy with prolonged fasts been raised as a concern here in the past?

 

I dunno about raised as a concern, but I did mention it in our previous exchange:

 

 

A related question is - Michael has presented arguments that CR has all the same benefits of periodic fasting ( and is indeed the mechanism) and induces a gradual cumulative autophagy vs intense rapid autophagy achieved by periodic fasting.

.... which is then even more profoundly turned off upon refeeding. 

 

Interested in thoughts and perspectives on their arguments for keeping fasts <24 hours.

As with much of what's in PHD, this is mostly just mechanistic speculation IMO — like much of the pro-fasting literature. At least there's no obvious "because autophagy!" handwaving here, tho' I imagine there's plenty of that in arguing for fasting in the first place.

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In a recent interview Valter Longo down played the value of autophagy in his 4 day fasting schemes.

I found that interesting and unexpected.

 

Here's the interview:

 

Apologizes for not specifying exactly where he makes that observation, but I know its there cause it caught me by surprise.

 

Randy

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A 24 hour fast for a rodent would be how many fasting days or weeks for a (healthy) person? And in 48 hours for a fasting rodent will lose how much of its body?

 

...

 

Regarding this delay in resumption of autophagy, they cite “a study of famine victims who had lost 25 percent of body weight during a famine and then were given unlimited food found that only 4.9 percent had detectable infections when refeeding began, but 29.1 percent had overt infections two weeks later. […] the infections that flared up were all intracellular infections—the kind that are fought by autophagy.” [3].Those authors, who saw increased malaria following fasting, concluded “Severe undernutrition can suppress certain infections, mostly those due to intracellular pathogens and especially P. falciparum. Refeeding reactivates suppressed infection and can increase vulnerability to certain new infections especially of viral origin.

 

Based on this, they argue that...

We aren't famine victims. We limit calories or go for some moderate fasting followed by a healthy diet obsessively recorded on Cronometer and attempting to hit RDAs.

 

Is a famine victim analogy appropriate? Researchers could choose to perform experiments in healthy, fasting humans, but they don't. I'd rather address why ignoring or failing to perform human studies is acceptable. For example, researchers could fast a group of ten people for three days, a group of ten ad lib feeders for three days, and then check before and after blood, and see what happens. Do you find that those studies have been done?

 

...we have less empirical data for the long-term health impact - including any cumulative metabolic damage from the hypothetical proliferation of intracellular parasitic and opportunistic infection -- of practicing lifelong regular prolonged complete fasts >24 hours.

 

But you mean in rodents? I don't base my eating and fasting decisions on mouse and rat studies. These studies could be performed in healthy people -- and maybe they're being done now -- but until then we're making educated guesses. If the goal is to delay the diseases of aging, our best choice seems to remain CR. But even if you practiced disciplined CR for your entire life, how many extra healthy years might you gain? No one knows. But I doubt it's very much added lifespan -- unless you're paying no attention to healthy lifestyle practices -- what maybe a few years? LS extension will come out of labs, not diet tweaking, imho.

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Thank you Randy! Appreciate the link and great hearing from you.

Are you perhaps referring to 5 minutes in, where he seems to characterize the mechanism of stem cell regeneration in prolonged fasting ( or his FMD version of that) to be apoptosis rather than classic autophagy, followed by proliferation during the re-feeding phase?
If so, while an interesting distinction and worthwhile subject, the mechanism of action for stem cell changes is another matter than the concern raised above that autophagy resumption is delayed on re-feeding with fasts > 24 hours, and has been demonstrated to increase susceptibility to and harm from intracellular organisms.

Whatever the mechanism it is not so much a matter of how it works - or even all the benefits autophagy - but rather the downside of longer complete fasts. Please let me know if you were referring to another part of the interview!

 
Yes that's what I was referring too. 
My point being that even if long term fasting decreases autophagy there still *might* be very signifcant benefits as reported by Longo in a number of his recent papers.
 
Randy

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My point, better stated, is that even if autophagy doesn't return to base line levels after refeeding from a longer fast - So what?

Until some real world problems are demonstrated, the best evidence I"ve seen (from Longo's work) is very positive. Haven't seen any downsides.

 

And that includes folks on chemo after 4 days fasts.

 

Thanks

Randy

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....

Until some real world problems are demonstrated, the best evidence I"ve seen (from Longo's work) is very positive. Haven't seen any downsides.

 

And that includes folks on chemo after 4 days fasts.

 

Thanks

Randy

 

Hi Randy, I'm a follower of Longo's FMD as well, but not everyone regards Longo's work as conclusive evidence. Luigi Fontana, for example, who is another eminent figure in the longevity scenario (a CR proponent), clearly stated that Longo's datasets are too limited to provide evidence that there is no harm in 'prolonged' fasting.

 

My personal view is different. That is, Presently, science is apparently unable to provide final answers to many biologic and metabolic aspects related to human nutrition and aging, due to the inherent complexity of the system and the huge financial and time resourced needed.

 

So, what rules is degree of belief, anedoctal experience, qualitative extrapolation from small datasets, simple inferential logic and so on. Until some results which can be replicated are offered.

 

My stance for example, presently might be that the metabolic setup, as a consequence of the natural cyclicity of abundance and scarcity of nutrients, results in cyclic patterns of fasting and ad libitum natural eating being the most favourable to health and survival. So the autophagy issue would be moot, that is, whatever the reasoning, if I mimick the ancestral cycles of fasting and 'feasting' with healthy and metabolically natural food, I'll be providing my body what it is geared to do best, that is, alternate proliferation (anabolism) and maintenance (catabolism/autophagy).

 

Anabolism obviously tends to decreas autophagy, which will resume at a later time. What's wrong with that?

 

Whereas the theory of CR may argue that results speak for themselves, lab rats live longer on constant CR and not cyclical fasts, to which we may retort that men are not rats, to which Luigi Fontana may retort that longevity parameters are more favourable in CR practictioners, to which we may again retort that CR actually may cause impairment of glucose tolerance, and so on and so forth. I regard that as an entertaining mental game.

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A 24 hour fast for a rodent would be how many fasting days or weeks for a (healthy) person? And in 48 hours for a fasting rodent will lose how much of its body?

 

 

 

 

Thomas Seyfried published a paper suggesting that rodents are much more sensitive  to CR (in certain regards) than  humans. He suggested that moderate rodent CR is equivalent to severe CR/Fasting in humans.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1513228/

 

Randy

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Hi Randy!

 

I read Dr. Seyfried's paper, given in your reference.  BTW, I enjoyed Dr. Seyfried's talk at the last CR Conference, and had the pleasure of asking him several questions.

 

In the paper that you've referenced, Dr. Seyfried is much more cautious in drawing analogues between human and rodent effects of CR or fasting.  He states:

 

"Our findings indicate that moderate CR in B6 mice mimics very low calorie diets or therapeutic fasting in humans. Hence, the numerous health benefits documented in mice following CR may be experienced in humans on very low calorie diets or during periodic therapeutic fasting."

 

It is unclear whether "very low calorie diets in humans" means means "moderate CR in humans", "substantial CR in humans", or "extreme CR in humans".  I think that Dr. Seyfried would be hesitant to answer this if asked; the analogy of mice to humans can be complicated.

 

So I question your assertion that Dr. Seyfried is asserting that"moderate CR in mice is analogous to severe CR in humans".I doubt  that Dr. Seyfried would be willing to answer this question himself.

 

  --  Saul 

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I personally think that temporary suspension of autophagy/catabolic processes during a heavy anabolic/regeneration period that occurs during a post-fast refeed is perfectly natural, and makes a lot of sense.  I don't know that there's any concerns there, it just seems like it's the mechanisms acting like I would expect them to.  Especially if you're supporting the prolonged fast with nutrients, a la the FMD, and thus avoiding the “Severe undernutrition" in the famine example they referenced, I personally don't think there's much danger there.  However, that's just my extrapolation based on the data we have and my understanding of how the mechanisms work.

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Hi Randy!

 

I read Dr. Seyfried's paper, given in your reference.  BTW, I enjoyed Dr. Seyfried's talk at the last CR Conference, and had the pleasure of asking him several questions.

 

In the paper that you've referenced, Dr. Seyfried is much more cautious in drawing analogues between human and rodent effects of CR or fasting.  He states:

 

"Our findings indicate that moderate CR in B6 mice mimics very low calorie diets or therapeutic fasting in humans. Hence, the numerous health benefits documented in mice following CR may be experienced in humans on very low calorie diets or during periodic therapeutic fasting."

 

It is unclear whether "very low calorie diets in humans" means means "moderate CR in humans", "substantial CR in humans", or "extreme CR in humans".  I think that Dr. Seyfried would be hesitant to answer this if asked; the analogy of mice to humans can be complicated.

 

So I question your assertion that Dr. Seyfried is asserting that"moderate CR in mice is analogous to severe CR in humans".I doubt  that Dr. Seyfried would be willing to answer this question himself.

 

  --  Saul 

Hi Saul,

I disagree. 

*Very low calorie diet in humans* typically refers to 600 - 800 calories a day. That's severe CR. And fasting, of course, is 0 calories

https://en.wikipedia.org/wiki/Very-low-calorie_diet

 

Regards

Randy

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Randy: *Very low calorie diet in humans* typically refers to 600 - 800 calories a day. That's severe CR.

 

VLCDs are generally conceived as  temporary regimes  designed for rapid weight loss or some specific therapeutic purpose.

 

In contrast, CR is generally  conceived  as a  very long-term regime  designed to  slow the biological aging process and increase lifespan/healthspan.

 

It seems to me that even "severe CR", if it  is a  long-term regime,  would in most cases involve more calories/day than a VLCD.

Edited by Sibiriak

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Randy: *Very low calorie diet in humans* typically refers to 600 - 800 calories a day. That's severe CR.

 

VLCDs are generally conceived as  temporary regimes  designed for rapid weight loss or some specific therapeutic purpose.

 

In contrast, CR is generally  conceived  as a  very long-term regime  designed to  slow the biological aging process and increase lifespan/healthspan.

 

It seems to me that even "severe CR", if it  is a  long-term regime,  would in most cases involve more calories/day than a VLCD.

 

Neither myself or Seyfriedd were suggesting that 600Kcal/day for a continual CR program. Death would eventually result.

 

I was responding to Saul's comment that it was unclear to what Seyfried meant by *very low calorie diet*. I was just pointing out that this is clear.

A VLCD diet, in the literature, refers to a human diet of 600 -800 Kcals and that's what Seyfried was meant.

 

Once again the point of Seyfried, papers is that *certain results* in rodents from moderate CR can only be reproduced in humans by severe calorie reduction or fasting.

 

Regards

Randy

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Hi again, Randy!

 

That's the definition in Wikopedia -- it's not clear that's what Dr. Seyfried meant.

 

Also, mice do well with "VLCD" (for mice) diets for prolonged periods of time; the 600-800 cal diet for humans, as noted in the Wikopedia article, is good short term -- but not long term.

 

Again, without quibbling over semantics, I reiterate -- Dr. Seyfried would, I think, be unlikely to draw too much of an equivalence between the effects of varying levels of CR on mice, with varying levels of CR on humans.  (I certainly wouldn't do that.)

 

What IS clear:  For humans, the best results (healthspan and lifespan), that you can hope to achieve by controlling diet, is likely to be maximized, by reducing your caloric input as far as you can bring yourself to go, while maintaining adequate nutrition (the latter, realistically, hard to compute: CRONometer gives numbers for "average" humans, but none of us is "average".  You should also do periodic bloodwork testing).  

 

Also unclear is the optimal macronutrient (carb/protein/fat) ratios:  I used t think that I was on a high carbohydrate diet -- since I, like most of us, eat mostly raw vegetables.  While (technically) I was correct -- soluble and insoluble fiber are complex carbohydrates -- what is meant by "carbohydrates" in these ratios is understood to be simple carbs (such as sugar, starch, sugar alcohols, etc.).  By this more correct, definition, my diet is actually low carb, low protein, high fat -- a ketotic diet.  This was verified with bloodwork -- my serum ketone measurement showed that I have "ketosis" (this is because the test is usually performed on diabetics, for which it is a serious complication).

 

  --  Saul

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In the article "Caloric restriction in C57BL/6J mice mimics therapeutic fasting in humans",  Seyfried does provide this definition of VLCDs:

 

Very low calorie diets (approximately 300 kilocalories per day) often produce effects that are similar to those seen during therapeutic fasting

 

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When thinking about it from a logical point of view, it always struck me as weird, why longer fasts should help autophagy more than shorter ones.

 

My logics was like this:

 

Autophagy is a way to provide glucose when the glycogen storage runs out. However, once keto-adaptation is reached, the requirement for glucose drops by like 75% to a really low amount. Hence less autophagy/catabolization is required to provide the remaining glucose.

 

So my theory was that autophagy would start peaking after 24 hours and then gradually reduce over the next 2-3 days until ketosis is reached. So it would basically be highest during the very unpleasant fasting-sickness.

 

Now hearing fasts even shorter than 24 hours beeing ideal is particularly awesome as that's what I'm doing (20:4) since I couldn't bear the fasting sickness I would get on longer fasts.

 

The other thing I'm wondering: When you do that every day is there even so much litter to be targetted by autophagy?

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Hey Saul,

 

We go back a ways, close to 2 decades for me on the old email list.

Always admired your CR disipline and consistentcy and in awe of anyone that cam pump an eliptical on max resistance for more than a minute much less an hour.

We also share an interest in meditation.

 

But I still disagree - Seyfried was specially refering to a 600 - 800 Kcal diet. VLCD have a specific meaning in the literature and Seyfried was not being sloppy.

 

That's the definition in Wikopedia -- it's not clear that's what Dr. Seyfried meant.

 

 


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Hi Randy!

 

Yes, I remember you well from the old List. If there's a CR X (I hope that they'll be one), I'll certainly go

-- hope that you, andmany others in the Forums, will too.

 

About Dr. Seyfried: His talk was very interesting. Also, I chatted with him on the way back home --we both took some of the same planes.

Dr. Seyfried thought that most people (really) doing CR, are in fact on a ketotic diet. I believe that too. (Of course, the only

way to be sure, is to have blood keytones tested.)

 

-- Saul

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This thread started with a claim that prolonged fasting isn't that useful due to a bunch of reasoning about autophagy. I'm surprised no one brought up cancer yet in the thread, especially given the several mentions of Seyfried. Surely there are other claimed benefits from fasting besides cleaning up cellular junk via autophagy. One of them clearly is the effect on cancer due to cancer cells and non-cancerous cells having different needs for and frailty in the face of glucose & ketones.

 

I don't think there is widespread scientific agreement on the exact dose-response of fasting or ketones effects on tumors, and thus probably not a clear case that longer than 24-hr fasts have statistically significant increased benefit over <24hr fasts, and certainly ketogenic greater-than-zero calorie consumption may achieve some of the same goals w.r.t. cancer without technically being a fast, but I think there is enough evidence that fasting should be seen as potentially helpful with cancer and thus no discussion of what fasting durations are best is complete without addressing cancer as well as autophagy.

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Mechanism: ... for CR definitions I'm going to let Michael answer this one but FYI I found his thread at http://www.longecity...quotidian-diet/which points to http://www.longecity.org/forum/topic/45958-calorie-restriction-targets/?do=findComment&comment=450451 most helpful.

Thanks for that link!! I was looking for a clear definition, i.e. "a person is CR'd iff..."

You're not going to get one ;)xyz. Go be a lab mouse ;)xyz. Sorry: that's just the best we can do.

 

Happily, you seem to have quite correctly understood the issue. I've also just pinned a FAQ post: How Many Calories Should I Eat? What's My Goal Weight? What's My Setpoint? What "%CR" Am I?. So, no one will ever ask this question ever again :) .

Sorry, but I'm asking a question ever again.

 

In that helpful pinned FAQ, we aren't allowed to post follow ups, nor quote the original text, so I'll ask here.

 

Michael writes in FAQ:

 

"People starting CR would very much like to have definitive, hard-and-fast answers to these questions, and unfortunately, there just isn't any way to give one in free-living humans! No one can tell you the exact point at which you're "on CR" or what "%CR" you are. These are guidelines and principles for entering the "CR continuum.""

 

Check. Understood. Guidelines and principles.

 

Michael writes:

 

"If you are lucky enough to have had a clear, healthy 'setpoint' in your youth — a weight to which you tended to gravitate when you were in your early twenties, and that was within the healthy BMI range — take that as your baseline, and restrict Calories down to a level that keeps you at least 15% below that."

 

Check. In my early twenties I was within the healthy BMI range, and my current BMI fluctuates between 10% and 20% below that. That would seem to indicate CR. But I've always been an ectomorph, says my mom, even when you were a baby, she says, you looked like a spider monkey. All arms and legs. But even now, below weight from the early twenties, I'm not sure if I'm on CR or not. Not for reasons of sickness or overexercise, I'm indeed cutting calories.

 

Michael writes:

 

"Wherever you start from, you need to cut Calories. Ultimately, the goal is to keep Calories lower than your physiology 'thinks' it needs, and a level of Calorie intake that only normalizes an overweight body will simply return you to the historical norm for our species, not induce the anti-aging metabolic shift that characterizes CR."

 

For background before my question: I've been more or less honestly measuring, weighing, and entering my daily diet into COM since 2010, so I'm going on nearly eight years of focused documentation. Recording what I eat and what I do not eat (e.g., "fasting" is programmed to record into COM as "zero" calories) has become a habit.

 

So, tallying up "Trends" in COM, clicking on "Report" for "All Time" (in an iPhone app) the zero calorie days from fasting add up to bring down the totals.

 

My all time food intake for the past nearly eight years is "1,806 kcal consumed" versus "2,040 kcal burned" or, roughly, I'm maybe around 10% CRed, which seems about right, at least if I go by body weight from early twenties to now.

 

My question is probably unanswerable, but who better to ask than Michael, and I'm probably not even looking for a definitive answer, just guidelines and principles, remember, but I don't think I've seen this question asked before.

 

I'm not practicing daily cutting of calories below my BMR, which is 2040 kcal. But I'm fasting -- longer fasts (8-10 days), medium fasts (5-8 days), short fasts (1-3 days), and all of that while also "intermittent fasting" (doing one meal per day, allowing 20-hours to elapse between refeedings).

 

Yet when I refeed from fasts, I tend to go over my BMR. I don't "gorge" but I do tend to eat around 2,500 to 3,000 kcal for a few days, more like "controlled feasting" and I'm following the "optimal nutrition" part of the equation, if that matters, eating only plants, following a Mediterranean thing, and so most of my extra calories derive from olive oil, legumes, nuts, and seeds.

 

Recently I've started eating sardines again, too, so I've transitioned for now away from my strict vegan and vegetarian past. No dairy or meat, though, but sometimes I eat a few cans of sardines.

 

The question is -- if I'm not practicing CR during refeeding after fasts, but sometimes going over my daily calorie requirements, am I still practicing CR?

 

The zero calorie days bring down the overall calorie intake -- even when I'm not practicing daily CR. Can CR be spaced out in time like this, or "should" it be daily CR practiced with daily consistency over long periods of time?

 

Sorry to be so long winded.., Like I said, there probably isn't any answer in humans to this, but I'm throwing it out there anyway, to fellow humans, while we all wait for something better to emerge from clinical trials that aims to repair the damages caused by aging, rather than this "messing-with-metabolism" CR project that we're practicing.

 

For me, fasting seems easier long term than daily CR because although I'm doing my best to measure, weigh, and document everything I eat, I assume I'm still getting numbers wrong. Food values aren't consistent. When I fast, I know for sure that I'm cutting calories to zero. When I eat, I'm only guessing.

Edited by Sthira

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