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Alternate-Day Fasting Only Works WITH Calorie Restriction


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#31 Brett Black

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Posted 05 March 2011 - 12:14 PM

is it all about caloric restriction (meaning there's a point below which this whole thing kicks in) or calories in general (meaning that there's a clear correlation between lifespan and calorie intake)?


I don't have the full the other one to this from Dean's page, and last time was not able to access it, but this will do.
Posted Image


Matt, the results shown on this graph only apply to rodents that are started on caloric restriction in childhood. They are not applicable to CR started after puberty.

Starting CR in childhood in rodents severely stunts their normal growth and ends up leading to a final adult body size(not weight) that is roughly half the body size of a normally-fed adult rodent(they're basically midgets.)

When CR is started after puberty the lifespan increase is at most only half of that shown on the graph. And, the later in adulthood CR is started, the less lifespan increase is seen.

The most severe caloric restriction that most humans are capable of surviving(if they start from a non-overweight or obese weight) is about 20%, and most humans start CR after puberty. Taken together, these two factors lead to less than a 10% lifespan increase in comparable rodent studies.

Edited by Brett Black, 05 March 2011 - 12:18 PM.


#32 sthira

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Posted 06 March 2011 - 03:29 AM

Reading over this thread is kind of like being in a bar where you've got this one highly-trained guy up on stage playing the violin beautifully for all to enjoy. In the audience are a bunch of people not really listening to the violinist, to each other's jabber, or to much else beyond their own half-thoughts. Which I guess is just the way life is: those who hear it and get it, hear it and get it. The others stumble away into the night having forgotten what they've heard within five easy footsteps.
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#33 Jens Østergaard

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Posted 15 June 2012 - 05:20 PM

I am looking for antiaging techniques that maximize benefits (longevity and health) and minimize pain (feeling hungry, weak and cold).

Other than the usual supplements and EOD moderate exercise, I am fasting OAW: once a week, water only, 24 hours from 7pm to 7pm).

I take 250mg olbetam (Acipimox) at about 11am during the fast to lower blood lipids an enhance the fast effects on my body.

My scientific rationale is as follows

Studies of monthly fasting by Mormons
http://www.ncbi.nlm....pubmed/18805103

Rat studies of EOD and OAW weekly fasting, with and without Acipmox to lower blood lipids and enhance autophagy
http://www.ncbi.nlm....pubmed/15236765

C. elegans study that suggests EOD fasting less beneficial than every 2 days
http://ouroboros.wor...y-to-longevity/

OAW fasting is pretty easy and it appears to allow me to eat AL on other days without penalty.

After a year of OAW fasting, my yearly blood work has not shown any marked change,
but it has always been pretty good.

250 seems much too little - the second ww adress u refer to says 50 mg/kg b.w.--- I guess u weight more than 5 kg ?

#34 Jens Østergaard

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Posted 16 June 2012 - 09:20 AM

I am looking for antiaging techniques that maximize benefits (longevity and health) and minimize pain (feeling hungry, weak and cold).

Other than the usual supplements and EOD moderate exercise, I am fasting OAW: once a week, water only, 24 hours from 7pm to 7pm).

I take 250mg olbetam (Acipimox) at about 11am during the fast to lower blood lipids an enhance the fast effects on my body.


Very interesting. I ready all the related articles u enclosed too.
But how u find it is 250 mg/ dosis ? they write 50mg/kg body weight in the rat tests.. ?

And, why not taking this several times a week, i mean also the days where u are not fasting?

Edited by Michael, 19 June 2012 - 04:06 PM.


#35 Krell

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Posted 18 June 2012 - 08:57 PM

I am looking for antiaging techniques that maximize benefits (longevity and health) and minimize pain (feeling hungry, weak and cold).

Other than the usual supplements and EOD moderate exercise, I am fasting OAW: once a week, water only, 24 hours from 7pm to 7pm).

I take 250mg olbetam (Acipimox) at about 11am during the fast to lower blood lipids an enhance the fast effects on my body.


But how u find it is 250 mg/ dosis ? they write 50mg/kg body weight in the rat tests.. ?

And, why not taking this several times a week, i mean also the days where u are not fasting?


I get some flushing on my chest and a little itching from a 250mg dose of Acipimox on an empty stomach. I now generally take one dose about noon on my weekly fasting days and another dose about 3pm because I read somewhere that is the 1/2 life of Acipimox in the body. That way I get several hours of drug action during the latter part of my fast rather then one brief peak. I do not take any Acipimox during the other week days when I am not fasting. I am trying to roughly follow the rat study protocol without going overboard, since there does not seem to have been any followup to the study.

The drug dose scaling between rats and humans has a scale factor that I do not remember exactly, but assuming it is about 7 to 1, then that would make my equivalent dose 84kg*50mg/kg/7=600mg which is pretty close to my actual 500mg total daily dose when fasting.

Edited by Michael, 19 June 2012 - 04:07 PM.


#36 Jens Østergaard

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Posted 19 June 2012 - 05:02 AM

The drug dose scaling between rats and humans has a scale factor that I do not remember exactly, but assuming it is about 7 to 1, then that would make my equivalent dose 84kg*50mg/kg/7=600mg which is pretty close to my actual 500mg total daily dose when fasting.


Hi Krell,
Thks for your comment.
I am just worried that once a week is only helping 1/7th. I mean the day after when we eat, then the insulin gets up, and the proteins starts damaging the cells again. I am worried that I see no logic explaination at all on why a single day should help as much as this single study has shown. And Yes, as you write yourself, there has been no other follow up or anything to this one..
Did you find anywhere a logic explanation to why once a week should help with obletam ?
thks !
Jens

Edited by Michael, 19 June 2012 - 04:08 PM.


#37 Krell

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Posted 19 June 2012 - 02:23 PM

I am just worried that once a week is only helping 1/7th. I mean the day after when we eat, then the insulin gets up, and the proteins starts damaging the cells again [...]


Maybe it does, maybe it does not. Unfortunately the experimental data is limited and we must make some guesses to interpret it in light of our values.

My recollection of the Bergamini paper is that they were comparing the "gold standard" of calorie restriction for life extension with once-a-week fasting aided by Acipimox. And the surprising result was that, at least for rats, the life extension results were similar. I do not remember if they had a detailed theory behind their hypothesis or if it was a lucky guess. It would be nice of they published more experiments varying other factors like Acipimox, but they have not.

For folks like me who are too lazy to do calorie restriction, but who want to have some effective life extension strategy, a once-a-week fast plus Acipimox is more inviting than calorie restriction. Your mileage may vary.

Who knows what the result would be if the experiment had included a cohort of rats that only got Acipimox every day? Since Acipimox is taken for various human medical problems we might expect that someone would have noticed if daily Acipimox had life extension effects. I am not aware of any such observations.

The reported benefits of the mormon once-a-month fasting may provide some confirmation that even brief periods of fasting may provide life extension. The rat study suggests that Acipimox "supercharges" brief periods of fasting to make them generate more life extension.

So the questions in my mind is "what is the most life extension benefit that I can get from fasting with the least effort." I find the once-a-week fast plus Acipimox to be easiest for me.

This is similar to my approach to exercise. I lift weights a couple of times a week and run a couple of miles twice a week. Of course I might get more benefit from more exercise, but the tradeoff between time spent exercising and benefits do not justify the extra time I could use otherwise. Your cost/benefit analysis may be different than mine.

Edited by Michael, 19 June 2012 - 04:09 PM.


#38 Michael

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Posted 19 June 2012 - 06:36 PM

My recollection of the Bergamini paper is that they were comparing the "gold standard" of calorie restriction for life extension with once-a-week fasting aided by Acipimox. And the surprising result was that, at least for rats, the life extension results were similar.


No: Bergamini has reported no lifespan benefits to Acipimox, with or without fasting.

I do not remember if they had a detailed theory behind their hypothesis [that once-weekly fasting and Acipimox would be enough] or if it was a lucky guess.


Their once-weekly protocol was based on previous observations that:

a single administration of a potent antilipolytic drug to fasted rats has very intense though transient metabolic and endocrine effects. These effects include a decrease in circulating FFA, which may ... last for hours ..., and a rapid decrease in plasma glucose levels ... [and] Basal insulinemia .... Besides the effects on insulin secretion, treatment with antilipolytic drugs may influence secretion of other hormones, including glucagon, glucocorticoid (Bergamini et al., 1993 ) and growth hormone (Peino et al., 1996 ). As an important consequence, the sudden, dramatic increase in the plasma glucagon/insulin ratio may stimulate autophagy and lysosomal proteolysis ... Present observation shows that treatment with the antilipolytic drug intensifies the anti-aging effects of submaximal calorie restrictions [on insulin, FFA, and other metabolites] and makes them maximal.


But whether this leads to life extension is an open question, seemingly at odds with the effects of alternate-day fasting itself. Again: there are no life extension effects reported for Acipimox, with or without fasting -- and as noted at the outset, "Alternate-Day Fasting Only Works WITH Calorie Restriction."

The reported benefits of the mormon once-a-month fasting may provide some confirmation that even brief periods of fasting may provide life extension.


Per contra, the Mormon studies (PMID: 22425331, 18805103) suggest a very small benefit indeed to fasting -- and these were patients presenting for coronary angiography, not members of the community as a whole. They also don't have any numbers on mortality. And remember, whatever benefits were observed are a confounded observation: fasting is a surrogate marker of Mormon religious adherence, which also likely carries over into other healthy Mormon dietary and lifestyle practices (though the authors did try to adjust for these), as well as with being an active part of the Mormon religious community, which in itself has health benefits.

So the questions in my mind is "what is the most life extension benefit that I can get from fasting with the least effort." I find the once-a-week fast plus Acipimox to be easiest for me.


Since, again, we have no direct evidence (as opposed to mechanistic speculation) that it will deliver any life extension benefit, the calculation would seem to go in the opposite direction: zero divided by anything is still zero, however small the numerator.

#39 cheezeweezel

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Posted 19 June 2012 - 08:07 PM

Since, again, we have no direct evidence (as opposed to mechanistic speculation) that it will deliver any life extension benefit, the calculation would seem to go in the opposite direction: zero divided by anything is still zero, however small the numerator.


Per contra, Michael, even if we restrict ourselves to real numbers, zero divided by itself is not still zero. It is, in the words of Berkeley's classic 1734 work [1] in critique of Isaac Newton, "the ghost of a departed quantity."

And what are these same evanescent Increments? They are neither finite Quantities nor Quantities infinitely small, nor yet nothing. May we not call them the Ghosts of departed Quantities?


In more modern times, we prefer the more prosaic "not defined; or not in the domain of the function" (mathematics), or "NaN" (CS geeks, IEEE floating-point standard).

-cw :)

[1] Berkeley, G., 1734, The Analyst, A DISCOURSE Addressed to an Infidel MATHEMATICIAN. WHEREIN It is examined whether the Object, Principles, and Inferences of the modern Analysis are more distinctly conceived, or more evidently deduced, than Religious Mysteries and Points of Faith.

Edited by cheezeweezel, 19 June 2012 - 08:09 PM.


#40 Krell

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Posted 19 June 2012 - 08:17 PM

No: Bergamini has reported no lifespan benefits to Acipimox, with or without fasting.


Yes, all of the rats seem to have been killed for testing during the study, so there were no lifespan measurements So what he showed is

Bergamini says

.. Present observation shows that treatment with the antilipolytic drug intensifies the anti-aging effects of submaximal calorie restrictions [on insulin, FFA, and other metabolites] and makes them maximal.


The paper also proposes that certain liver tests are markers for aging and these tests were enhanced by both CR and by antilipolytic drug combined with occasional fasting.
So if his liver tests were actually aging markers, then his experiments suggest that there were lifespan benefits. Not conclusive, but tantalizing.

I find Bergamini's ideas and experiments compelling enough to try to emulate them. But I do not see anyone else doing likewise, except perhaps Bergamini.

you say

But whether this leads to life extension is an open question, seemingly at odds with the effects of alternate-day fasting itself. Again: there are no life extension effects reported for Acipimox, with or without fasting -- and as noted at the outset, "Alternate-Day Fasting Only Works WITH Calorie Restriction.


Llifespan experiments are on the side of CR at present, but that does not prove that other techniques can not work. You seem to imply that nothing else could possibly work. BTW: I am doing once-a-week, not alternate-day fasting.

you say

...the Mormon studies (PMID: 22425331, 18805103) suggest a very small benefit indeed to fasting -- and these were patients presenting for coronary angiography, not members of the community as a whole. They also don't have any numbers on mortality. And remember, whatever benefits were observed are a confounded observation: fasting is a surrogate marker of Mormon religious adherence, which also likely carries over into other healthy Mormon dietary and lifestyle practices (though the authors did try to adjust for these), as well as with being an active part of the Mormon religious community, which in itself has health benefits.


Your glass seems to be half empty and mine half full. Yes, there is no mortality data in these studies but there are suggestions of significant health benefits which might translate into lifespan benefits.

PMID 22425331

In conclusion, prospective hypothesis testing showed that routine periodic fasting was associated with a lower prevalence of diabetes mellitus in patients undergoing coronary angiography. A reported fasting association with a lower coronary artery disease risk was also validated and fasting associations with lower glucose and BMI were found.


PMID: 18805103

Fasting was also associated with lower diabetes prevalence (p = 0.048). In regression models entering other secondary behavioral measures, fasting remained significant with a similar effect size. In conclusion, not only proscription of tobacco, but also routine periodic fasting was associated with lower risk of coronary artery disease.


You conclude

Since, again, we have no direct evidence (as opposed to mechanistic speculation) that it will deliver any life extension benefit, the calculation would seem to go in the opposite direction: zero divided by anything is still zero, however small the numerator.


Sorry I wasted your time

#41 treonsverdery

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Posted 03 August 2016 - 08:42 PM

The first article that Micheal wrote says that C57BL/6J mice gained greater longevity from eating less food, while A/J mice did not.  The very slight genetic difference between these two types of mice could actually describe the genetics of high longevity response to calorie restriction (CR) What are the few genes at C57BL/6J mice that cause them to be CR responders?  does the human genome have greater similarity to the A/J (less response) or the high response C57BL/6J?  Finding the protein cascades that result from the C57BL/6J mouse genes as compared to A/J mice could describe protein effects that cause CR based longevity.  These new protein effect genetics could become human therapies.

 

Also, noting the variation of mouse variety on CR responsiveness, it is possible that a human tendency to automatic CR, the genetics of anorexia at humans, could be traced to greater longevity among say an anorexics ancestors.  So if the grandparents of an anorexic live longer because they are genetic "light eaters", that represents a human longevity gene.  so, partial, rather than disease anorectic genes, could be human longevity genes.



#42 pone11

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Posted 07 August 2016 - 10:26 PM

What do others make of the work by Valter Longo and others on Fasting Mimicking Diets?  In his latest paper Vongo summarizes other research on FMD by saying:

 

"...the FMD cycles started at 16 months of age caused an 18% increase in the 75% survival point, and an 11% increase in the mean lifespan."

 

These were mice that did not go into caloric deficit and did not lose any muscle mass.   Their protocol was four days of a low-protein, low-glucose, high fat diet twice a month.

 

http://www.cell.com/...4131(16)30250-9



#43 Michael

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Posted 07 August 2016 - 11:15 PM

All:
 

What do others make of the work by Valter Longo and others on Fasting Mimicking Diets?  In his latest paper Vongo summarizes other research on FMD by saying:
 
"...the FMD cycles started at 16 months of age caused an 18% increase in the 75% survival point, and an 11% increase in the mean lifespan."[/size]
 
These were mice that did not go into caloric deficit and did not lose any muscle mass.   Their protocol was four days of a low-protein, low-glucose, high fat diet twice a month.[/size]
 
http://www.cell.com/...4131(16)30250-9

 
When you dig into the results, there's no real evidence for an anti-aging effect. However, it may improve various risk factors in people eg. with metabolic syndrome, and as in other fasting-based protocols, if you find it more convenient than straightforward reductions in energy intake, it's promising.
 

The first article that Micheal wrote says that C57BL/6J mice gained greater longevity from eating less food, while A/J mice did not.  The very slight genetic difference between these two types of mice could actually describe the genetics of high longevity response to calorie restriction (CR) ...  Finding the [responsible] protein cascades  ... could describe protein effects that cause CR based longevity.  These new protein effect genetics could become human therapies.


There are lots of studies now on the differential responses to CR of different strains, any of which could also uncover such mediators. I'm skeptical that this is productive.
 

Also, noting the variation of mouse variety on CR responsiveness, it is possible that a human tendency to automatic CR, the genetics of anorexia at humans, could be traced to greater longevity among say an anorexics ancestors.  So if the grandparents of an anorexic live longer because they are genetic "light eaters", that represents a human longevity gene.  so, partial, rather than disease anorectic genes, could be human longevity genes.

 

No: people suffering with anorexia nervosa are not "natural light eaters," but are highly restrained eaters who are initially constantly battling the urge to eat, just as any starved animal does, although they may adapt somewhat over time. They intentionally restrain their food intake as a result of psychological disturbance, usually related to distorted body image.

 

Similarly, there is no such thing as being 'naturally' on CR. People who are "naturally skinny" or "naturally" don't eat much are not on CR: that lighter weight or food intake is their ad libitum baseline. The retardation of aging (if CR translates to humans) kicks in when they start actively restricting from their default baseline. (This is one of the reasons why resort to the BMI epidemiology for evidence for or against a benefit from CR is a fool's errand).



#44 pone11

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Posted 08 August 2016 - 07:22 PM

All:
 

What do others make of the work by Valter Longo and others on Fasting Mimicking Diets?  In his latest paper Vongo summarizes other research on FMD by saying:
 
"...the FMD cycles started at 16 months of age caused an 18% increase in the 75% survival point, and an 11% increase in the mean lifespan."[/size]
 
These were mice that did not go into caloric deficit and did not lose any muscle mass.   Their protocol was four days of a low-protein, low-glucose, high fat diet twice a month.[/size]
 
http://www.cell.com/...4131(16)30250-9

 
When you dig into the results, there's no real evidence for an anti-aging effect. However, it may improve various risk factors in people eg. with metabolic syndrome, and as in other fasting-based protocols, if you find it more convenient than straightforward reductions in energy intake, it's promising.

 

Right, increasingly it looks to me like all variations of the fasting idea are mainly about improving quality of life, probably through some upregulation of autophagy lessening the mess of cellular malaise from misfolded proteins, bad mitochondria, viruses, and bacteria.   But I am very taken with Valter Longo's claim that old mice were "reset" to have the immune markers of four month old mice.  

 

It would be very shocking for so many immune and cellular markers to reset after fasting, yet not have mean age of death go up.   Even without affect maximum lifespan, increased health alone should push the age of death to the higher limit of what normal lifespan would allow?  How could it be otherwise?

 

What do you think is the primary mechanism of action for CR affecting aging?   


Edited by pone11, 08 August 2016 - 07:31 PM.


#45 pone11

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Posted 10 August 2016 - 03:38 AM

Michael, I am finding many other studies on various intermittent fasting regimens in rodents other than the ones you cite, and some of these show impressive life extension versus control groups.  One of the ones I like most is in mice where they fast four consecutive days every two weeks, and this results in a 64 week life versus 47.9 of controls.   Before you object that the fasted mice must have eaten fewer calories, one of the remarkable things about this study was the fasted mice had *more lean body mass* than the controls.

 

See:

"Influence of short-term repeated fasting on the longevity of female (NZB×NZW)F1 mice"

Hiroshi Sogawa, , Chiharu Kubo

Volume 115, Issues 1–2, 17 May 2000, Pages 61–71

 

http://www.sciencedi...047637400001093

 

What do you think the defect in that study might be?


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#46 Michael

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Posted 11 August 2016 - 07:34 PM

All:
 

 

When you dig into the results, there's no real evidence for an anti-aging effect. However, it may improve various risk factors in people eg. with metabolic syndrome, and as in other fasting-based protocols, if you find it more convenient than straightforward reductions in energy intake, it's promising.

 
It would be very shocking for so many immune and cellular markers to reset after fasting, yet not have mean age of death go up.   Even without affect maximum lifespan, increased health alone should push the age of death to the higher limit of what normal lifespan would allow?  How could it be otherwise?

Well, look at the actual results:
 

gr5.jpg

 
Clearly, it not only could be otherwise — it was otherwise. Even the 25% survivorship was only increased 7.6%, to 31.1 mo (940 days). This is far from "push[ing] the age of death to the higher limit of what normal lifespan would allow". As to how such a thing could be: well, for starters, as I noted in my analysis, the superior health outcomes of the diet animals seems to have been exaggerated by relatively sickly and short-lived controls:
 

[In the survival curve] you see a ragged falloff of the control animals, and a somewhat squarer but still suboptimal survival curve in the intervention group. This isn't a sign of a good intervention: it's a sign of sickly controls. I alluded to this in my original post: "This actually means that their controls were somewhat short-lived, and even their FMD animals lived less long than normal, healthy, well-husbanded AL mice should have, albeit they did live longer than their controls." Those numbers correspond to 775 d mean and 1015 d maximum LS in controls, and 860 and 1049 d respectively in FMD, whereas (as I have hammered home repeatedly in my ≈18 y participation in online discussion forums about life extension) the numbers for normal, healthy, nonobese, non-genetically-messed-up, non-toxin-fed mice should be ≈900 and 1100 d, respectively.

 

But even if that artifact wasn't confounding the result, it wouldn't necessarily be surprising for an intervention to slow the rate of age-related loss of a selected set of health markers and still not affect maximum lifespan. Obvious possibilities would be that either (a) it's failing to hit a variety of other relevant aging processes, and/or (b) lifespan is being limited by some of the deleterious effects of the diet. I discussed the evidence for the latter in my earlier analysis too:
 

Normally, of course, that forces the question "so what's killing all these healthy mice?", but in this case we apparently know: at older ages, the animals don't tolerate the very fasting cycles that have given them much of their improved health, and it triggers their death. And note that in the FMD, even the "fasting" days still contained some energy, so this wasn't as severe a shock as a periodic water or juice fast. Indeed, it was a concern that just this kind of problem might be leading to false negatives in adult-onset CR studies that led Weindruch and Walford, in their seminal adult-onset studies of "regular daily CR," to institute CR gradually instead of all at once as is usually done without problem in juvenile mice (and to modify the diet to include a full regimen of micronutrients, protein, and essential fat at fewer Calories, instead of just feeding them half of the AL diet as had been successfully done with juveniles). Using such a protocol gave them the first clear-cut evidence that CR extends lifespan in early-adult mice — an effect later replicated in progressively older animals, including Spindler's study in "early-old" (50-60 mouse years) animals.

This might argue that even if some modified fasting regimen works well for you in mid-adulthood, you'd have to gradually shift into "regular daily CR" as you age to reap life extension benefits and avoid the metabolic shock of the super-low-Calorie periods. However, that, of course, remains to be proven -- in mice ;) .

 
 So, in general, please read my posts before asking questions about them ;) .
 

What do you think is the primary mechanism of action for CR affecting aging?

 
I don't think there is a primary MoA: CR forces a very wide sweep of changes to adapt to chronic energy restriction, a subset of which collectively retard the aging process.
 

Michael, I am finding many other studies on various intermittent fasting regimens in rodents other than the ones you cite, and some of these show impressive life extension versus control groups.  One of the ones I like most is in mice where they fast four consecutive days every two weeks, and this results in a 64 week life versus 47.9 of controls.   Before you object that the fasted mice must have eaten fewer calories, one of the remarkable things about this study was the fasted mice had *more lean body mass* than the controls.
 
See:
"Influence of short-term repeated fasting on the longevity of female (NZB×NZW)F1 mice"
Hiroshi Sogawa, , Chiharu Kubo
Mechanisms of Ageing and Development
Volume 115, Issues 1–2, 17 May 2000, Pages 61–71
 
http://www.sciencedi...047637400001093
 
What do you think the defect in that study might be?


The thing to know about the mice in this study, which is not a "defect" but makes the results not extrapolable to otherwise-normal, healthy people's aging, is the fact that (NZB×NZW)F1 mice (inconsistently referred to as B/W mice) are not normal animals, but a strain of mice that suffers from a severe autoimmune disease similar to lupus and causing fatal glumerulosclerosis. They live extremely short lives as a result: in this study, av'g LS for control and fasted mice were 47.9 and 64.0 weeks (335.3 and 448 days), respectively; median survivorship was 46 and 67 weeks (322 and 469 d), respectively. They don't crunch out an experiment-specific "maximum LS," but you can see from tehir Fig. 5 that the last control and fasted mouse died at 65 and 90 weeks, respectively. Again, normal healthy mice that are raised competently live close to 900 d on average.
 
CR and IF have significant anti-inflammatory effects in general and profoundly retard the progression of glumerulosclerosis in these mice, so they live longer. This can't really be taken as informative about the anti-aging effect (or lack of it) in such a diet in normal, healthy humans or rodents. And as we've just seen, a similar protocol in a genetically normal strain of mouse did not extend maximum lifespan, and didn't even really do much for median LS compared to better-husbanded AL mice of the same species in other labs.
 
The authors speculate that the higher body weight in the fasted animals indicates that they probably took in more total energy, but food intake wasn't actually tracked, and my hypothesis would be that a significant am't of the effect would be because alleviating their severe autoimmunity and (in particular) slowing the progression of their severe renal disease would have enabled a more normal growth pattern. 
 
Finally, although I would again emphasize that one shouldn't place too much weight on results in models of disease for healthy people not suffering from a similar pathology, it's worth noting that this extended fasting regimen "only" increased mean LS by ≈33%; in a previous report in the same strain of mice by the same scientists,(1) 40% CR doubled the LS of the mice on a high-fat chow, and tripled it on a high-sucrose-and-glycerol chow. So pish tosh yer fasting ;) .
 
Reference
1: Kubo C, Johnson BC, Gajjar A, Good RA. Crucial dietary factors in maximizing life span and longevity in autoimmune-prone mice. J Nutr. 1987 Jun;117(6):1129-35. PubMed PMID: 3598724.


Edited by Michael, 11 August 2016 - 07:35 PM.

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#47 sthira

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Posted 11 August 2016 - 08:53 PM

So pish tosh yer fasting ;)



Dear Dr. Longo:

Pish tosh def: "Rubbish, bunk, a ridiculous proposition.

"Popularized in the quippy expression; "Pish Tosh and a bottle of Pinosh on a hot summer's day in Koshkonong!"

skinny hugs,
Michael
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#48 Michael

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Posted 11 August 2016 - 09:18 PM

Ha ha!

 

To be clear, tho' (Sthira and all): Longo is doing some very interesting things with fasting, most notably on its potential ability to enhance efficacy and/or reduce the toxicity of chemotherapy. And, again, if fasting works for you as a substitute for a conventional diet for risk factor management, have at.

 

But don't think of intermittent fasting without concomitant CR as an anti-aging intervention.



#49 pone11

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Posted 16 August 2016 - 03:12 PM

To Michael's point, are there are *any* fasting or calorie restriction studies on rodents where the control group lives to the full age controls should live to?  In mice, Michael is saying that this is 900 days mean and 1100 days maximum.

 



#50 Michael

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Posted 16 August 2016 - 04:25 PM

Sure: otherwise the numbers would be made up ;) . Look at anything by Spindler, Weindruch, Miller, Walford, etc. Guarantee the mean/median will be >800 d and max >1000.



#51 pone11

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Posted 22 August 2016 - 06:37 PM

Sure: otherwise the numbers would be made up ;) . Look at anything by Spindler, Weindruch, Miller, Walford, etc. Guarantee the mean/median will be >800 d and max >1000.

 

Do you have any opinion about what element of care promotes those mean/medium numbers, and why do so many researchers fail to achieve those?

 

The implication in your posts is that the researchers are trying to make their data look good by not taking good care of the control group.  I am sure that does happen on occasion, but it might also just be hard to care for rodents as well as those numbers require you to do.

 

Do you happen to have a handy reference for the mean/median and max numbers for various species of rodents used in research?  Now that you have made me aware of this very important issue, I want to develop some references around that so I can constantly compare reasonable lifespan expectation against what the researcher's controls achieved.



#52 nickdino

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Posted 02 November 2016 - 04:56 AM

Can anyone provide Valter Longo's official or other correct protocols of one or more of the variations of fasting mimicking diets please? Especially the more intense ones.

#53 Richard McGee

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Posted 16 December 2016 - 05:42 AM

Perhaps it's just me, but I am acutely disturbed by the unwillingness of CR advocates to commit to specific caloric input protocols. If I have a BMI of 30 do I get the same benefit from a 10% CR as another person with a BMI of 20%? What is the baseline I am measuring from - my average caloric intake over the last year, last five years? How do I have some reasonable confidence that my target caloric intake has a fair chance of reproducing life extension effects seen in animal tests? 

 

 



#54 sthira

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Posted 16 December 2016 - 10:27 AM

Perhaps it's just me, but I am acutely disturbed by the unwillingness of CR advocates to commit to specific caloric input protocols. If I have a BMI of 30 do I get the same benefit from a 10% CR as another person with a BMI of 20%? What is the baseline I am measuring from - my average caloric intake over the last year, last five years? How do I have some reasonable confidence that my target caloric intake has a fair chance of reproducing life extension effects seen in animal tests?

I understand your frustration with CR; but there are handy-dandy calculator tools online for free to help you determine your "specific calorie protocols." Check it out:

http://www.scientifi...alth/cron1.html

"...The Harris-Benedict and the Mifflin-St Jeor equations provide an estimate of the Basal Energy Expenditure (BEE), also called the Resting Metabolic Rate (RMR), or Basal Metabolic Rate (BMR). Predictive energy equations are routinely used in hospitals and nutrition clinics to determine the calorie requirements of various patients. Of the four most commonly used predictive energy equations, the Mifflin-St Jeor equations give the most reliable results.

The Mifflin-St Jeor equations are:

Male: BMR = 10×weight + 6.25×height - 5×age + 5

Female: BMR = 10×weight + 6.25×height - 5×age - 161..."

Determine your BMR with the calculator tool on that helpful site, and then play with it and figure out for yourself what would indicate CR for you.

Please note, however, that CR is yet another mystery of science (bless their hearts); whether CR will extend life in humans, who knows. Plenty of rodent and mammal data exists, mind you, since mammal and rodent studies are easy, and who doesn't love easy at the expense of other animal creatures without defense?

For you, with a BMI of 30, I'd answer the personal question of whether this 30 BMI is because you're a heavily chiseled athlete with fine muscle tone, or is this BMI of 30 because you have a lot of body fat, particularly around your waist and belly. The latter ain't so good.

Of course we've all been drilled repeatedly ad nauseum about what a poor measurement tool BMI is; however, we do "know" (what is knowledge anyway?) we do seem to realize that being lean -- with a Body Mass Index of say 19-21 -- may reduce the incidence of diseases like cancer, heart disease, and diabetes. Stay lean, but keep in mind that body weight isn't a fair measure of your CR depths. It's "calories, calories, calories..."

Hope this helps! Good luck if you decide to pursue calorie restriction as a personal goal. CR can be very interesting and fun -- if you want to attempt to "slow aging" here in late 2016, what the hell else have we got currently that's "better?" CR doesn't come without some risks and side effects, but many people who practice CR love it and would live no other way -- even if it's shown later to have no lifespan benefits.

And don't forget the ON (optimal nutrition) part of your behavior. A tool like cronometer.com is instrumental in any CR practice. You must know what you're consuming, what your levels of nutrition are, and what your dietary shortfalls look like, and then how to meet them or diminish them. Weigh, measure and record your food for awhile to get a (rough) estimate of how closely you're tracking RDA. RDA is an import measure -- despite the controversies, the doubters, and the haters. My own approach is to supplement shortfalls.

Finally, consider checking in over at the CR Society's Forum. It's a quiet place but filled with extremely intelligent and self-aware folks who really know their stuff: https://www.crsociety.org/index

Edited by sthira, 16 December 2016 - 10:39 AM.


#55 Michael

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Posted 16 December 2016 - 03:31 PM

 

Perhaps it's just me, but I am acutely disturbed by the unwillingness of CR advocates to commit to specific caloric input protocols.

I understand your frustration with CR; but there are handy-dandy calculator tools online for free to help you determine your "specific calorie protocols." Check it out:

http://www.scientifi...lth/cron1.html

 

 

*Groan* ...

 

No, no ... I'll have more to say on Richard's question later, but in the meantime, please do not use this calculator: it is sheer voodoo.
 



#56 Michael

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Posted 18 August 2017 - 10:31 PM

Belatedly:
 

 

Sure: otherwise the numbers would be made up ;) . Look at anything by Spindler, Weindruch, Miller, Walford, etc. Guarantee the mean/median will be >800 d and max >1000.

 
Do you have any opinion about what element of care promotes those mean/medium numbers, and why do so many researchers fail to achieve those?

The most common thing I see is the unfortunately widespread protocol of giving experimental access unlimited access to food, 24 hours a day, which (although they can't measure it, because they don't have properly-fed lean controls to which to compare them internally) we know from many studies leads to obesity, metabolic disease, and altered responses to toxins.(1-5)  The need to slightly restrict lab animals' food intake in order to keep them healthy is kind of self-evident, and ever since Weindruch and Spindler's breathrough study showing CR was still effective when implemented in mid-life,(0) scientists have been drafting editorials warning their colleagues of the distorting effects that literal ad lilbitum feeding introduces into toxicology, carcinogenesis, and above all lifespan studies — yet it continues to be common practice.
 
However, there are lots of other ways to screw up a lifespan study.(2)
 
pone11 said: The implication in your posts is that the researchers are trying to make their data look good by not taking good care of the control group.  I am sure that does happen on occasion, but it might also just be hard to care for rodents as well as those numbers require you to do.
 
I think you're saying that I'm implying (or that the problem of short-lived controls implies) that scientists are intentionally following bad protocols in order to kill off their control mice in order to make their treated mice look good. To be clear, I absolutely do not believe that. Rather, most people doing lifespan studies are not, in fact, trained as gerontologists, or if they are, have never done a lifespan study except in C. elegans or flies: they're used to raising mice for a few weeks, which is all that's needed for the vast majority of animal studies. Very few studies are looking at the long-term health effects of some intervention or exposure, so laboratory animal scientists are not trained to follow protocols that such studies require.
 
That doesn't mean it's hard to do it right — but it's certainly harder (and more expensive) than the way it's commonly done, and you do have to know what you're doing in the first place.
 
pone11 asked: Do you happen to have a handy reference for the mean/median and max numbers for various species of rodents used in research?  Now that you have made me aware of this very important issue, I want to develop some references around that so I can constantly compare reasonable lifespan expectation against what the researcher's controls achieved.
 
As I've indicated a couple of times, the mean and maximum LS of normal, healthy, nonobese, non-genetically-messed-up, non-toxin-fed mice should be ≈900 and 1100 d, respectively. Certainly, at an absolute minimum, they should be > 800 and >1000 d, respectively.
 
(6) is a good resource, but they don't report the actual quantitative data by the strains. The SAGE KE Experimental Rodent Strains database is useful, though it includes the short-lived, badly-messed-up DBA/2 strain, which should not be used in lifespan studies.
 

 

Perhaps it's just me, but I am acutely disturbed by the unwillingness of CR advocates to commit to specific caloric input protocols.

I understand your frustration with CR; but there are handy-dandy calculator tools online for free to help you determine your "specific calorie protocols." Check it out:

http://www.scientifi...alth/cron1.html

 
As I said in my original reply, this calculator is sheer voodoo. Please see here on the question of how many Calories one should eat on CR.
 
References
0: Weindruch R, Walford RL. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science. 1982 Mar 12;215(4538):1415-8. PMID: 7063854 [PubMed - indexed for MEDLINE]
 
1: Carey GB, Merrill LC. Meal-feeding rodents and toxicology research. Chem Res Toxicol. 2012 Aug 20;25(8):1545-50. doi: 10.1021/tx300109x. Epub 2012 Jun 13. PubMed PMID: 22642213.
 
2: Spindler SR. Review of the literature and suggestions for the design of rodent survival studies for the identification of compounds that increase health and life span. Age (Dordr). 2012 Feb;34(1):111-20. doi: 10.1007/s11357-011-9224-6. Epub 2011 Mar 22. Review. PubMed PMID: 21424790; PubMed Central PMCID: PMC3260350.
 
3: Martin B, Ji S, Maudsley S, Mattson MP. "Control" laboratory rodents are metabolically morbid: why it matters. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6127-33. doi: 10.1073/pnas.0912955107. Epub 2010 Mar 1. PubMed PMID: 20194732; PubMed Central PMCID: PMC2852022.
 
4: Festing MF. Fat rats and carcinogenesis screening. Nature. 1997 Jul 24;388(6640):321-2. PubMed PMID: 9237745.
 
5: Keenan KP, Laroque P, Ballam GC, Soper KA, Dixit R, Mattson BA, Adams SP, Coleman JB. The effects of diet, ad libitum overfeeding, and moderate dietary restriction on the rodent bioassay: the uncontrolled variable in safety assessment. Toxicol Pathol. 1996 Nov-Dec;24(6):757-68. Review. PubMed PMID: 8994307.
 
6: Turturro A, Witt WW, Lewis S, Hass BS, Lipman RD, Hart RW. Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program. J Gerontol A Biol Sci Med Sci. 1999 Nov;54(11):B492-501. PubMed PMID: 10619312.


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