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Alternate-Day Fasting Flunks in Humans, Again


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#1 Michael

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Posted 28 September 2009 - 04:14 PM


All:

I've previously posted a series of studies showing that alternate-day fasting does not provide the metabolic effects of CR in humans, despite the fact that it has some parallel effects in rodents (eg, improved insulin sensitivity) -- although intermittent feeding raises IGF-1 whereas CR lowers it in mice (3) and, crucially, alternate-day fasting without lowering Calories does not extend lifespan even in rodents. (See also here and here). Now, as pointed out by Al Pater on the CR Society list, we have yet another human study, once again showing no effect on major CR-related parameters:

BACKGROUND: Intermittent fasting (IF) was shown to increase whole-body insulin sensitivity, [see below on this previous report ((2) below -MR] but it is uncertain whether IF selectively influences intermediary metabolism.

DESIGN: Glucose, glycerol, and valine fluxes were measured after 2 wk of IF and a standard diet (SD) in 8 lean healthy volunteers in a crossover design, in the basal state and during a 2-step hyperinsulinemic euglycemic clamp, with assessment of energy expenditure and phosphorylation of muscle protein kinase B (AKT), glycogen synthase kinase (GSK), and mammalian target of rapamycine (mTOR). We hypothesized that IF selectively increases peripheral glucose uptake and lowers proteolysis, thereby protecting protein stores.

RESULTS: No differences in body weight were observed between the IF and SD groups. Peripheral glucose uptake and hepatic insulin sensitivity during the clamp did not significantly differ between the IF and SD groups. Likewise, lipolysis and proteolysis were not different ... IF decreased resting energy expenditure. IF had no effect on the phosphorylation of AKT but significantly increased the phosphorylation of glycogen synthase kinase. Phosphorylation of mTOR was significantly lower after IF than after the SD.

CONCLUSIONS: IF does not affect whole-body glucose, lipid, or protein metabolism in healthy lean men despite changes in muscle phosphorylation of GSK and mTOR. The decrease in resting energy expenditure after IF indicates the possibility of an increase in weight during IF when caloric intake is not adjusted. (1)


Re (2): as they note in the full text,

Although Halberg et al showed an increased glucose infusion rate during the hyperinsulinemic clamp in their study we were not able to discern differences in peripheral or hepatic insulin sensitivity despite equal diets and a crossover design. The lack of an effect on peripheral insulin sensitivity was strengthened by the data on phosphorylated AS160-thr642-a downstream target of AKT that is involved in the translocation of GLUT4 to the plasma membrane. Insulin-mediated phosphorylation ofAS160 was shown to be decreased in patients with type 2 diabetes and after short-term fasting, but it is uncertain whether IF selectively influences intermediary metabolism. Such selectivity might be advantageous when adapting to periods of food abundance and food shortage.


Certainly, none of the other human intermittent fasting studies have suggested improved glucose metabolism or insulin sensitivity.

Re the more interesting effect on mTOR:

pmTOR-ser2448 [the residue whose activating phosphorylation rapamycin blocks -MR] was not different between the IF and SD groups in the basal state but was significantly lower during the clamp after IF ... [We found no differences in the total muscle content of AKT, GSK-3, or mTOR … Because we did not assess protein synthesis rates, we cannot support that the lower mTOR phosphorylation in the basal state after IF than after the SD reflects lower protein synthesis, as shown earlier for short-term fasting (14). LBM was not affected, although the duration of our study may have been insufficient to observe measurable effects on muscle mass


This would be more promising ... but again, the rodent data is pretty clear that whatever the narrow metabolic benefits of EOD/ADF/IF may be, it doesn't retard aging except when it's associated with an actual reduction in Caloric intake.

See the full text here.

-Michael

1. Intermittent fasting does not affect whole-body glucose, lipid, or protein metabolism.
Soeters MR, Lammers NM, Dubbelhuis PF, Ackermans MT, Jonkers-Schuitema CF, Fliers E, Sauerwein HP, Aerts JM, Serlie MJ.
Am J Clin Nutr. 2009 Sep 23. [Epub ahead of print]
PMID: 19776143

2. Halberg N, Henriksen M, Söderhamn N, Stallknecht B, Ploug T, Schjerling P, Dela F.
Effect of intermittent fasting and refeeding on insulin action in healthy men.
J Appl Physiol. 2005 Dec;99(6):2128-36. Epub 2005 Jul 28.
PubMed PMID: 16051710.

3. Anson RM, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A, Ingram DK, Lane MA, Mattson MP. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6216-20. Epub 2003 Apr 30. PubMed PMID: 12724520; PubMed Central PMCID: PMC156352.

Edited by Michael, 28 September 2009 - 04:19 PM.

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#2 Blue

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Posted 28 September 2009 - 04:59 PM

Thanks. I have missed your previous posts regarding the lack of effect of IF on lifespan in the absence of CR. Is there any study finding that lifespan extension can be achieved with a high IGF-1? That it, IF with some CR that combines lifespan extension and high IGF-1? That lifespan extension could be achieved with a high IGF-1 has been used as an argument against the importance of IGF-1.

#3 Bluejay1

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Posted 08 December 2009 - 09:40 PM

Thank you so much for this post / thread. I've been considering intermittent, but now it looks less appealing

All:

I've previously posted a series of studies showing that alternate-day fasting does not provide the metabolic effects of CR in humans, despite the fact that it has some parallel effects in rodents (eg, improved insulin sensitivity) -- although intermittent feeding raises IGF-1 whereas CR lowers it in mice (3) and, crucially, [url="http://www.imminst.o.......restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6216-20. Epub 2003 Apr 30. PubMed PMID: 12724520; PubMed Central PMCID: PMC156352.



#4 Castiel

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Posted 30 January 2014 - 12:11 AM

although intermittent feeding raises IGF-1

In animals calorie restriction extends life more and more up to around 50% when death from starvation starts to occur if you keep going lower because of energy deficits. If IF leads to IGF-1 increase it may be because it went too far in calorie reduction in fast days or alternatively if tendencies to gorge far above and beyond normal during feast days. 5:2 fasting with 500-600 cals decreases IGF-1 by about 50% in humans(horizon- eat fast and live long) something that CR practicioners don't get without moderate protein restriction

Edited by Castiel, 30 January 2014 - 12:19 AM.


#5 deadwood

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Posted 09 February 2014 - 05:15 PM

There is tons of research that shows a 24-36 hr. fast vastly increases HGH in men and women. Men also get a testosterone boost and DHT decrease. How can this be bad?
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#6 Castiel

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Posted 10 February 2014 - 05:58 AM

There is tons of research that shows a 24-36 hr. fast vastly increases HGH in men and women. Men also get a testosterone boost and DHT decrease. How can this be bad?

Well there's a difference between HGH and IGF1, if I'm not mistaken. It may be that it increases one while it decreases the other one.

Edited by Castiel, 10 February 2014 - 05:58 AM.

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#7 deadwood

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Posted 10 February 2014 - 03:23 PM

There is tons of research that shows a 24-36 hr. fast vastly increases HGH in men and women. Men also get a testosterone boost and DHT decrease. How can this be bad?

Well there's a difference between HGH and IGF1, if I'm not mistaken. It may be that it increases one while it decreases the other one.



No kidding.


The point is a DECREASE in IGF1 is not a bad thing. IGF1 has been linked to increased cancer, CVD, diabestes, decreased life span etc. HGH is a hormone you want more of.

This is exactly my point. If the studies show an increase in HGH and decrease in IGF1- so what? That's a good thing. Every single science review I read about fasting said it was a positive thing. He just put a negative spin on it.

#8 Darryl

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Posted 13 February 2014 - 06:03 PM

IGF-1 mediates most anabolic effects of pituititary GH. There some debate regarding how much effect pituitary GH has independent of IGF-1.

GH increases muscle mass and bone mineral density. It also increases high blood pressure, diabetes, and carpal tunnel syndrome, and doubles the death rate of critically ill patients.

For longevity, there's very good reasons for lowering GH and IGF-1 is much as possible, maintaining just enough for acceptable muscle and bone mass. I think this will be recognized as among the best ways of preventing growth of occult cancers or relapses - and anyone can implement it today.

Fontana, Luigi, et al. "Dietary protein restriction inhibits tumor growth in human xenograft models of prostate and breast cancer." (2013)

I anticipate targeted therapies (myostatin and bone resorption inhibitors) will be available to prevent adverse effects (like sarcopenia and osteoporosis) of a markedly reduced GH/IGF-1 axis.

Edited by Darryl, 13 February 2014 - 06:07 PM.


#9 Castiel

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Posted 13 February 2014 - 07:01 PM

IGF-1 mediates most anabolic effects of pituititary GH. There some debate regarding how much effect pituitary GH has independent of IGF-1.

GH increases muscle mass and bone mineral density. It also increases high blood pressure, diabetes, and carpal tunnel syndrome, and doubles the death rate of critically ill patients.

For longevity, there's very good reasons for lowering GH and IGF-1 is much as possible, maintaining just enough for acceptable muscle and bone mass. I think this will be recognized as among the best ways of preventing growth of occult cancers or relapses - and anyone can implement it today.

Fontana, Luigi, et al. "Dietary protein restriction inhibits tumor growth in human xenograft models of prostate and breast cancer." (2013)

I anticipate targeted therapies (myostatin and bone resorption inhibitors) will be available to prevent adverse effects (like sarcopenia and osteoporosis) of a markedly reduced GH/IGF-1 axis.

Loss of bone mass seems inevitable with age, muscle mass loss is also another thing that happens unless resistance exercise is done(serious resistance exercise requires protein), regards the issue with death rate(you'd need many studies to fully conclude so imho, and two it said high doses of growth hormone, we'd have to see how those compare with those levels achieved through fasting in addition fasting is likely to modify other properties of tissues and other elements in the blood.). Growth of cancers pertains some of the population, there is likely highly cancer resistant humans akin to the rodents with immune systems that voracious digested many cancers(this could help explain 60 cigarette a day cancer free centenarians. I've known individuals who like to burn black their food and have eaten such highly carcinogenic food for decades without developing cancer.).

Regards protein restriction, there have been suggestions that daily it may impair glucose tolerance, ADF can result in similar protein restriction and should be similar to the blood results obtained via 5:2 fasting which show improved blood profile and reduced igf1.

Myostatin has to be delivered to skeletal muscle, as I've heard it can cause problems if changed levels affects cardiac tissue, bone resorption inhibitors could have side-effects, we'd need to analyze it.




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