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Mess Up Your Heart with Intermittent Fasting


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#1 Michael

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Posted 02 March 2011 - 09:06 PM


As discussed many times before, and contrary to what is often said or implied, there is no specific benefit of alternate-day fasting (ADF)/every-other day feeding (EOD)/intermittent fasting (IF) on lifespan, long-term health, or aging, at the same Calorie intake. Feeding animals once, twice, or several times/day at the same net Calorie intake yields the same lifespan benefit: the limited effect on lifespan boils down entirely to the small Caloric difference. See links here (scroll down).

The notion that it is otherwise is the result of a mixture of wildly-extrapolated cell studies, and short-term studies (many by Mark Mattson's group) showing that EOD animals undergo a variety of favorable-looking short-term metabolic shifts, such as lower insulin and glucose levels -- and, importantly for THIS post, lower blood pressure, heart rate, and blood pressure variability (1,2). However, these shifts, while consistent with the effects of CR proper, do not lead to life extension except to the degree that they lead to actual Calorie restriction. (Again, see links in the post linked above).

So far, these studies seem to show that EOD is of no special benefit in the long term -- but have not implied any deleterious effect, either. Surprisingly, Mattson's most recent study ((3) -- published, appropriately, in the Journal of Cardiac Failure) finds that EOD in rats actually damages the heart:

Four-month-old male Sprague-Dawley rats were started on ADF or continued on ad libitum diets and followed for 6 months ... [A]t the end of the study, and hearts were harvested for histological assessment. The 6-month-long ADF diet resulted in a 9% reduction (P < .01) of cardiomyocyte diameter and 3-fold increase in interstitial myocardial fibrosis. Left ventricular chamber size was not affected by ADF and ejection fraction was not reduced, but left atrial diameter was increased 16%, and the ratio of early (E) and late atrial (A) waves, in Doppler-measured mitral flow was reduced (P < .01). Pressure-volume loop analyses revealed a "stiff" heart during diastole in ADF rats, whereas combined dobutamine and volume loading showed a significant reduction in left ventricular diastolic compliance and a lack of increase in systolic pump function, indicating a diminished cardiac reserve.

CONCLUSION: Chronic ADF in rats results in development of diastolic dysfunction with diminished cardiac reserve. ADF is a novel and unique experimental model of diet-induced diastolic dysfunction. [!] The deleterious effect of ADF in rats suggests that additional studies of ADF effects on cardiovascular functions in humans are warranted.(3)

I suggest that anyone out there still engaged in EOD fasting study exit that uncontrolled implementation of that last call.

References
1: Wan R, Camandola S, Mattson MP. Intermittent food deprivation improves cardiovascular and neuroendocrine responses to stress in rats. J Nutr. 2003 Jun;133(6):1921-9. PubMed PMID: 12771340.

2: Mager DE, Wan R, Brown M, Cheng A, Wareski P, Abernethy DR, Mattson MP. Caloric restriction and intermittent fasting alter spectral measures of heart rate and blood pressure variability in rats. FASEB J. 2006 Apr;20(6):631-7. PubMed PMID: 16581971.

3: Ahmet I, Wan R, Mattson MP, Lakatta EG, Talan MI. Chronic alternate-day fasting results in reduced diastolic compliance and diminished systolic reserve in rats. J Card Fail. 2010 Oct;16(10):843-53. Epub 2010 Jul 1. PubMed PMID: 20932467; PubMed Central PMCID: PMC29534

Edited by Michael, 02 March 2011 - 09:09 PM.

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#2 PWAIN

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Posted 03 March 2011 - 12:17 AM

Wow, throw in a double standard here! Anything of benefit and the rat model is inadequate due to their differing rate of metabolism and physiology (to humans) but when you have an agenda, then all bets are off. Did they have a control on CR? Now that would be interesting.

Edit to add (to humans)

Edited by PWAIN, 03 March 2011 - 12:19 AM.

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#3 Michael

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Posted 03 March 2011 - 01:26 AM

Wow, throw in a double standard here! Anything of benefit and the rat model is inadequate due to their differing rate of metabolism and physiology (to humans) but when you have an agenda, then all bets are off.

I'm unclear about the nature of your objection, here. Like CR, all of the beneficial studies on EOD are also in rodent models. (Indeed, if you'd followed my link, you'd see where I noted that:

Moreover, most of the apparently beneficial metabolic changes in EOD mice [...] don't translate to humans. On that:

http://www.imminst.o...ndpost&p=299810
http://www.imminst.o...ndpost&p=350036

By contrast, similar metabolic outcomes in rodents map well onto humans, as well as dogs, nonhuman primates, etc.

Is your thought that I am applying a double standard based on the idea that *I* reject rat studies elsewhere because "Anything of benefit and the rat model is inadequate due to their differing rate of metabolism and physiology (to humans)"? I certainly don't hold that. If not, what is the double standard to which you refer?

Did they have a control on CR? Now that would be interesting.

No, but there have been multiple studies showing that CR protects rodents against cardiomyopathy, cardiac hypertrophy, interstitial fibrosis, etc; and in this case, we don't have much to argue about on the question of translatability, since "Long-term caloric restriction ameliorates the decline in diastolic function in humans" ((1) -- including, he notes gleefully, his own human self ;) ).

References
1. Meyer TE, Kovács SJ, Ehsani AA, Klein S, Holloszy JO, Fontana L. Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol. 2006 Jan 17;47(2):398-402. PMID: 16412867 [PubMed - indexed for MEDLINE]

#4 Sillewater

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Posted 03 March 2011 - 02:41 AM

Nutr Rev. 2009 Oct;67(10):591-8.Nibbling versus feasting: which meal pattern is better for heart disease prevention?Bhutani S, Varady KA.

Here is a great review looking at meal frequency on cholesterol levels and it seems the majority of studies find a detrimental effect (note: studies looked at were isocaloric, so in the 1 meal/day groups they basically feasted). The negative effect probably has to do with the amount of glucose and lipids that are unleashed on the body, basically the post-prandial state is not only prolonged but magnified, and its probably best to keep post-prandial states to a minimum (avoid, hyperglycemia, NEFAs).

When fasting (and I'm not saying you should) one should probably have a simple meal that is not 2000 calories. Personally I break a fast with two meals. One meal contains fiber, some carbohydrate and protein, and I eat the rest 30 to 1 hour later. However this means you have to eat extra nutritious foods on the other days to make up for the volume you couldn't consume on the fasting day.

This is just my take on the issue. If you are fasting you're doing it to lower caloric intake because at our metabolic rate no one is sure whether the beneficial autophagy actually occurs (like MR said).
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#5 Logan

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Posted 03 March 2011 - 04:34 AM

Isn't fasting one day a week considered a form of intermittent fasting? Eating a very healthy well balanced diet, maybe not calorie restricted but calorie controlled, along with a one day a week fast is what I am speaking of, not eating like shit and fasting once a week. I need to do a search, but I thought I read somewhere that this kind of fasting may have several benefits on health.

#6 Ark

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Posted 03 March 2011 - 04:52 PM

Those doing cardio daily should'nt worry.

#7 niner

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Posted 03 March 2011 - 07:42 PM

Those doing cardio daily should'nt worry.

Why not?

#8 Brett Black

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Posted 04 March 2011 - 12:14 AM

Michael, the study you are referring to involved rats, so why did you give this post the title "Mess up YOUR heart with intermittent fasting"? I doubt there are any rats reading your post.


As discussed many times before, and contrary to what is often said or implied, there is no specific benefit of alternate-day fasting (ADF)/every-other day feeding (EOD)/intermittent fasting (IF) on lifespan, long-term health, or aging, at the same Calorie intake. Feeding animals once, twice, or several times/day at the same net Calorie intake yields the same lifespan benefit: the limited effect on lifespan boils down entirely to the small Caloric difference.



Of the very few studies in CR'ed rodents that have examined the effects of multiple feedings per day(as opposed to the ubiquitous single food ration per day), the gap between rations per day in rats was still a whopping 16 hours. That's only 8 hours less than the normal ADF feeding schedule. I think there are still significant questions regarding the importance(or lack thereof) of fasting in CR.


From a post here:
"Why Almost Everybody May Be Doing Caloric Restriction Incorrectly"
http://www.longecity...on-incorrectly/


"The overwhelming majority of caloric restriction(CR) experiments in rodents, whether studying lifespan, longevity or health effects, involve rodents on CR being served a single ration of food per day...."


"It is sparsely mentioned or dealt with in the CR literature, but this difference in feeding regimes is known to result in dramatic differences in feeding behaviours between CR'ed and ad-libitum fed rodents."


"50% of CR'ed rats are going for more than 20.5 hours per day without any food at all, and 90% of the CR'ed rats are going for more than 19 hours without any food per day....."


"This major difference in fasting duration between ad-libitum and CR rodents results in a raft of very significant physiological differences....."


"When subjected to only 16 hours without food(considerably less than that experienced by the average CR'ed rodent), rats lose an average of 6.9% body weight, their serum glucose concentrations drop by an average of 34.9%, triglycerides drop by 48.4% and cholesterol drops by 21.7%. CR'ed rats deplete their glycogen stores during the period of fasting between meals and transition into a daily state of ketosis, as well as experiencing hypothermia during this period...."


"The time scale for many aspects of rodent metabolism is radically different to that of humans, so what seems like a short period of time for a human may actually represent a very long period by rodent standards...."


"....there is from a 6:1 to 10:1 ratio between humans and rodents in terms of speed and duration of these particular metabolic processes."


"....approximately 20 hours of fasting that regular CR'ed rodents experience on a daily basis, is equivalent to 120 to 200 hours of fasting for a human(5 to 8 days.)"


"For a human male of 70kg, the daily weight-cycling of about 7% that rodents experience on CR would be equivalent to continuously rapidly losing and then gaining 5kg of body weight."


"The two studies(that I am aware of) that increased feeding frequency and reduced fasting duration the most, still left rats with a daily 16 hour gap between food rations..."




I couldn't find any detailed information on the feeding regime used in the study that was the basis of your initial post to this thread, but I would assume that its "alternate day fasting" regime most likely involved 24 hours access to ad-lib food followed by 24 hours without any access to food.

If we were to use the 6:1 to 10:1 metabolic ratio of human to rat, then 24 hours without food in a rat would be equivalent to about 6 to 10 days without food in a human. Obviously this would be a major departure from the probably most common 24 hour fast and 24 hour feed used by human practioners of intermittent fasting.

Trying to compare ADF in rats to ADF in humans is potentially fraught with some very obvious and very basic metabolic problems - it's in some ways akin to arguing that CR'ed humans should be eating the same *absolute* number of calories that CR'ed rats do in order to receive the same effects.


The notion that it is otherwise is the result of a mixture of wildly-extrapolated cell studies, and short-term studies (many by Mark Mattson's group) showing that EOD animals undergo a variety of favorable-looking short-term metabolic shifts, such as lower insulin and glucose levels -- and, importantly for THIS post, lower blood pressure, heart rate, and blood pressure variability (1,2). However, these shifts, while consistent with the effects of CR proper, do not lead to life extension except to the degree that they lead to actual Calorie restriction. (Again, see links in the post linked above).


The very study that is the central focus of your post here arguably bases its diastolic dysfunction conclusion on a similar type of extrapolation and short-term study - because assuming ADF always does cause diastolic dysfunction in rats, these "dysfunctional" changes can still lead to a longer lifespan anyway.

Don't get me wrong though, I still think this study is cause for some concern. It's not the first to show potentially harmful results to the heart from similar dietary interventions. In fact, there was this study in rats, not on ADF, but on your currently favoured CR which sounds somewhat ominous:


"Effect of long-term food restriction on cardiac mechanics"
http://ajpheart.phys...73/5/H2333.full
"In summary, FR altered many aspects of cardiac mechanical performance....some of the changes, such as the increase in the sensitivity to ß-adrenergic stimulation, were opposite to ordinary age-related trends.....Others, such as prolongation of time to peak tension and half-relaxation time, AMPLIFIED THE AGING TRENDS."


It also appears to be rather commonly accepted that fasting and more severe caloric restriction can pose some serious risks to human hearts:

"Cardiac effects of starvation and semistarvation diets: safety and mechanisms of action"
http://www.ajcn.org/...1/230S.abstract
"A major concern with the use of starvation or semistarvation diets for weight reduction in severely obese people has been the reports of sudden death due to ventricular arrhythmias....


"Sudden death associated with very low calorie weight reduction regimens"
http://www.ajcn.org/.../34/4/453.short
"We studied the cases of 17 individuals who died suddenly of ventricular arrhythmia after prolonged use (median 5 months) of very low calorie weight reduction regimens consisting entirely or largely of protein...."

Edited by Brett Black, 04 March 2011 - 12:22 AM.

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#9 Skötkonung

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Posted 04 March 2011 - 01:06 AM

Nutr Rev. 2009 Oct;67(10):591-8.Nibbling versus feasting: which meal pattern is better for heart disease prevention?Bhutani S, Varady KA.

Here is a great review looking at meal frequency on cholesterol levels and it seems the majority of studies find a detrimental effect (note: studies looked at were isocaloric, so in the 1 meal/day groups they basically feasted). The negative effect probably has to do with the amount of glucose and lipids that are unleashed on the body, basically the post-prandial state is not only prolonged but magnified, and its probably best to keep post-prandial states to a minimum (avoid, hyperglycemia, NEFAs).

When fasting (and I'm not saying you should) one should probably have a simple meal that is not 2000 calories. Personally I break a fast with two meals. One meal contains fiber, some carbohydrate and protein, and I eat the rest 30 to 1 hour later. However this means you have to eat extra nutritious foods on the other days to make up for the volume you couldn't consume on the fasting day.

This is just my take on the issue. If you are fasting you're doing it to lower caloric intake because at our metabolic rate no one is sure whether the beneficial autophagy actually occurs (like MR said).

What are the postprandial effects of fat? I thought the process that breaks down dietary fat into its component fatty acids is a lengthy process as compared to the breakdown of carbs. Once the fat has broken down, it has to combine with bile salts to make it into a form that is water soluble and can be taken up by the intestinal cells. Once taken up, unlike carbs, which are sent directly to the bloodstream, fats go into the lymphatic system, a much smaller and more static transport system than the vasculature. Once in the lymphatics, fats make their way to the thoracic duct, which empties into a large vein in the upper chest. The lymphatics are small vessels and take a long time to move their contents along since there is no heartbeat pushing them as there is with blood.

By some accounts, fat, especially long-chain saturated fat digests very slowly, and doesn’t reach the blood until much later than the two hour mark. This study certainly seems to indicate that there is a delay in the fat metabolism not shared with the carbohydrate metabolism:
http://www.springerl...7/fulltext.html

I've also read that if you eat a ton of fat (without much fiber) in one sitting, your body will actually pass in the feces it without digesting it at all. At any rate, I tend to eat when hungry. For me, that's usually a large dinner with a 12 hour fast (8pm to 8am) and then only about 500 calories of snacking before dinner again (7pm). So, for most of the day I am in an un-fed state.
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#10 Sillewater

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Posted 04 March 2011 - 04:03 AM

Those doing cardio daily should'nt worry.


J Appl Physiol. 2011 Feb 17. [Epub ahead of print]Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes.Wilson MG, O'Hanlon R, Prasad S, Deighan A, Macmillan P, Oxborough D, Godfrey RJ, Smith G, Maceira A, Sharma S, George KP, Whyte G.


What are the postprandial effects of fat? .....



There is definitely a delay as compared to carbohydrates but reading about NEFAs (non-esterified fatty acids) in the blood and non-fasting triglyceride levels (and its correlation to heart problems) and also possible beta-cell toxicity. I wouldn't say that eating tons of fat is as safe as eating tons of carbs. When I have time I'll do a short update on this stuff (swamped in school work).


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#11 Skötkonung

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Posted 05 March 2011 - 12:59 AM

There is definitely a delay as compared to carbohydrates but reading about NEFAs (non-esterified fatty acids) in the blood and non-fasting triglyceride levels (and its correlation to heart problems) and also possible beta-cell toxicity. I wouldn't say that eating tons of fat is as safe as eating tons of carbs. When I have time I'll do a short update on this stuff (swamped in school work).

NEFAs are interesting. I've heard that eating low-carb rapidly induces insulin resistance. This seems like a normal physiological response to carbohydrate restriction. Carbohydrate restriction drops insulin levels. Low insulin levels activate hormone sensitive lipase. Fatty tissue breaks down and releases non esterified fatty acids. These are mostly taken up by muscle cells as fuel and automatically induce insulin resistance in those muscles. There are a couple of nice summaries by Brand Miller here and here and Wolever has some grasp of the problem too.

This is patently logical as muscle runs well on lipids and so glucose can be left for tissues such as brain, which really need it. Neuronal tissue varies in its use of insulin to uptake glucose but doesn't accumulate lipid in the way muscle does, so physiological insulin resistance is not an issue for brain cells.

However, while muscles are in "refusal mode" for glucose the least input, from food or gluconeogenesis, will rapidly spike blood glucose out of all proportion. This is fine if you stick to LC in your eating. It also means that if you take an oral glucose tolerance test you will fail and be labelled diabetic. In fact, even a single high fat meal can do this, extending insulin resistance in to the next day. Here's a reference for this.

As for triglycerides, I'm curious why you think that would be influenced by dietary fat? Mine are pretty low, (47 mg/dl) and I've been doing the LC ad-lib. I've always understood that a rise in triglycerides from fat were actually chylomicrons. So what determines the size of the rise in chylomicrons? As Dr Volek has pointed out, a ketogenic diet for six weeks markedly reduces your chylomicron concentration after an OFTT, ie you clear the chylomicrons from your blood stream more rapidly. This should hardly be surprising. If you have been in ketosis for 6 weeks you are hardly going to be running your metabolism on sugar. Fat comes in, fat gets used. But it still has to be transported.

Dietary fat (medium chain triglycerides excepted) is ALWAYS transported in bulk as chylomicrons. "Regulated" fat, for metabolic needs, is ALWAYS transported as free fatty acids. These FFAs can be attached to albumin as their transport molecule in the plasma or can be accessed directly from chylomicrons via lipoprotein lipase, at the sites on the vascular wall where FFAs are needed by the tissues. But we can never transport all of a bulk fat meal as free fatty acids. Even when we are in ketosis. In ketosis we clear our chylomicrons faster because we are using a lot of fat. But we can never get rid of them altogether.

The only study I've seen showing that increased chylomicrons induce CVD was The Copenhagen Heart Study. The study itself was observation and full of problems (like not correcting for smoking, BMI, activity level, fasting blood glucose). It's hard to make the assertion that the postprandial effect of dietary fat is killing you.

Attached File  Copenhagen+hazard+ratios.jpg   233.76KB   15 downloads

Attached File  Copenhagen+baseline+characteristics.jpg   201.31KB   15 downloads

We know from Volek that if you eat a ketogenic diet your OFTT "improves". I'll just say that again. Elevated chylomicrons levels after a fat challenge reduce if you have been eating a VERY high fat diet. I think it is a reasonable extrapolation to say that a high carbohydrate diet might worsen OFTT results. So in Denmark a high post prandial chylomicron count, which can be viewed as a surrogate marker for the metabolic syndrome, correlates positively with your risk of heart disease. The hallmark of metabolic syndrome is hyperinsulinaemia. If that hyperinsulinaemia is inadequate to maintain normoglycaemia in the face of carbohydrate consumption then HbA1c rises and other nasty hyperglycaemic stuff happens. And the bulk fat transport gets the blame. Certainly in Copenhagen and perhaps other places too!
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#12 Sillewater

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Posted 05 March 2011 - 06:06 AM

Thanks for the explanation. If you've been following Peter's (@Hyperlipid) stuff he explains really well the "physiological" insulin resistance that occurs during a low-carbohydrate high-fat diet. It all makes sense, the brain is selfish, in emergency situations your muscles need power, etc....

Warning: this is my very limited understanding (I still have tons of papers to read through).

Yes, the part that worries me is the insulin resistance part. While fasting triglycerides are low, what about non-fasting, post-prandial (which is what I think may cause problems on a EOD diet, the feasting). It has been shown that NONFASTING triglyceride levels are associated with various heart problems. In a prospective cohort study in Denmark the hazard ratios (HRs) increased as nonfasting triglyceride levels increased (1). As far as I know the triglyceride levels measured are due to dietary (chylomicrons) and NEFAs (VLDL).

For an older but good review on this topic of how NEFAs and triglycerides can effect the vascular system read this review (2).

In a study that used fairly paleo foods the authors found that the high-fat meal increase oxLDL/LDL ratios, while high carbohydrate increased 3-deoxyglucosone (3). Both in my opinion are not good. What I think a lot of people have done is traded the risk of hyperglycemia (even though fasting levels are that low) for hypertriglyceridemia. However I think it would be prudent to keep both low. [to see chylomicron stacking you can look at this study (4)]

Some studies that make me think more carbohydrate is better are some that compare dextrose to whipping cream and while at lower intakes (dextrose <150g and lipids <33g) found limited oxidative stress (as measured by MDA), higher intakes of lipid cause oxidative stress (more than 150g of pure glucose, maybe fructose may be different, however fructose leads to uric acid production which has its own problems [they used NOW Foods brand dextrose, first time I've seen NOW Foods in a study).

While in most people hyperglycemia occurs first, then hyperlipidemia [5] based on what I read it is still not very good states to be in.

Also the fact that post-prandial lipemia is associated with endothelial dysfunction doesn't quite make me happy [6].

As I said before, maybe I'm just not seeing the big picture because I haven't done enough research so for now this is what I have.

One review paper I don't have access to is this one: "The Postprandial State and its Influence on the Development of AtherosclerosisAuthors: Moreno-Luna, R.; Villar, J.; F. Costa-Martins, A.; Vallejo-Vaz, A.; Stiefel, P.Source: Immunology, Endocrine & Metabolic Agents - Medicinal Chemistry (Formerly, Volume 11, Number 1, March 2011 , pp. 1-9(9)" If anyone does have access please PM me.

The other thing that makes me think is the Kitavan diet. Stephan from Whole Health Source has talked about it. They have a high-carbohydrate diet with a horrible lipid profile (which doesn't matter because cholesterol doesn't cause heart disease, however those doing CR do have impeccable lipid profiles, as do many doing paleo, however some shoot through the roof, which may be due to the high NEFAs floating around), but the Kitavans have low HbA1c and low fasting glucose, and probably excellent glucose tolerance. The road to diabetes is elevated NEFAs due to insulin resistance in adipose, leading to insulin resistance everywhere else. The step before this pre-pre-diabetic state seems to be lack of NEFAs with excellent glucose tolerance. This is one of the reasons I have been increasing my carb intake and eating less on fasting days (not binging).

Sorry if the thoughts are everywhere, but it'll take me a couple months to get through the material.

References
[1] JAMA. 2007 Jul 18;298(3):299-308.Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women.Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A.

[2] Diabetologia. 2002 Apr;45(4):461-75.Beyond postprandial hyperglycaemia: metabolic factors associated with cardiovascular disease.Heine RJ, Dekker JM.

[3] Diabetes Care. 2007 Jul;30(7):1789-94. Epub 2007 Apr 27.Fasting and postprandial glycoxidative and lipoxidative stress are increased in women with type 2 diabetes.Schindhelm RK, Alssema M, Scheffer PG, Diamant M, Dekker JM, Barto R, Nijpels G, Kostense PJ, Heine RJ, Schalkwijk CG, Teerlink T.

[4] Metabolism. 2008 Sep;57(9):1262-9.Determinants of postprandial triglyceride and glucose responses after two consecutive fat-rich or carbohydrate-rich meals in normoglycemic women and in women with type 2 diabetes mellitus: the Hoorn Prandial Study.Alssema M, Schindhelm RK, Dekker JM, Diamant M, Nijpels G, Teerlink T, Scheffer PG, Kostense PJ, Heine RJ.

[5] Eur Rev Med Pharmacol Sci. 2005 Jul-Aug;9(4):191-208.Postprandial hyperglycemia and hyperlipidemia-generated glycoxidative stress: its contribution to the pathogenesis of diabetes complications.Rebolledo OR, Actis Dato SM.

[6] Int J Clin Pract. 2010 Feb;64(3):389-403.Postprandial lipaemia, oxidative stress and endothelial function: a review.Wallace JP, Johnson B, Padilla J, Mather K.

Edited by Sillewater, 05 March 2011 - 06:07 AM.

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#13 Brett Black

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Posted 06 March 2011 - 04:16 AM

Part of the problem, I think, is how we define "intermittent fasting" vs "regular meals." I'm not sure that there is actually any data on regular meals-CR and lifespan for Michael or anyone else to use in the first place.

There is evidence to suggest that almost all conventionally CR'ed rats are, simply by default, fasting for around 20 hours every single day*. This occurs because they are only fed a single food ration per day, and they gorge down the entire thing within about 4 hours of it being supplied.

20 hours without eating is, arguably, a long time for a rat. There are significant physiological changes in the CR'ed rats that are subjected to this daily 20 hour fast(including daily ketosis.)

To my knowledge, there are currently less than 5 studies that examine if shorter gaps between rations in CR'ed rodents still result in increased lifespan. The study that reduced the gaps between rations the most, still left the rats for 16 hours a day between rations. Is 16 hours between rations every day reasonably described as "regular meals"? Studies show that control ad-libitum fed rats rarely go for more than 3 or 4 hours without eating, as a comparison.

Further, alternate-day-fasting animals are only fasting for 24 hours, which, on the face of it, doesn't seem particularly significant given the approximately 20 hour daily fasts that most conventionally CR'ed animals are apparently undergoing anyway. And, remember too that the CR'ed animals experience this fasting every single day, whilst the ADF animals only have to endure the fast every second day.

The differences between CR and ADF begin to appear much less when these(relatively unknown) details are added to the picture.

Michael has recommended that humans should avoid intermittent fasting based, at least partly, on the results from ADF in rodents. If one is to base human feeding frequency recommendations on CR'ed rodent data in this way, then CR'ed humans should be fasting for about 20 hours a day and then gorging on their entire day's worth of food over a 4 hour window - because this is exactly what almost all studies involving Cr'ed rodents have (from the limited available evidence) involved.


*Note: All the references for the studies and data described in this post, as well as further analysis, can be found in a post I made here: http://www.longecity...on-incorrectly/ ("Why almost everybody may be doing caloric restriction incorrectly.")
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#14 Michael

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Posted 01 April 2011 - 12:50 AM

Michael, the study you are referring to involved rats, so why did you give this post the title "Mess up YOUR heart with intermittent fasting"? I doubt there are any rats reading your post.

Because (a) it's a headline, not an essay (the post was clear enough, methinks), and (b) the entire issue is humans adopting EOD on the basis of the rodent studies thereon (compounded by popular misinterpretation thereof). I am not going to add an elaborate caveat about the level of scientific support for the likely translatability of rodent CR data into humans into every single CR- or EOD- or even dietary-supplement-related animal study that I post or discuss.

As discussed many times before, and contrary to what is often said or implied, there is no specific benefit of alternate-day fasting (ADF)/every-other day feeding (EOD)/intermittent fasting (IF) on lifespan, long-term health, or aging, at the same Calorie intake. Feeding animals once, twice, or several times/day at the same net Calorie intake yields the same lifespan benefit: the limited effect on lifespan boils down entirely to the small Caloric difference.


Of the very few studies in CR'ed rodents that have examined the effects of multiple feedings per day(as opposed to the ubiquitous single food ration per day), the gap between rations per day in rats was still a whopping 16 hours. That's only 8 hours less than the normal ADF feeding schedule.


While studies where the rodents are out of food ≤12 h are the minority, there are several -- including one of the direct-comparison meal timing studies cited previously:

Female CD2Fi mice … on a daily schedule of fluorescent lighting from 0600 to 1800, darkness from 1800 to 0600 … were then assigned to four different feeding regimens … [including] six smaller meals at intervals of ~2 h beginning at the onset of darkness and ending near the onset of light, a regimen intended to approximate the pattern of ad libitum feeding (pattern-fed, PF). … Adherence to this schedule was confirmed by direct observation and also by remote recording of the activity of transensor-bearing mice, based on changes in field strength at the antennae. Thus, the longest span without food for this group was about 12 h, roughly comparable to that of ad libium controls, for which feeding is largely nocturnal."(4)

Lab animals mostly eat during waking and sleep during sleeping, and in the wild most animals including humans spend most of the dark hours asleep. I don't think anything can be read into a routine overnight "fasting" period.

I couldn't find any detailed information on the feeding regime used in the study that was the basis of your initial post to this thread, but I would assume that its "alternate day fasting" regime most likely involved 24 hours access to ad-lib food followed by 24 hours without any access to food.

If we were to use the 6:1 to 10:1 metabolic ratio of human to rat, then 24 hours without food in a rat would be equivalent to about 6 to 10 days without food in a human. [...] Trying to compare ADF in rats to ADF in humans is potentially fraught with some very obvious and very basic metabolic problems - it's in some ways akin to arguing that CR'ed humans should be eating the same *absolute* number of calories that CR'ed rats do in order to receive the same effects.

Since rats live on the same planet that we do, with the same sunrise and sunset, and (again) rarely eat during artificial or real daylight hours, I really don't think that's relevant. IAC, as documented earlier, the human data on EOD or even once-daily feeding don't replicate the apparent (misleading) short-term metabolic advantages of EOD, whereas human CR studies show very strong parallels, as due the more invasive and controlled nonhuman primate data.

The notion that it is otherwise is the result of a mixture of wildly-extrapolated cell studies, and short-term studies (many by Mark Mattson's group) showing that EOD animals undergo a variety of favorable-looking short-term metabolic shifts, such as lower insulin and glucose levels -- and, importantly for THIS post, lower blood pressure, heart rate, and blood pressure variability ([refs]). However, these shifts, while consistent with the effects of CR proper, do not lead to life extension except to the degree that they lead to actual Calorie restriction. (Again, see links in the post linked above).

The very study that is the central focus of your post here arguably bases its diastolic dysfunction conclusion on a similar type of extrapolation and short-term study - because assuming ADF always does cause diastolic dysfunction in rats, these "dysfunctional" changes can still lead to a longer lifespan anyway.

You do have a point here, to a limited degree, except that WT rodents very rarely die OF (as vs WITH) cardiac and cardiovascular pathology, whereas these are major causes of mortality in humans. As noted already, while likely only very minor contributors to their extended LS, "CR protects rodents against cardiomyopathy, cardiac hypertrophy, interstitial fibrosis, etc; and in this case, we don't have much to argue about on the question of translatability, since "Long-term caloric restriction ameliorates the decline in diastolic function in humans" (([ref]) -- including, he notes gleefully, his own human self ;) )."

Don't get me wrong though, I still think this study is cause for some concern. It's not the first to show potentially harmful results to the heart from similar dietary interventions. In fact, there was this study in rats, not on ADF, but on your currently favoured CR which sounds somewhat ominous:

"Effect of long-term food restriction on cardiac mechanics"
http://ajpheart.phys...73/5/H2333.full
"In summary, FR altered many aspects of cardiac mechanical performance....some of the changes, such as the increase in the sensitivity to ß-adrenergic stimulation, were opposite to ordinary age-related trends.....Others, such as prolongation of time to peak tension and half-relaxation time, AMPLIFIED THE AGING TRENDS."

First, this study was done in isolated, perfused hearts, and all the performance metrics were after treatment with various drugs. I don't think that's a terribly relevant model to begin with, and even within that experimental model, they had a variety of incompletely-addressed challenges:

First, the number of interventions necessitated that the experiments run for ∼3.5 h. This is a relatively long time for the isolated heart preparation, especially in view of the fact that we used crystalloid perfusion. It was notable that we used coronary perfusion pressures of 60 mmHg, which tended to minimize edema. ... Second, we did not perform testing over a complete dose range of isoproterenol in our hearts. As such, the maximal response to this agonist was not defined in each heart. We feel, nonetheless, that the conclusions on sensitivity to the lowest concentration of isoproterenol are valid. ... Third, the use of isolated hearts entails many inherent weaknesses. Clearly, studies in intact, conscious animals would be preferable. Whether loss of nervous system control, alterations in temperature, use of artificial pacing, and other aspects of our procedure altered our results is not known. Because, however, each group was treated in an identical fashion, the differences we found between groups are likely to represent real effects of FR on cardiac mechanics. [Unless, of course, there IS a CR-specific effect to the conditions which don't apply when the heart is still firmly ensconced in the little buggers' rib cages and beating under their own volition -MR]

Finally, it should be pointed out that because the hearts of the different groups were of different size, the question of how to properly normalize the data from the mechanical studies is important.

By contrast, while one of the tests in the EOD study under discusssion did involve a drug-response test (dobutamine volume stress test), everything else was done under physiological conditions, and all of them in intact, living animals (except, of course, the histopathology studies, where the increased fibrosis was in direct opposition to the REDUCTION in fibrosis in CR proper, just as the reduced diastolic function and cardiac elasticity were the reverse of the findings in CR.

Secondly, the one parameter where CR "AMPLIFIED THE AGING TRENDS" was not identified by the author as being a pathological trend, and not linked AFAIK to any known problem of the aging heart in vivo in humans.

It also appears to be rather commonly accepted that fasting and more severe caloric restriction can pose some serious risks to human hearts:

"Cardiac effects of starvation and semistarvation diets: safety and mechanisms of action"
http://www.ajcn.org/...1/230S.abstract
"A major concern with the use of starvation or semistarvation diets for weight reduction in severely obese people has been the reports of sudden death due to ventricular arrhythmias....

"Sudden death associated with very low calorie weight reduction regimens"
http://www.ajcn.org/.../34/4/453.short
"We studied the cases of 17 individuals who died suddenly of ventricular arrhythmia after prolonged use (median 5 months) of very low calorie weight reduction regimens consisting entirely or largely of protein...."


CR is not equivalent to these diets in any sense: the level of restriction is extreme, the initiation immediate, the diets piss-poor, and frank malnutrition not only present, but positively identified by Lockwood and colleagues as responsible for the problem. After a series of case reports of people following liquid protein diets presenting with arrhythmias, they performed a controlled study which confirmed the effect (3) and demonstrated the rapid depletion of some of the minerals in which the basic formula was deficient (2). But by supplementing the original diet with a broader range, & a higher quantity, of essential minerals, the cardiac abnomalities vanished (1).

This is especially reassuring as it was the most primitive possible method of improving the diet: basically, mixing in a couple of multimineral pills, rather than including a whole food with all of its nutritional complexities. Cf the 'big mac + Centrum' approach of many diets in the CR literature.

A variety of things could've accounted for the correction, but looking at the diets in (1), it's easy to see that the repletion of Mg & Cu -- deficiency of either of which is known, in humans, to cause cardiac abnormalities (incl arrhythmia in the case of Cu) -- was likely a major factor.

And, again: no such phenomenon has been documented in mouse nor man, and indeed, "CR protects rodents against cardiomyopathy, cardiac hypertrophy, interstitial fibrosis, etc; and in this case, we don't have much to argue about on the question of translatability, since "Long-term caloric restriction ameliorates the decline in diastolic function in humans" (([ref]) -- including, he notes gleefully, his own human self ;) )."

References
1. Am J Med 1983 Jun;74(6):1016-22
Vigorous supplementation of a hypocaloric diet prevents cardiac
arrhythmias and mineral depletion.
Amatruda JM, Biddle TL, Patton ML, Lockwood DH.
PMID: 6859052 [PubMed - indexed for MEDLINE]

2: Am J Med 1981 Nov;71(5):767-72
Adverse effects of liquid protein fast on the handling of magnesium,
calcium and phosphorus.
Licata AA, Lantigua R, Amatruda J, Lockwood D.
PMID: 7304647 [PubMed - indexed for MEDLINE]

3: N Engl J Med 1980 Sep 25;303(13):735-8
Cardiac arrhythmias associated with a liquid protein diet for the
treatment of obesity.
Lantigua RA, Amatruda JM, Biddle TL, Forbes GB, Lockwood DH.
PMID: 7402271 [PubMed - indexed for MEDLINE]

4. Nelson W, Halberg F. Meal-timing, circadian rhythms and life span of mice. J Nutr. 1986 Nov;116(11):2244-53. PMID: 3794831; UI: 87085847
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#15 Sillewater

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Posted 26 May 2011 - 05:42 AM

Nutr Rev. 2009 Oct;67(10):591-8.Nibbling versus feasting: which meal pattern is better for heart disease prevention?Bhutani S, Varady KA.
....


http://www.scienceda...10403090259.htm

This article reflects the results in the paper I quote above (fasting/feasting increases tChol, LDL, and HDL [more increase in LDL then HDL]). This occurs probably because fasting is hormetic and your body increases cholesterol production for whatever it needs. Again we see the huge increase in HGH:

This recent study also confirmed earlier findings about the effects of fasting on human growth hormone (HGH), a metabolic protein. HGH works to protect lean muscle and metabolic balance, a response triggered and accelerated by fasting. During the 24-hour fasting periods, HGH increased an average of 1,300 percent in women, and nearly 2,000 percent in men.


Whether this leads to increase in IGF-1 (which is probably does) I do not know. But if we look at rat studies the robustness of removing HGH in rats/mice are much more consistent then removal of IGF-1 as far as I can see. If indeed one of the effects of CR is reduced IGF-1[read post by MR] (with concomitant decrease in protein intake) then fasting may be detrimental to life span extension (but beneficial to lean muscle growth, lean mass, what not).

Wish IGF-1 was available through a doctor here in Vancouver. Have to find another way. Currently my protein intake is sitting at 1g/kg (w/ 10g from gelatin). But I do fast twice a week (just makes life easier).

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#16 Brett Black

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Posted 10 June 2011 - 03:57 AM

Michael, the study you are referring to involved rats, so why did you give this post the title "Mess up YOUR heart with intermittent fasting"? I doubt there are any rats reading your post.

Because (a) it's a headline, not an essay (the post was clear enough, methinks), and (b) the entire issue is humans adopting EOD on the basis of the rodent studies thereon (compounded by popular misinterpretation thereof). I am not going to add an elaborate caveat about the level of scientific support for the likely translatability of rodent CR data into humans into every single CR- or EOD- or even dietary-supplement-related animal study that I post or discuss.


There'd be no need for a caveat(elaborate or otherwise) if you simply refrained from using misleading post titles. I think appending the title with a question mark would have been sufficient...


Of the very few studies in CR'ed rodents that have examined the effects of multiple feedings per day(as opposed to the ubiquitous single food ration per day), the gap between rations per day in rats was still a whopping 16 hours. That's only 8 hours less than the normal ADF feeding schedule.


While studies where the rodents are out of food ≤12 h are the minority, there are several -- including one of the direct-comparison meal timing studies cited previously:


All of the studies you refer to had at least a 12 hour gap period between meals each day. Of the three studies, two of them left a 16 hour period between meals per day, the other left a 12 hour gap and was in mice(which have faster metabolisms.)


Lab animals mostly eat during waking and sleep during sleeping, and in the wild most animals including humans spend most of the dark hours asleep. I don't think anything can be read into a routine overnight "fasting" period.


Do you have reference(s) for that?

In this(supposedly supporting) post I wrote that "ad libitum rats normally experience a maximum of just 3 to 4 hours between meals, and ad libitum mice just 1 hour gap":
http://www.longecity...on-incorrectly/

A re-examination of some of the sources I was using for that statement show that the data was based upon group feeding behaviour, not individual feeding behaviour, which means I badly misinterpreted it. So, I retract that statement.

Also, since originally making my argument about the potentially important difference in feeding frequency between ad-libbers and CRs, I realized something else. Isn't it correct that many modern CR studies subtley restrict the "ad-lib" animals too? In order to prevent obese controls? If that's the case, my guess would be that a similar feeding frequency protocol, namely a single ration per day, would be used with the controls too. If that's true, then perhaps the difference in feeding frequency and daily fasting duration would be expected to be reduced between such semi-restricted "ad-libs" and fully-restricted CR animals.

My argument is looking considerably weaker I think: which is good, I want ("nibbling") CR to work!



The very study that is the central focus of your post here arguably bases its diastolic dysfunction conclusion on a similar type of extrapolation and short-term study - because assuming ADF always does cause diastolic dysfunction in rats, these "dysfunctional" changes can still lead to a longer lifespan anyway.


You do have a point here, to a limited degree, except that WT rodents very rarely die OF (as vs WITH) cardiac and cardiovascular pathology, whereas these are major causes of mortality in humans. As noted already, while likely only very minor contributors to their extended LS, "CR protects rodents against cardiomyopathy, cardiac hypertrophy, interstitial fibrosis, etc; and in this case, we don't have much to argue about on the question of translatability, since "Long-term caloric restriction ameliorates the decline in diastolic function in humans" (([ref]) -- including, he notes gleefully, his own human self ;) )."


My point was largely academic anyway. You might've managed to wring good health out of these actual practices. You win; I'm happy for you. :-D


CR is not equivalent to these diets in any sense: the level of restriction is extreme, the initiation immediate, the diets piss-poor, and frank malnutrition not only present, but positively identified by Lockwood and colleagues as responsible for the problem. After a series of case reports of people following liquid protein diets presenting with arrhythmias, they performed a controlled study which confirmed the effect (3) and demonstrated the rapid depletion of some of the minerals in which the basic formula was deficient (2). But by supplementing the original diet with a broader range, & a higher quantity, of essential minerals, the cardiac abnomalities vanished (1).


Maybe because of your lack of caveats I felt compelled to chuck in some poorly-related negative heart studies. CR is experimental in humans, and I think the potential for unknowns and negative effects needs to be frequently pointed out, particularly in the face of unwarranted optimism.





References
1. Am J Med 1983 Jun;74(6):1016-22
Vigorous supplementation of a hypocaloric diet prevents cardiac
arrhythmias and mineral depletion.
Amatruda JM, Biddle TL, Patton ML, Lockwood DH.
PMID: 6859052 [PubMed - indexed for MEDLINE]

2: Am J Med 1981 Nov;71(5):767-72
Adverse effects of liquid protein fast on the handling of magnesium,
calcium and phosphorus.
Licata AA, Lantigua R, Amatruda J, Lockwood D.
PMID: 7304647 [PubMed - indexed for MEDLINE]

3: N Engl J Med 1980 Sep 25;303(13):735-8
Cardiac arrhythmias associated with a liquid protein diet for the
treatment of obesity.
Lantigua RA, Amatruda JM, Biddle TL, Forbes GB, Lockwood DH.
PMID: 7402271 [PubMed - indexed for MEDLINE]

4. Nelson W, Halberg F. Meal-timing, circadian rhythms and life span of mice. J Nutr. 1986 Nov;116(11):2244-53. PMID: 3794831; UI: 87085847


Edited by Brett Black, 10 June 2011 - 04:05 AM.


#17 Krell

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Posted 12 August 2011 - 03:39 PM

Free Radic Biol Med. 2011 Jul 21. [Epub ahead of print]
Long-term intermittent feeding, but not caloric restriction, leads to redox imbalance, insulin receptor nitration, and glucose intolerance.
Cerqueira FM, da Cunha FM, Caldeira da Silva CC, Chausse B, Romano RL, Garcia CC, Colepicolo P, Medeiros MH, Kowaltowski AJ.
Abstract
Calorie restriction is a dietary intervention known to improve redox state, glucose tolerance, and animal life span. Other interventions have been adopted as study models for caloric restriction, including nonsupplemented food restriction and intermittent, every-other-day feedings. We compared the short- and long-term effects of these interventions to ad libitum protocols and found that, although all restricted diets decrease body weight, intermittent feeding did not decrease intra-abdominal adiposity. Short-term calorie restriction and intermittent feeding presented similar results relative to glucose tolerance. Surprisingly, long-term intermittent feeding promoted glucose intolerance, without a loss in insulin receptor phosphorylation. Intermittent feeding substantially increased insulin receptor nitration in both intra-abdominal adipose tissue and muscle, a modification associated with receptor inactivation. All restricted diets enhanced nitric oxide synthase levels in the insulin-responsive adipose tissue and skeletal muscle. However, whereas calorie restriction improved tissue redox state, food restriction and intermittent feedings did not. In fact, long-term intermittent feeding resulted in largely enhanced tissue release of oxidants. Overall, our results show that restricted diets are significantly different in their effects on glucose tolerance and redox state when adopted long-term. Furthermore, we show that intermittent feeding can lead to oxidative insulin receptor inactivation and glucose intolerance.

Copyright © 2011. Published by Elsevier Inc.

PMID: 21816219 [PubMed - as supplied by publisher]

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#18 douglis

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Posted 05 September 2011 - 11:07 AM

I thought this study is relevant:


Comparison of effects of diet versus exercise
weight loss regimens on LDL and HDL particle
size in obese adults

.....The present study adds to this body of evidence
by demonstrating that ADF may be more effective than
CR at modulating LDL particle size.

http://www.lipidworl...511X-10-119.pdf

#19 douglis

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Posted 05 September 2011 - 11:12 AM

I thought this is relevant:


Comparison of effects of diet versus exercise
weight loss regimens on LDL and HDL particle
size in obese adults

.....The present study adds to this body of evidence
by demonstrating that ADF may be more effective than
CR at modulating LDL particle size.

http://www.lipidworl...511X-10-119.pdf

#20 Sillewater

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Posted 17 December 2011 - 07:13 PM

Before I dive into the question I was wondering if anyone here knew. Does IF lead to increased IGF-1 levels at the same caloric intake across different feeding schedules (e.g. 1/day, 2/day, 3/day)? If so, then is the lifespan extension still the same?

Or maybe it doesn't matter that much as MR posted before: http://www.longecity...gf-1-primarily/

Does anyone know of studies comparing different feedings to mitochondrial stress (e.g. complex 1 levels, state3:4, H2O2 etc...)?

Edited by Sillewater, 17 December 2011 - 07:18 PM.


#21 APBT

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Posted 16 April 2012 - 06:23 PM

Rather than start a new thread, I thought I'd contribute to an existing one on IF.
While this neither supports nor refutes Michael's "Mess Up Your Heart With Intermittent Fasting" concept, it's lends credence to the idea that IF can aide in body fat loss while maintaining lean tissue. The author, a well-trained athlete, who was already muscular and lean, lost substantial body fat and maintained muscle using IF.
Here's a link to the free report:
http://www.precision...mittent-fasting

#22 Leapmind

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Posted 18 April 2012 - 11:57 AM

I am on the 16h fast after my last meal. I am not doing it because of any benefits besides that I need to eat less frequently, longevity is linked to low calorie intake. A fast is just a fast, even if it means that your only meal consists of 6500 calories.

The only shift I have noticed is that my heart starts bouncing because norepinephrine after the last meal. The more carbs I eat, or the more fast carbs during the last meal, the more norepinephrine I sense is going through my system. I find this as something positive, it makes me calm and more sociable! Although alcohol ruins it and makes me uncomfortable being with people.

Here´s a few thoughts that might be of guidance, I hope it is somewhat useful.

There are two type of personality types when it comes to stress. One of the types are those who perform better under stressed conditions. these are more prone to heartattacks. The other type is those who feel uncomfortable under stressed conditions but they don´t have the same heart issues as the other personality types.

I don´t know if it is relevant. But rocketfueling your heart on a constant basis could lead to these problems. I know my parents are high performers under stress and the more stressed they get , the more powerful they feel. Especially my mother!

The norepinephrine shift has made me aware of this and made me realise some stuff about those high performers under stressed situations. I have tried SNRI´s but they didn´t work at all in the same way. I don´t even believe that they work as norepinephire reuptake inhibitors.

Modafinil has some of the norepinephrine components but they are also linked to anxiety. It seems that there something else linked to positivity and high performing under stress than just norepinephrine.

So clearly the fast is doing something else than just give me the norepinephrine shift. Although it can also be linked to circaidian changes in the brain.

#23 Castiel

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Posted 29 January 2014 - 11:46 PM

"We studied the cases of 17 individuals who died suddenly of ventricular arrhythmia after prolonged use (median 5 months) of very low calorie weight reduction regimens consisting entirely or largely of protein...."

IMO it is likely the use of protein as main or sole source of calories that might be causing the problem. As addressed above it seems it led to micronutrient deficiency.
As for ADF, I think it should make it easier to perform CR over a given window of time.

Whether this leads to increase in IGF-1 (which is probably does) I do not know. But if we look at rat studies the robustness of removing HGH in rats/mice are much more consistent then removal of IGF-1 as far as I can see. If indeed one of the effects of CR is reduced IGF-1

2:5 fasting(500-600 cal) reduces IGF-1 by 50% in humans. CR requires reduction of proteins for reducing IGF-1 in humans.-(horizon: eat fast and live longer documentary)

Edited by Castiel, 29 January 2014 - 11:48 PM.





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