Protein cycling diet for life extension

protein cycling diet for life extension

Part of a protein cycling diet

Valter Longo is a scientist at the University of Southern California who has done many studies on the anti-aging effects of fasting. He’s studied not just intermittent fasting, but prolonged fasting of several days as well, which improves biomarkers of aging.

A study that Longo and colleagues published last year studied prolonged fasting in relation to the immune system. [1] From the abstract to this study:

Immune system defects are at the center of aging and a range of diseases. Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSCs) and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration.


It’s clear from the abstract that Longo et al. believe that suppression of insulin-like growth factor 1, or IGF-1, is largely behind the fasting-caused reversal of immunosuppression. What appears to happen during prolonged fasting is first a profound elimination of circulating immune (white) cells, followed by regeneration of stem cells, resulting in new, young immune cells.

Dietary protein appears to be a major determinant of IGF-1 levels in humans and other animals. Longo and colleagues recently wrote another paper – incidentally, much criticized – concluding that low protein intake is associated with a major reduction in cancer, IGF-1, and mortality in humans – but only if those humans are under 65 years old. [2] If they were over 65, a high protein diet caused lower cancer and mortality. So go figure; it’s no wonder the paper was criticized, not just because that doesn’t make a lot of sense, but for other methodological problems.

In any case, it seems that lowered protein intake is largely responsible for the anti-aging effects of fasting.

Or is it? A paper published over 20 years ago concluded that “carbohydrate regulates the adaptive response to fasting”.[3]

In this study, one group of people were fasted for 84 hours (3.5 days), quite a long time for going without food. Another group also fasted, but received an infusion of a lipid emulsion to the tune of about 3,000 calories a day, enough to cover energy requirements. In the end, there was no difference between groups: “plasma glucose, free fatty acids, ketone bodies, insulin, and epinephrine concentrations during fasting were the same in both the control and lipid studies.”

The authors conclude: “These results demonstrate that restriction of dietary carbohydrate, not the general absence of energy intake itself, is responsible for initiating the metabolic response to short-term fasting.”

However, IGF-1 was not measured.

Other studies have shown associations of dietary protein with IGF-1, but seemingly no association of dietary fat with it. 

Methionine restriction

Methionine is an essential amino acid, and restricting methionine in the diet results in robust lifespan extension in rats.[4] Several lines of evidence have led investigators to conclude that lifespan extension by calorie or protein restriction may largely be due to the scarcity of this one amino acid, methionine.

A recent paper found that growth hormone is necessary for the lifespan extension effects of methionine restriction.[5] Mice that are deficient in growth hormone – dwarf mice – do not live longer if their diet is restricted in methionine. Same with growth hormone receptor knockout (GHRKO) mice, which have been bred to have no growth hormone receptors. Only mice with normal growth hormone levels and receptors, or mice with higher than normal levels, live longer with methionine restriction. This indicates that lower levels of growth hormone are involved in the lifespan extension effects of protein/calorie restriction.

Carbohydrates, fat, and IGF-1


Dietary carbohydrates also increase insulin and IGF-1 levels.[6] The risk of recurrence of breast cancer in women who have IGF-1 positive tumors – about half of all breast cancers – is 5-fold higher in the face of stable or increased carbohydrate consumption.[7]

The evidence linking carbohydrate consumption with increased IGF-1 is relatively sparse, as far as I can see. Carbohydrates do of course greatly increase insulin, and this hormone is an anabolic one as is IGF-1.

Dietary fat, however, doesn’t appear to increase insulin, growth hormone, or IGF-1, or not very much anyway.


So far, we see that fasting decreases IGF-1, as do protein and methionine restriction. Carbohydrate restriction may do the same.

So, could we get the benefits of fasting for health and anti-aging purposes by merely not eating protein and carbohydrates, i.e. eating nothing but fat? I think we could. This would be protein cycling, where we either extend the fasting period by eating only fat when we break the fast, or just not fasting at all and eating only fat.

Others have thought of this too. You can read a fairly extensive e-book on a protein cycling diet here. The author notes that protein restriction increases autophagy and thus has the potential to slow or even reverse neurological diseases. Where I believe the author goes wrong is that his proposed diet is high in carbohydrates and low in fat. Carbohydrates increase insulin levels and thus abolish autophagy.

If my line of thinking above is correct, then eating carbohydrates won’t lower IGF-1 levels either. We need a different approach to a protein cycling diet.

Protein-cycling diet

Here’s what I’ve started to do. When I fast intermittently, generally every third day, I don’t break my fast with anything high in protein, but with food low in carbohydrates and high in fat.

My fast has increased my autophagy levels and by breaking it with high-fat food I keep autophagy going. One of the main purposes of autophagy is to supply the body with a constant level of amino acids by breaking down muscle tissue. If no protein is supplied through eating, then the body still needs that amino acid supply from tissue and will keep supplying it.

As we saw above in the fasting/lipid infusion study, it appears that fasting itself may not even be necessary to get some or all of the effects of increased autophagy, lower IGF-1 and insulin, and neuroprotection. All you would need to do is eat only fat for several days.

If you did this, you would also enter a state of ketosis, and this promotes brain autophagy, which is markedly neuroprotective.[8] The author of that study has proposed something similar to what I’ve been discussing, an intermittent ketogenic diet. Essentially, you wouldn’t have to give up carbohydrates and other “normal” food completely, but only intermittently, for a day to several days at a time. He proposes the use of medium-chain triglyceride (MCT) oil, coconut oil, and hydroxycitrate among other things.

When I come to the end of a 16-hour fasting window, I’ll eat fat. So far about the only thing suitable I’ve found is cream cheese, 3 ounces of which have only 5 grams of protein and zero carbohydrates, and about 300 calories. (The small amount of protein in it will be metabolized and out of the system quickly.) I can’t even eat that much and it holds me all afternoon. But I do need to explore some other food options, as plain cream cheese is pretty bland tasting. If I’m hungry and want to continue my fast this way, I’ll sometimes make a cup of chocolate: one heaping teaspoon of baking chocolate, add about 5 ounces of water, microwave one minute; then add several ounces of heavy cream. Made this way, it both stimulates the nervous system and keeps you fed, besides allowing autophagy to continue. There’s no protein in it, and chocolate itself activates AMPK and autophagy.

Then at dinner that evening I’ll eat a normal, protein-rich meal. The next day is workout day, and I’ll eat relatively high protein that day to build muscle. You wouldn’t want to keep protein low all the time as this would lead to muscle loss, a big scourge of aging.

A protein cycling diet could give you many of the beneficial effects of fasting without going hungry.

PS: Be sure to keep an eye out for my upcoming book, “Muscle Up: How Strength Training Beats Obesity, Cancer, and Heart Disease, and Why Everyone Should Do It.”



Leave a Comment:

Andreas says October 3, 2015

P.D. — Interesting idea. Dave Asprey developed something similar he called his “Rapid Fat Loss Protocol” for other reasons – probably nuts to follow it over a long period of time, but used in the kind of timeframes you describe for protein cycling it may make lots of sense.

Essentially, coffee or chocolate with high quality butter and MCT oil + a well chosen set of supplements and activated charcoal timed through the day to help move toxins (in Asprey’s description) through the body when the high fat forces their release and plenty of mineral water or water with a pinch of Himalayan salt.

A cup or two of buttered/MCTed coffee gets one well into the afternoon with no hunger at all in my experience. Repeat between 2 pm & 3 pm to take you well into the evening (you could go with decafe). Snack on butter or cream or MCT oil to get through to bed time.

I’ve gone 3 to 4 days on this and have found it easy to do.

Asprey calls for BCAAs. Not certain if these would throw off your protein-cycling theory.

    P. D. Mangan says October 4, 2015

    Andreas, thanks, it sounds like Asprey’s protocol has a protein cycling component to it. As for BCAAs, they will abolish autophagy, since plasma leucine level is a major determinant and signal of whether autophagy proceeds; the cells sense whether enough leucine is available, and if not, break down tissue to provide it. Hence adding leucine, one of the BCAAs, will stop this. This may be fine for fat loss but for anti-aging purposes, BCAAs should be taken in the fed state.

JoeS says October 3, 2015

Hey PD, keep up the great work! I have a few questions about your fasting schedule:

Do you include sleep time in your 16 hour fasting window? So 8pm to noon the next day would qualify for a 16 hour fast?

How did you come up with 16 hours? For comfort? Is more than 16 hours too intolerable for you? Does fasting more than 16 hours affect your muscle strength too much?

    P. D. Mangan says October 4, 2015

    Thanks, Joe. yes, sleep time is included in the fasting window, and 8 PM to noon is a 16 hour fast. As for this particular length of time, 16 hours, it’s long enough that it should have beneficial health effects – longer than the 12 hours or so overnight that’s a normal fast. And yes, it’s comfortable enough – I’ve fasted longer, up to 22 hours, but it takes quite a bit more willpower and also affects what else you can accomplish during that time – sometimes it becomes difficult to ignore the hunger so you can’t get much work done.

    There’s a possibility that longer fasts may be more detrimental to muscle strength, but I think it’s minimal. As long as you eat enough calories and protein after breaking the fast, you should be fine.

    There are no rigid scientific studies of fasting for 16 hours vs longer as to how they affect muscle, autophagy, insulin resistance, etc. Much of this is necessarily guesswork.

Ferex says October 5, 2015

“What appears to happen during prolonged fasting is first a profound elimination of circulating immune (white) cells, followed by regeneration of stem cells, resulting in new, young immune cells.”

This part sounds very interesting indeed, could you give more details and/or references? Thank you kindly in advance.

    P. D. Mangan says October 5, 2015

    Ferex, the white cells seem to be eliminated due to lack of calories, i.e. fasting. Apparently these immune cells are among the first to go, possibly for use as energy for the rest of the organism. Refeeding brings a population of brand new immune cells. Details are in the paper by Longo, first reference.

      Ferex says October 5, 2015

      Mangan, my interest was woken because it might also have applications to autoimmune diseases.

      I suffer from light-to-moderate arthritis myself, but recently found, after getting a bad cold and bedding down for three days, that I was feeling much better afterwards, with considerably reduced symptoms (less joint pains, etc). My (entirely unscientific) hypothesis then was that the immune system had been recruited for kicking the invaders out rather than messing around with me, which was a bit interesting. But since I didn’t eat much or anything while ill, for a duration which is in the “fasting window” they mention, the Longo paper provides what might be a better as well as more useful explanation. Having fasting as a relief technique would be very interesting indeed.

      Thanks again for finding this.

Gruesome says October 7, 2015

In order to prolong fasting, increase fat intake, reduce hunger and cycle proteins all at the same time and kill all the birds with one stone, you might try this on weekdays only:

(1) Eating a large dinner only;

(2) Strength training on Monday, Wednesday and Friday in fasted state;

(3) Breaking your fast with a rich cream soup made from bone broth and fat trimmings or drippings from roasts (you can blend in a milieu of greens, herbs, spices, cream cheese, raw milk, kefir, avocado, nuts, Himalayan salt etc.) followed up by the dinner feast 2 hours later.

This will take you all the way to dinner the next day. If the hunger pangs become unbearable in the daytime, a raw carrot, apple, orange and water every 2 hours will do the trick.

Drifter says November 24, 2015

Thanks for this great series. I’m curious why you didn’t mention the methionine/glycine ratio and supplementing glycine. It was my understanding that the issue with methionine was too much of it in relation to glycine, and that supplementing glycine had the same (and in practical terms, a better) benefit as restricting methionine…

Undercover Slob says November 28, 2015

I am new to your blog and I must say, you seem to cover many of the areas of health and nutrition that I am currently interested in. I have questions, however. For instance, I am with you in this particular article but confusion pervades my reading comprehension in this paragraph; “My fast has increased my autophagy levels and by breaking it with high-fat food I keep autophagy going. One of the main purposes of autophagy is to supply the body with a constant level of amino acids by breaking down muscle tissue. If no protein is supplied through eating, then the body still needs that amino acid supply from tissue and will keep supplying it.”

I was made to understand that the main purpose of autophagy was to recycle cellular “junk” and/or clean up the mitochondria so as to make it more efficient. Furthermore, I was also made to understand that the fasting state promotes HGH in order to “spare muscle” through the period (no food) that would otherwise be catabolic. Aren’t amino acids mainly utilized for hypertrophy and if so, isn’t that consistent with the HGH dispatch as well as the body’s energy needs being fulfilled by ketones? After all, it would stand to reason that the amino acids the body needs throughout the fast would come from cells that either need repair or else ones that are beyond repair and not robust cells themselves. In other words, I have thought that fasting doesn’t elicit a catabolic response.

    P. D. Mangan says November 28, 2015

    Hi Undercover, glad we have some interests in common.

    Your understanding that the main purpose of autophagy is recycling of cellular junk is correct. The question is, what triggers autophagy or increases it, and the main answer is the absence of food – although exercise and some supplements can also increase it. Mainly carbohydrates and protein in food raise autophagy levels, fat seeming to have little effect. Amino acids are used for hypertrophy (growth) but also for cell maintenance – proteins like enzymes or signaling molecules are turned over constantly, so the cell must have a constant supply.

    You wrote, “After all, it would stand to reason that the amino acids the body needs throughout the fast would come from cells that either need repair or else ones that are beyond repair and not robust cells themselves.” That is also correct. The other purpose of autophagy beyond recycling junk is to assure a steady supply of amino acids. HGH release on fasting spares lean mass from being broken down and causes an increase in fat burning to supply fuel, so breaking down protein to supply glucose from gluconeogensis isn’t necessary. One of the main actions of HGH is to increase fat burning.

    Hope I’ve answered your question. Let me know if I can help further.

      Rob H says December 28, 2015

      Hi Dennis, I’m just re-reading this post again to refresh my memory. One thing struck me here in your above comment, ie: “HGH release on fasting spares lean mass from being broken down and causes an increase in fat burning to supply fuel, so breaking down protein to supply glucose from gluconeogensis isn’t necessary.” Now, I’m pretty lean at the moment from following the paleo diet/ strength training as I’m sure quite a few of your readers are too. That means we don’t have a huge amount of body fat left to burn. So, if our primary goal now is actually to build lean muscle mass, would it not be BETTER to be ingesting pure fat throughout the ‘fast’ (as opposed to pure fasting/ calorie restriction) to prevent the breakdown of skeletal muscle in the absence of significant amounts of body fat as a fuel source? (I know we don’t want to be taking BCAAs in a fasted state as this will stop autophagy). I’ve found that taking a bulletproof coffee, or even just snacking on a teaspoon of pure coconut oil to be really useful, and has the additional benefit of completing removing hunger. Would be interested to hear your thoughts on that…

        P. D. Mangan says December 28, 2015

        Sure, I think bulletproof coffee or similar (MCT oil, coconut oil, just coffee with lots of cream) is fine, if you have no desire to lose any more fat. It’s the protein and carbs that are to be avoided during a fast. There’s some evidence that eating pure fat is physiologically nearly identical to fasting.

Rob H says November 29, 2015

Hi P.D.,

I’ve just come across your blog and am extremely impressed – you’ve clearly got your finger on the pulse of the latest research, and I am so refreshed by your open-minded approach to this area. My question is this: in figure 1 of the Melnik, John & Schmitz paper, it shows that whey protein increases IGF-1 via the tryptophan it contains, being converted to serotonin then into growth hormone, leading to increased IGF-1. This seems to be the primary factor driving the higher IGF-1 in the 2 scenarios in the diagram. By contrast, according to the diagram Leucine (the primary branched chain amino acid) seems to have no effect on IGF-1 levels, only increasing insulin (presumably a good thing after a workout to get nutrients quickly to the muscles).

So: I can see that you recommend taking whey protein after a workout, but would it not be preferable to take BCAAs instead (ie Leucine) to avoid increases in IGF-1? I realise that would not have an anabolic effect on its own (Leucine merely prevents catabolism) – but maybe to follow up the BCAAs with the other essential amino acids in a whole food protein source, eg chicken/ fish for post workout lunch? You could then additionally supplement with NAC tablets (relatively cheap here in the UK) to provide for the cysteine which would have been provided by the whey..

Effectively, what I’m trying to resolve is how can we reduce IGF-1 levels as much as possible whilst still promoting anabolism after a workout (I workout fasted by the way a la Martin Berkhan’s leangains). The article above seems very down on whey protein with regards to IGF-1 levels! Would be great to get your thoughts on how to optimise here…

    P. D. Mangan says November 29, 2015

    Hi Rob, and thanks. Everything you wrote here is spot on as far as I can tell. One question is to what extent whey and other proteins raise IGF-1 and insulin. As for insulin, carbohydrates seem to raise levels far more than proteins, but I don’t know about IGF-1. Muscle growth, contrary to what is popularly believed, doesn’t seem to require additional systemic IGF-1 _ I have a post here about how doing squats, which increases growth hormone, doesn’t add to muscle growth in the biceps.

    BCAAs signal growth and prevent catabolism, but essential amino acids are required for growth, so you’ll need them at some point.

    Don’t know if I’ve answered your question; I think your schema could work though, obviously Berkhan’s does.

Undercover Slob says February 29, 2016

Hello again, P.D. I have a couple questions regarding this insightful post. This approach isn’t very different from the IF/fat adapted diet of Mark Sisson and others of the Paleo/Primal communtiy but firstly; you seem to agree that autophagy is shut down upon substantial protein ingestion (for its obvious elicitation of insulin) but go on to mention that “one of the main purposes of autophagy is to supply the body with a constant supply of amino acids by breaking down muscle tissue…) I believe that this was a mis-typed sentence. Can you confirm that. I believe that one of the main directives of autophagy is cellular “clean up” through a second round metabolism and recycling of “cellular junk” as it were. Autophagy is in fact known to be muscle sparing as it elicits HGH in order to achieve this task. Eventually, autophagy and fasting become a starvation situation but for our purposes here, that’s not what we’re talking about. Was this indeed a mis-type?

Secondly, you also mentioned that you’ll go to a much higher protein diet on the day before and after a work out session. This is obvious but there was no mention of the day after that work out day. I thought that to properly build lean mass, one must load up on protein for a couple of days after a training session. Is this not true? Does protein loading for a single 24 hour period following a resistance training episode suffice? That would be spectacular if so.

As always, your input is greatly appreciated.

    P. D. Mangan says February 29, 2016

    Hi Undercover, no, that wasn’t a mis-type. Autophagy does indeed have the cleaning of cellular junk as a main purpose, but supplying amino acids is another one. That’s why fasting (or starvation) strongly induces autophagy, as the body senses the need for amino acids that are not being supplied by food. But fasting doesn’t break down much muscle, because the level of amino acids required in the bloodstream for maintenance purposes is small. The degradation and building of muscle is a constant, daily process. I emphasized how we can use that for anti-aging purposes in my book Stop the Clock.

    Re protein and workouts, novice bodybuilders experience a longer period of time in which they have increased muscle protein synthesis after a workout; it’s higher than normal for as long as 48 hours after. Experienced bodybuilders have increased rates for only about 24 hours. Novice bodybuilders also have higher protein requirements, since they have a longer window and their building lots of muscle. Experienced bodybuilders don’t need as much.

    Since I’m an experienced bodybuilder – by dint of duration if not results! – then I want extra protein in the 24 hours after a workout, the rest of the time not so much.

      Undercover Slob says February 29, 2016

      Got it. Makes sense.

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