5 Day Fast – Using the Fast Mimicking Diet

Recently I began a 3-day fast, which then got extended to 5 days.

The intention was to use the “Tim Ferriss method” (described here). Essentially accelerating the shift from glucose burning to fat burning as quick as possible, avoiding the negative physical feelings associated with the transition period. (60 second video primer on ketones if you’re not familiar).

However, in the process of researching more about the measurement of blood glucose and blood ketones, I realised its possible to experiment a bit.

There has been some excellent research done by Valter Longo and his colleagues at the University of Southern California on a way to do fasts, without completely stopping eating.

Essentially, they were aware of all the health benefits associated with fasting, but wanted to tackle the problem of compliance. For most people these days, the thought of not eating for 5 days is too much to handle.

They have come up with a 5 day diet that is low enough in calories and carbohydrates, that the user gets the vast majority of the benefits from fasting.

Actually, they have patented their specific diet as prolonfmd.com – and are selling it to hospitals to prescribe to their patients. Your first thought is probably…huh? But its more about “playing the game”, and finding ways to get fasting into hospitals, than it is about money. I believe Valter has even gone as far as to pledge his profits from the endeavour to charity. For more on Valter Longo and the FMD diet – check out Rhonda Patrick’s podcast with him.

What patients would find when they use the prescription Prolon diet

Luckily for us, we can use Valter’s research into fasting, without getting a prescription for his diet. In the paper that they published to cell.com, they describe the details of the diet:

The human FMD diet consists of a 5 day regimen:
– Day 1 of the diet supplies 1,090 kcal (10% protein, 56% fat, 34% carbohydrate)
– Days 2–5 are identical in formulation and provide 725 kcal (9% protein, 44% fat, 47% carbohydrate).

Damien, of Quantified Body figured out that this is similar to the macronutrient composition of avocados. So for example, you could have 2 medium sized avocados per day on each of the 5 days.

It doesn’t have to be avocados though, it could be anything that fits the above macros.

The other interesting piece of the puzzle, that contributed to this fast, was a paper by Dr Seyfried on treating brain cancer.

They found that if they could keep patients in what they termed “nutritional ketosis”, then they could achieve remission in some patients. Nutritional ketosis differs from simply measuring blood ketone levels, instead it measures the ratio between blood glucose and blood ketones. I’ve written in more detail here about it.

The sweet spot where blood glucose drops and blood ketones rise. This graph comes from Seyfried’s experiment to halt tumor growth.

My 5 Day Fast Details

The crux of my experiment, is that adding in some calories/nutrition makes the whole process MUCH easier. And you can do it in a calculated way.

Here’s the rough breakdown of what I consumed:

  • Day 1 (after 24h) – 2 tablespoons of MCT oil (C8)
  • Day 2 – 2 tablespoons of MCT oil (C8) + 1 tablespoon of coconut oil
  • Day 3 – 1 avocado (with Himalayan sea salt + apple cider vinegar) + 1 tablespoon of coconut oil
  • Day 4 – 2 avocados (again with Himalayan sea and apple cider vinegar) + 1 tablespoon of coconut oil + 1 tablespoon of MCT oil (C8)
  • Day 5 – Nothing until I broke the fast in the evening

You can see I didn’t adhere strictly to the fast mimicking diet, and was generally under the prescribed amount of calories. But was far in excess of a simple water fast.

From the end of day 1, my ketones were elevated (no doubt helped by the MCT oil). Highest they reached was about 4.4mmol/L, with blood glucose simultaneously at 2.8mmol/L.

2.8 mmol/L blood glucose reading (about 39 mg/dL)


4.4 mmol/L blood ketone

The measurement of blood ketones and blood glucose come in useful for 3 main things:

  1. Tracking your transition into ketosis – and correlating how you feel with where you are in ketosis
  2. Giving you a measurable goal to aim for and maintain! (this is huge)
  3. You can use the blood measurements to test how different foods / ketone sources affect them

Regarding #3 – when I ate the second avocado on day 3, my bloods actually showed I came out of nutritional ketosis. Even though my ketones were at 2.5 mmol/L, my blood glucose was at 4.3 mmol/L. Which is a ratio of 1.72 – rather than the desired ratio of 1.0 or lower.

After Thoughts

All in all this experiment was a success.

Its becoming increasingly more obvious that fasting is an important tool in humanities arsenal against disease. Once upon a time, as hunter and gatherers, these fasted states were forced on us by the environment. Now in today’s abundant first world, we have to artificially create them. As with any “medicine”, one of the big hurdles is compliance.

The last 5 day fast I did was back in November, and it was taxing to say the least. I certainly didn’t feel in a rush to do another one. However, this time around, I felt much more functional throughout the fast – and can see a way to make this a more regular thing. Regular being something in the order of twice per year.

Exiting The Fast + Ketosis

Probably the worst part of the fast this time was the exit. I think it comes down to the harsh way I went from nutritional ketosis, to consuming reasonably high levels of carbohydrates. In retrospect, I’d probably prepare a meal with some fatty meat + vegetables. That way it fulfils the need I have to *eat everything*, but won’t cause such a harsh crash after.

I’ve never been a strong believer in living in ketosis, and I’m still not. But there’s something about seeing the effect on your body when it goes from ketosis to glucose burning, that makes you question if you’re doing it a favour!

Further Questions

There’s a few points from this experiment I’d like to learn more about:

  • Evening of day 3 I was still producing ketones, but out of nutritional ketosis. Morning of day 4 I was back in nutritional ketosis. What effect does coming out of nutritional ketosis have on the overall efficacy of the fast?
  • If we were to compare a completely water based fast, to the fast mimicking diet, what are we losing out on?
  • If we are losing out on something, could this be mitigated by going to 6 or 7 days?

Anyway, that’s a rather large brain dump. Hopefully if you’ve got this far you’ve been able to extract some nuggets to help you in your journey. If you’ve got any questions or comments, please leave them below. As for any blogger, feedback is wonderful.

Fasting decreases hunger which makes it more effective than dieting

Ghrelin is the so-called hunger hormone, first purified from rat stomach in 1999 and subsequently cloned. It binds to growth hormone (GH) secretagogue receptor, which strongly stimulates GH. So, eating, by itself does not makes you gain lean tissue (like muscle and bone), despite what all the makers of supplements like whey protein and creatine claim. Rather, hunger may be a strong growth stimulus.

Nothing turns off Growth Hormone like eating and you need GH to grow functional tissue. Of course, food provides the nutrients needed to grow, so in fact, you need both feeding and fasting cycles to properly grow. Not all feeding, and not all fasting. Life lies in the balance of the two. The cycle of life is feast and fast. But in today’s world, many people would have you believe that fasting is detrimental to your health, and that you should eat all the time.

The biggest worry about fasting is dealing with hunger. People assume that hunger will get worse and worse until you cannot help yourself and start an IV donut slurry in your garage. Oooh… donuts…. Ghrelin, the hunger hormone, increases appetite and weight gain. It also antagonizes the effect of leptin (in rats at least). Leptin is a hormone produced by fat cells which turns off appetite and makes us stop eating.

Ghrelin turns on appetite. So, if you want to lose weight on a long term basis, you need to tune down ghrelin. If you don’t eat (fast), don’t you get hungrier and hungrier, ghrelin goes up and up and you’ll just gain weight?

Well, no. As we discussed last week, eating all the time sounds like it will turn off hunger and ghrelin. But that’s far too simplistic. Surprisingly, the answer to turning down ghrelin (and hunger) is the opposite — fasting.

Let’s look at this study “Spontaneous 24-h ghrelin secretion pattern in fasting subjects“. Patients undertook a 33 hour fast, and ghrelin was measured every 20 minutes. Here’s what ghrelin levels look like over time.

There are several things to notice. First, ghrelin levels are lowest at approximately 8:00 – 9:00 in the morning.

Circadian rhythm studies consistently find that hunger is lowest first thing in the morning, also generally the longest period of the day where you have not eaten.

This reinforces the fact that hunger is not simply a function of ‘not having eaten in a while’. At 9:00, you have not eaten for about 14 hours, yet you are the least hungry. Eating, remember, does not necessarily make you less hungry.

Next, notice that there are 3 distinct peaks corresponding to lunch, dinner and the next day’s breakfast. BUT IT DOES NOT CONTINUALLY INCREASE. After the initial wave of hunger, it recedes, even if you don’t eat.

Ghrelin shows a “spontaneous decrease after approximately 2 h without food consumption”. This correlates perfectly to our clinical experience in the Intensive Dietary Management Program that ‘hunger comes in waves’.

If you simply ignore it, it will disappear. Think of a time that you were too busy and worked right through lunch. At about 1:00 you were hungry, but if you just drank some tea, by 3:00 pm, you were no longer hungry. I often feel the same level of hunger whether I ate lunch or not — exactly what the ghrelin studies show. Ride the waves — it passes.

Also note that ghrelin does have a learned component since all these subjects were used to eating 3 meals per day. It is not merely by coincidence that these peaks of ghrelin happen. This is similar to the ‘cephalic phase’ of insulin secretion that we’ve discussed previously.

There was one other big finding of this study. Look at the average ghrelin levels over 24 hours. Over the entire day of fasting, ghrelin stays stable! In other words, eating nothing over 33 hours made you no more or less hungry than when you started! Whether you ate or did not eat, your hunger level stayed the same.

Eating more sometimes makes you more hungry, not less. In the same vein, eating less can actually make you less hungry. That’s terrific, because if you are less hungry, you will eat less, and are more likely to lose weight.

So what happens over multiple days of fasting? This study looked at the question specifically. 33 subjects had their ghrelin measured over 84 hours of fasting and they divided the results by men and women, as well as obese and lean.

There were no significant differences between the lean and obese subjects, so I won’t dwell on that further. Once again, there were distinct circadian variations.

Over 3 days of fasting, ghrelin gradually DECREASED. This means that patients were far LESS hungry despite not having eaten for the past 3 days. This jives perfectly with our clinical experience with hundreds of patients undergoing extended fasting in our IDM program.

Everybody expects to be ravenously hungry after fasting multiple days, but actually find that their hunger completely disappears.

They always come in saying ‘I can’t eat much anymore. I get full so fast. I think my stomach shrank’. That’s PERFECT, because if you are eating less but getting more full, you are going to be more likely to keep the weight off.


Notice, also the difference between men and women. There’s only a mild effect for men. But the women show a huge decrease in ghrelin. Again, this addresses one of the major worries that women are not able to fast.

Actually, women would be expected to have more benefit from fasting because their hunger can be expected to decrease better than men. Notice, too, how much higher women’s ghrelin level reaches.

I suspect this correlates to the clinical observation that many more women are ‘addicted’ to certain foods eg. chocoholics. Sugar addicts. etc.

So many women have remarked how a longer fast seemed to completely turn off those cravings. This is the physiologic reason why.

A few other notes about the hormonal changes of fasting. Notice that cortisol does go up during fasting.

Yes, fasting is a stress to the body and cortisol acts as general activator as well as trying to move glucose out of storage and into the blood. So, if too much cortisol is your problem, then fasting may not be right for you.

Insulin also goes down, which is what we expect. Growth hormone, as we’ve previously noted, goes up during fasting. This helps to maintain lean muscle tissue and to rebuild lost protein when you start to eat again.

An interesting study of food cravings found exactly what we have been discussing. When patients were put on low calorie diet (1200) versus very low calorie (500) diets, food cravings didn’t change much on the former, but virtually disappeared on the latter. Yes. By eating almost nothing, food cravings did not get worse, they got much, much better.
This effect on food cravings is true for all food, since all foods are restricted. So cravings for sweets, carbs and high fat foods are all reduced.
This is very important in the fight to lose weight. Controlling hunger by eating little bits at a time simply does not work.

During intermittent and extended fasting, ghrelin, the main hormonal mediator of hunger does not increase to unmanageable levels. Rather it decreases — which is exactly what we are looking for.

We want to eat less, but be more full. Fasting, unlike caloric restriction diets is the way to do that.

Proof that Ketogenic Diets Increase NAD+ to Curb Inflammation and prevent brain degeneration


Ketogenic diets — extreme low-carbohydrate, high-fat regimens that have long been known to benefit epilepsy and other neurological illnesses — may work by lowering inflammation in the brain, according to new research by UC San Francisco scientists. The UCSF team has discovered a molecular key to the diet’s apparent effects, opening the door for new therapies that could reduce harmful brain inflammation following stroke and brain trauma by mimicking the beneficial effects of an extreme low-carb diet

New research uncovers and replicates the mechanism by which a ketogenic diet curbs brain inflammation. The findings pave the way for a new drug target that could achieve the same benefits of a keto diet without having to actually follow one.

The keto diet is focused on reducing the amount of carbohydrates as much as possible and increasing the amount of protein and fat.

Besides its weight loss-related benefits, recent studies have pointied to many other advantages. For instance, Medical News Today recently covered research suggesting that the diet may increase longevity and improve memory in old age.

Other studies have noted the neurological benefits of the diet. The keto diet is used to treat epilepsy, and some have suggested that it may prove helpful in Alzheimer’s and Parkinson’s disease.

However, the mechanism by which a keto diet may benefit the brain in these illnesses has been a mystery. The new research – which was led by Dr. Raymond Swanson, a professor of neurology at the University of California, San Francisco – suggests that it may do so by reducing brain inflammation.

In the new study, Dr. Swanson and team show the molecular process by which the keto diet reduces brain inflammation. The researchers also identify a key protein that, if blocked, could create the effects of a keto diet.

This means that a drug could be designed to reduce inflammation in patients who cannot follow a keto diet because of other health reasons.

The findings were published in the journal Nature Communications.

A keto state lowers brain inflammation

A keto diet changes the metabolism, or the way in which the body processes energy. In a keto diet, the body is deprived of glucose derived from carbs, so it starts using fat as an alternative source of energy.

In the new study, Dr. Swanson and his colleagues recreated this effect by using a molecule called 2-deoxyglucose (2DG).

The 2DG molecule stopped glucose from metabolizing and created a ketogenic state in rodents with brain inflammation as well as in cell cultures. Levels of inflammation were drastically reduced – almost to healthy levels – as a result.

“We were surprised by the magnitude of our findings,” said Dr. Swanson. “Inflammation is controlled by many different factors, so we were surprised to see such a large effect by manipulating this one factor. It reinforces the powerful effect of diet on inflammation.”

The restricted glucose metabolism lowered the so-called NADH/NAD+ ratio. Dr. Swanson explained to MNT what this ratio refers to, saying, “NAD+ and NADH are naturally occurring molecules in cells that are involved in energy metabolism.”

“Cells convert NAD+ to NADH, as an intermediary step in generating energy from glucose, and thus increase the NADH/NAD+ ratio,” he added.

When this ratio is lowered, the CtBP protein gets activated and attempts to turn off inflammatory genes. As Dr. Swanson told us, “CtBP is a protein that senses the NADH/NAD ratio and regulates gene expression depending on this ratio.”

So, the scientists designed a molecule that stops CtBP from being inactive. This keeps the protein in a constant “watchful” state, blocking inflammatory genes in an imitation of the ketogenic state.

Significance of the findings, future research

Speaking to MNT about the clinical implications of the study, Dr. Swanson said, “Our findings show that it is […] possible to get the anti-inflammatory effect of a ketogenic diet without actually being ketogenic.”

[The keto] diet is difficult to follow […], especially for people who are acutely ill. Our work identifies a potential drug target that can produce the same effect as [the] ketogenic diet.”

“I think the work also increases the scientific legitimacy of the ketogenic diet/inflammation link,” he added.

Dr. Swanson went on to highlight how important it is that the research conducted by he and his team uncovered a causal mechanism rather than simply pointing to an association.

“Most scientists,” he told us, “are reluctant to accept cause-effect relationships between events in the absence of a defined mechanism. Here we have provided a biochemical mechanism by which diet affect inflammatory responses.”

Dr. Swanson also shared with us some directions for future research. “Our work was very focused on brain trauma,” he said, but “next steps will be to expand the list of pro-inflammatory conditions that can be modulated by the CtBP mechanism.”

The findings could apply to other conditions that are characterized by inflammation. In diabetes, for example, the excessive glucose produces an inflammatory response, and the new results could be used to control this dynamic.

“[The] ultimate therapeutic goal would be to generate a [drug] that can act on CtBP to mimic the anti-inflammatory effect of [the] ketogenic diet,” Dr. Swanson concluded.

“It’s a key issue in the field — how to suppress inflammation in brain after injury,” said Raymond Swanson, MD, a professor of neurology at UC San Francisco, chief of the neurology service at the San Francisco Veterans Affairs Medical Center, and senior author of the new study.

In the paper, published online September 22, 2017 in the journal Nature Communications, Swanson and his colleagues found the previously undiscovered mechanism by which a low carbohydrate diet reduces inflammation in the brain. Importantly, the team identified a pivotal protein that links the diet to inflammatory genes, which, if blocked, could mirror the anti-inflammatory effects of ketogenic diets.

“The ketogenic diet is very difficult to follow in everyday life, and particularly when the patient is very sick,” Swanson said. “The idea that we can achieve some of the benefits of a ketogenic diet by this approach is the really exciting thing here.”

Low-Carb Benefits

The high-fat, low-carbohydrate regimen of ketogenic diets changes the way the body uses energy. In response to the shortage of carb-derived sugars such as glucose, the body begins breaking down fat into ketones and ketoacids, which it can use as alternative fuels.

In rodents, ketogenic diets — and caloric restriction, in general — are known to reduce inflammation, improve outcomes after brain injury, and even extend lifespan. These benefits are less well-established in humans, however, in part because of the difficulty in maintaining a ketogenic state.

In addition, despite evidence that ketogenic diets can modulate the inflammatory response in rodents, it has been difficult to tease out the precise molecular nuts and bolts by which these diets influence the immune system.

Intricate Molecular Waltz

In the new study, the researchers used a small molecule called 2-deoxyglucose, or 2DG, to block glucose metabolism and produce a ketogenic state in rats and controlled laboratory cell lines. The team found that 2DG could bring inflammation levels down to almost control levels.

This image shows hippocampal slices.

Immunostaining for Iba1 and iNOS identify activated microglia in mouse hippocampal slice cultures after 24 h incubation with LPS (10 μg/ml) or LPS + 2DG (1 mM) NeuroscienceNews.com image is credited to Swanson et al./Nature Communications.

“I was most surprised by the magnitude of this effect, because I thought ketogenic diets might help just a little bit,” Swanson said. “But when we got these big effects with 2DG, I thought wow, there’s really something here.”

The team further found that reduced glucose metabolism lowered a key barometer of energy metabolism — the NADH/NAD+ ratio — which in turn activated a protein called CtBP that acts to suppress activity of inflammatory genes.

In a clever experiment, the researchers designed a drug-like peptide molecule that blocks the ability of CtBP to enter its inactive state —essentially forcing the protein to constantly block inflammatory gene activity and mimicking the effect of a ketogenic state.

Peptides, which are small proteins, don’t work well themselves as drugs because they are unstable, expensive, and people make antibodies against them. But other molecules that act the same way as the peptide could provide ketogenic benefits without requiring extreme dietary changes, Swanson said.

The study has applications beyond brain-related inflammation. The presence of excess glucose in people with diabetes, for example, is associated with a pro-inflammatory state that often leads to atherosclerosis, the buildup of fatty plaques that can block key arteries. The new study could provide a way of interfering with the relationship between the extra glucose in patients with diabetes and this inflammatory response.



How the war on Cholesterol caused our diabetes epidemic


Cholesterol is a molecule required by every cell of the body in fairly large amounts. It can be easily synthesised by these cells, or taken up by them from LDL and other ApoB lipoproteins, but cannot be broken down. Cholesterol is not soluble in water, and thus must be carried through the blood on lipoprotein particles. When the cholesterol produced or taken up by the cells of the body becomes surplus to requirements it is extracted by HDL (ApoA1 lipoproteins) and carried back to the liver for disposal as bile salts and acids (most of this cholesterol is reabsorbed and recycled, but there is also a variable amount lost in faeces). Reverse cholesterol transport (RCT) is the term used for this extraction of unneeded cholesterol. Here we describe a simplified version of reverse cholesterol transport, how this has been modified by new research into HDL, and we explain the effect of raising or lowering insulin and insulin sensitivity on RCT.

This video gives a good overview of the systems we’ll be describing. (The brain has its own, largely separate cholesterol system which we’ll ignore for now).

Cholesterol and insulin

We have about 30g of cholesterol in our bodies, and synthesise well over a gram a day. Only 10% of this is synthesised in the liver, and even less if we eat cholesterol or have a reduced requirement. Our requirement goes up when we are growing (cells are expanding and new cells being made) and down when we are fasting or losing weight (when fat cells and glycogen cells are shrinking, and autophagic processes are clearing unwanted cells). Thus it makes sense, and helps to keep cholesterol in balance with requirements, that cholesterol synthesis is stimulated by insulin (the fed state hormone) and inhibited by glucagon (the fasting state hormone).[1] An additional check on cholesterol synthesis in the fasting state is the activation of AMPK by the ketone body B-hydroxybutyrate.[2] No surprises then that cholesterol synthesis is found to be increased in type 2 diabetes.[3]

If scientists want to create the early signs of heart disease in animals, they need to feed them doses of cholesterol much larger than the total capacity of the body to make cholesterol.[4] However, Jerry Stamler, one of the founding fathers of the diet heart hypothesis, found in the early 1960’s that animals treated in this way got better when the cholesterol feeding stopped – unless they were given extra insulin.[5] This vital clue was missed in the later rush to change our diets – Jerry Stamler advised the population to avoid egg yolk and replace fat with refined carbs, yet human diets never supplied the amount of cholesterol he fed his animals – unfortunately, the new, modified human diet would start to increase insulin to the high levels seen in those chickens once the diabesity epidemic got underway.


Reverse Cholesterol Transport

Fortunately our gut and liver cells make a protein called ApoA1, which the liver turns into something called a nascent HDL particle. Unlike VLDL and the other ApoB particles, which are released from the liver as large, fat and cholesterol laden spheres, HDL is produced in an embryonic state, just a few proteins with little if anything in the way of lipids (lipid-poor ApoA1), and only becomes what we call HDL by performing its cholesterol-gathering role out in the body.


If we focus on the cells believed to play the major role in atherosclerosis, macrophages (large immune cells) which can turn into foam cells if they become overloaded with cholesterol, we can see HDL at work. Macrophages clear the blood of infectious agents and damaged particles, and have a particular affinity for oxidised LDL particles (oxLDL).[6] LDL becomes oxidised if it stays in the blood too long (more likely with higher levels or small, dense particles) and is exposed to excessive glucose and fructose levels after meals, or to smoking and other oxidative stressors.[7,8,9] Brown and Goldstein, who won the Nobel Prize for discovering the LDL receptor, estimated that 30-60% of LDL is cleared from circulation by macrophages. (Macrophages exposed to excess insulin increase their uptake of oxLDL by 80%).[10] The oxLDL is then broken down and the cholesterol stored – remember it can’t be broken down. As in other cells, any excess is sent to the surface of the cell, to transporters and other structures that make it available for HDL to pick up, as free cholesterol (cholesterol efflux). If this doesn’t happen for some reason, over a long period, there’s a risk of foam cell formation and atherosclerosis. (Macrophages exposed to excess insulin decrease their efflux of cholesterol to HDL by 25%).[10]

LCAT and esterification

After HDL picks up free cholesterol, this is esterified by an enzyme called lecithin cholesterol acyltransferase (LCAT), making the HDL particle larger. Cholesteryl ester (CE) is cholesterol joined to a fatty acid, usually an unsaturated fatty acid, which is supplied from the phospholipids also picked up from cells by HDL. The more effectively HDL can esterify cholesterol, the sooner it can return to pick up more from the macrophage (or other cell) – this is called HDL efflux capacity – and the phospholipids found in egg yolk have been shown to increase HDL efflux capacity.[11] Phospholipids, found in all whole foods, especially fatty ones like eggs, nuts, seeds, liver, shellfish, and soya beans, are good things to have in your diet; you won’t get them from eating flour, sugar, and oil.


Cholesteryl oleate – a cholesteryl ester


CETP – swapping cholesteryl esters for triglycerides

HDL renews itself in the bloodstream by moving cholesteryl esters onto VLDL and other ApoB particles, in more-or-less equal exchange for triglycerides (TGs), through a banana-shaped protein tunnel called Cholesteryl Ester Transport Protein (CETP) which docks between ApoA1 and ApoB particles. HDL can then shed the TGs picked up to help feed cells along its path (as ApoB particles also do), turning them into free fatty acids and glycerol by the action of lipase enzymes. However, the CETP exchange is another place where things can go wrong. If there are too many TGs on VLDL, and too many TG-rich VLDL particles, and fats are not being burned by the body (yes, we’re talking about insulin resistance again), then the piling of TGs onto HDL via CETP will result in its recall to the liver after limited efflux.[12] Carrying lots of TGs back to the liver that made them is not a good use of HDL’s time. And the cholesterol esters being transferred to former TG-rich VLDL is what makes the “Pattern B” lipoproteins, small dense LDL, which are more likely to oxidise and more easily taken up by macrophages. LDL really, once it’s done its job of delivering fat, cholesterol, antioxidants and proteins to cells that need them, ought to be helping in reverse cholesterol transport by ferrying the extra cholesterol esters it received from HDL back to the liver. Large, cholesterol-dense LDL particles – “Pattern A” – are better at this. Small, dense LDL particles aren’t taken up as avidly by the liver, so tend to stay in circulation and oxidize. Hence the TG/HDL ratio is a critical predictor of cardiovascular risk, whether or not we factor in LDL.

The exchange via CETP action is thought responsible for the inverse relationship between levels of TG and HDL-C. Specifically, the larger the VLDL pool (higher TG level), the greater the CETP-mediated transfer of CE from HDL to VLDL in exchange for TG, resulting in TG-rich small, dense HDL which are catabolized more rapidly, leading to low levels of HDL-C. These small, dense HDL also have reduced antioxidant and anti-inflammatory properties. Thus, the greater the increase in hepatic VLDL-TG synthesis and secretion that characterizes insulin-resistant/hyperinsulinemic individuals, the lower will be the HDL-C concentration.[12]


Insulin LDL

Insulin resistance in this population (n=103,000) was stratified by tertiles of TG and HDL, with the insulin sensitive tertile having a mean TG/HDL ratio of 1.1 [13]

Fasting, weight loss, and LDL

People who are naturally lean and active and have good insulin sensitivity are at very low risk of cardiovascular disease; they tend to burn fat and have low TG/HDL ratios on any diet. Paradoxically, LDL rises sharply when such people fast for long periods.[14] Despite this, no-one as far as we know has ever suggested that not eating enough causes atherosclerosis. Of course TGs and insulin also fall, while HDL stays the same. But strangely, this rise in LDL does not happen in obese people or people with atherosclerosis.[15]


Fasting LDL Apo B

In healthy lean individuals, LDL and ApoB rise as Insulin-like growth factor falls during a fast.[14]

Fasting Chol athero

In obesity or T2DM, or in this case a patient with arteriosclerosis, cholesterol and LDL do not rise during a fast.[15]

Phinney and colleagues found that LDL first fell, then rose significantly, during major weight loss. They calculated that this was due to the delayed removal of around 100g extra cholesterol from the adipose of obese people. LDL became normal when a weight maintenance diet replaced the (low fat, reduced calorie) weight loss diet.[16]
Think about this – all of this extra 100g of cholesterol, 3x the usual whole body content, was eventually removed by reverse cholesterol transport. Some of it ended up on LDL, increasing the LDL count to the level where statins would be indicated according to guidelines. This did not prevent its removal. There is no “LDL gradient” that forces cholesterol back into the body. The LDL level doesn’t tell you whether cholesterol is coming or going – the TG/HDL ratio is the best guide to that.[17]


Hepatic lipase – burning fat.

ApoA1 and HDL production increases the release of hepatic lipase, so in a sense ApoA1 is a fat-burning protein, which helps to explain why eating fat increases ApoA1 output.[18, 19] More lipase means lower TGs all round. So, making more HDL can lower TGs, just as making too many TGs can lower HDL – but only the latter is likely to be harmful.

Of course, a low fat, high carbohydrate diet decreases ApoA1, but this doesn’t mean it’s bad if you’re insulin sensitive and have low TGs (and low LDL) eating such a diet, as many people do; the lower lipid circulation all round probably just means that less ApoA1 will be required for equilibrium. However, the old assumption that the lower fat higher carb diet is the “Prudent” diet hasn’t aged well.

We have previously reported that apoA-I and HDL directly affect HL-mediated triacylglycerol hydrolysis, and showed that the rate of triacylglycerol hydrolysis is regulated by the amount of HDL in plasma.

The antioxidant and antiinflammatory benefits of HDL.

Reverse cholesterol transport is the core business of HDL, but it isn’t the only business; HDL is like a busy doctor with a useful bag of healing tricks trundling up and down your bloodstream. For example, HDL carries an antioxidant protein, PON1. When a fatty hamburger meal rich in lipid peroxides was fed to 71 subjects, those with higher HDL experienced a much smaller rise in oxLDL.[20]

The pre-meal HDL level was associated with the extent of the postprandial rise in oxidized LDL lipids. From baseline to 6 h after the meal, the concentration of ox-LDL increased by 48, 31, 24, and 16 % in the HDL subgroup 1, 2, 3, and 4, respectively, and the increase was higher in subgroup 1 compared to subgroup 3 (p = 0.028) and subgroup 4 (p = 0.0081), respectively. The pre-meal HDL correlated with both the amount and the rate of increase of oxidized LDL lipids. Results of the present study show that HDL is associated with the postprandial appearance of lipid peroxides in LDL. It is therefore likely that the sequestration and transport of atherogenic lipid peroxides is another significant mechanism contributing to cardioprotection by HDL.

Tregs or T regulatory cells are a type of immune cell that switches off inflammatory responses. They are also a type of cell that takes up HDL, and HDL selectively promotes their survival. This is a good thing.[21]

Can LDL help in reverse cholesterol transport?


The answer is yes – if it’s large LDL particles (Pattern A), not so much small dense ones. Triglycerides and VLDL, on the other hand, are no help at all.

There are two pathways by which RCT can occur. In the first, the scavenger receptor class B type 1 (SRB-1) mediates hepatic uptake of CE from HDL particles without uptake of apoA-I or the whole HDL particle [74]. In the second pathway, cholesteryl ester transfer protein (CETP) catalyzes the transfer of CE from HDL to apoB-containing lipoproteins (VLDL and LDL) in exchange for TG from the apoB-containing lipoproteins (Fig. 1) [21, 75]. This exchange results in apoB-containing lipoproteins which are enriched with CEs and depleted of TGs, and HDL particles which are depleted of CEs and enriched with TGs. The TG-rich and CE-poor HDL particles are catabolized faster than large, CE-rich HDL (apoA-I FCR is increased as noted in Fig. 1), a finding resulting in lower levels of HDL-C in the setting of high TG levels [76]. The apoB-containing lipoproteins, now enriched in CE, can also be taken up by the liver receptors as previously described [75]. When TG levels are high, the apoB particles are TG-enriched and hepatic lipase then hydrolyzes the TGs within the TG-rich LDL to release FFAs, a process which remodels the LDL particles into smaller and denser LDL particles which can enter the arterial intima more easily than larger LDL particles, thus making them more atherogenic (Fig. 1). Small, dense LDL particles also bind less avidly to the LDL receptor, thus prolonging their half-life in the circulation and making these particles more susceptible to oxidative modification and to subsequent uptake by the macrophage scavenger receptors [12].

An unusual experiment (using a radioactive nanoemulsion mimetic of LDL) showed that LDL cholesterol is removed from circulation more rapidly in resistance-trained healthy men than in sedentary healthy men. oxLDL was 50% lower in the resistance-trained men – but total LDL levels were the same, probably as a result of increased beta-oxidation (fat burning).[22]

Why are doctors being confused about HDL and reverse cholesterol transport?

There’s a trend in mainstream medicine to be dismissive of HDL and treat reverse cholesterol transport as unimportant; LDL lowering is the thing. New evidence from genetics, epidemiology, and drug trials is increasingly misinterpreted in this way – probably because drugs that increase HDL have, with some exceptions, been failures. However, drugs that raise HDL, and lower LDL, by inhibiting CETP are not helping either particle do its job; so far, they have neither decreased nor increased the rate of heart attacks in people taking them. Drugs that raise HDL by increasing ApoA1 and nascent HDL output, like the fibrates (e.g. gemfibrozil), do decrease CHD – but only in people with lower HDL and higher TGs! Moderate alcohol use, which also increases ApoA1 output, seems to have a similar effect, though the first randomised controlled trial of this observational hypothesis is only beginning.[23, 24] Even statins help with RCT by decreasing the synthesis of cholesterol in peripheral tissues, thus leaving more room on HDL for efflux cholesterol – again, statins only seem to reduce CHD in the subgroup of people with lower HDL. Clearly reverse cholesterol transport is very important, and efficient reverse cholesterol transport can best explain why so many people with high LDL and high cholesterol do enjoy long lives free from cardiovascular disease. Some ApoA1 genes that especially promote RCT are associated with reduced CVD risk, notably ApoA1 milano – which is actually associated with low HDL, because HDL clearance is so rapid – a paradox which highlights the trickiness of measuring a dynamic process across all tissues only by what appears in the blood.[25] Efficient RCT is associated with lean genes, but it’s largely something you have to work for – eating right, exercising, and looking after yourself in various ways – including giving up smoking, or not starting – which may be why the drug industry has largely given up on it.[26]

We observed that normolipidemic smokers present higher total plasma and HDL phospholipids (PL) (P < .05), 30% lower postheparin hepatic lipase (HL) activity (P < .01), and 40% lower phospholipid transfer protein (PLTP) activity (P < .01), as compared with nonsmokers. The plasma cholesteryl ester transfer protein (CETP) mass was 17% higher in smokers as compared with controls (P < .05), but the endogenous CETP activity corrected for plasma triglycerides (TG) was in fact 57% lower in smokers than in controls (P < .01). Lipid transfer inhibitor protein activity was also similar in both groups. In conclusion, the habit of smoking induces a severe impairment of many steps of the RCT system even in the absence of overt dyslipidemia.

The latest study on very, very high HDL – why isn’t it good?

Last year we wrote about the CANHEART study, which seemed to show adverse health effects of higher HDL. We wrote then that this was probably showing an effect of alcoholism, hereditary CETP defects, and other factors, and not an increase in heart disease. A new study allows us to look at this problem in more detail.[27]

When compared with the groups with the lowest risk, the multifactorially adjusted hazard ratios for all-cause mortality were 1.36 (95% CI: 1.09–1.70) for men with HDL cholesterol of 2.5–2.99 mmol/L (97–115 mg/dL) and 2.06 (1.44–2.95) for men with HDL cholesterol ≥3.0 mmol/L (116 mg/dL). For women, corresponding hazard ratios were 1.10 (0.83–1.46) for HDL cholesterol of 3.0–3.49 mmol/L (116–134 mg/dL) and 1.68 (1.09–2.58) for HDL cholesterol ≥3.5 mmol/L (135 mg/dL).

Those are some very high HDL levels, and not surprisingly fewer than 4% of men and even fewer women had HDL levels so high that they were associated with any extra risk.
Compare that with 40% of both men and women having low HDL levels that were associated with an equally elevated risk!
Further, the risk associated with very high HDL, though it does include cardiovascular deaths, doesn’t seem to include much increased risk of heart attacks and strokes.


This is consistent with alcoholism (a confounder not measurable with accuracy, as we described in the CANHEART analysis) increasing deaths from heart failure, cancer, and other causes, and with no further benefit (but maybe not much harm overall) from CETP variants elevating HDL.[28] Furthermore, interactions between heavy alcohol consumption and genes associated with higher HDL have been noted in some populations.[29]
Note that the HDL level associated with lowest heart disease and stroke incidence in this study is well to the right of the bell curve of population HDL distribution. Most of these people could have done with more HDL.
Madsen et al discuss their results soberly; although they fail to discuss the potential role of alcohol, which would explain the exact pattern of increased mortality seen well, and don’t highlight the 10-fold larger impact associated with low HDL in their study, there is nothing biased about their analysis. The European Heart Journal’s editorial was also worth reading.[30]


However, as reported in medical media, the message changed a bit.

“It appears that we need to remove the focus from HDL as an important health indicator in research, at hospitals and at the general practitioner. These are the smallest lipoproteins in the blood, and perhaps we ought to examine some of the larger ones instead. For example, looking at blood levels of triglyceride and LDL, the ‘bad’ cholesterol, are probably better health indicators,” he notes.

Well yes, looking at everything is good, and TGs and the TG/HDL ratio as well as LDL will give you extra information about the likely reasons for low HDL and whether you need to worry about it. However, Denmark, where the extremely high HDL study was done, is a place where high LDL (the ‘bad’ cholesterol, remember) is associated with lower all-cause mortality in those over 50 free from diabetes or CVD at the start of the study.[31] Over 50 is when most CVD and type 2 diabetes is diagnosed, so LDL might not be all that informative unless you can look at the subclasses of oxLDL, sdLDL, particle number, and so on (of course part of the effect of LDL in Denmark will be due to that country’s higher dairy fat intake, which will also raise HDL and LDL particle size, maybe helping to explain why the association is so favourable in that population).

If we look at the PURE study, higher fat consumption is associated with both higher LDL and higher ApoA1 and HDL, with saturated fat (like all fat types) tending to improve the ApoB/ApoA1 ratio.[32] This is consistent with many other lines of evidence.

Intake of total fat and each type of fat was associated with higher concentrations of total cholesterol and LDL cholesterol, but also with higher HDL cholesterol and apolipoprotein A1 (ApoA1), and lower triglycerides, ratio of total cholesterol to HDL cholesterol, ratio of triglycerides to HDL cholesterol, and ratio of apolipoprotein B (ApoB) to ApoA1 (all ptrend<0·0001).

This is just what fat-burning does, and there’s maybe not a lot of reason to think it’s good or bad per se. What is good about it is, that fat burning lowers insulin. Insulin is what makes your cells hoard cholesterol, and it’s also one of the things that can mess with reverse cholesterol transport. If you’re making or using excess insulin, the switch to a fat burning metabolism allows the insulin to normalise and causes your cells, including the macrophages, to let go of cholesterol – and when they do, the lipoproteins are there ready to carry it away.


Reverse cholesterol transport manages cholesterol flux through all cells and helps us reach a healthy old age.

LDL cholesterol is not a reliable guide to the state of cholesterol flux unless TG/HDL (and HbA1c) are factored in as well. LDL may increase when cholesterol is being removed or in states where it is not being taken up by cells.

Reverse cholesterol transport can remove prodigious amounts of cholesterol from the body during weight loss.

Excessive triglycerides due to insulin resistance can impair reverse cholesterol transport, as can smoking.

Various nutritional factors found in whole food diets have been found to assist in reverse cholesterol transport (including phospholipids, CLA, and polyphenols).

HDL in the high (if not the “extremely high”) range usually correlates with efficient reverse cholesterol transport and has benefits for cardiovascular health, inflammation, antioxidant status etc, but people with HDL outside (higher or lower than) the ideal range can be equally healthy if their overall metabolic health (insulin sensitivity) is good.

The TG/HDL ratio is a good measure of insulin sensitivity, and if excessive can be improved by lowering excessive insulin levels. A low carb diet, intermittent fasting, exercise, or weight loss are all effective ways to correct the TG/HDL ratio.


[1] https://themedicalbiochemistrypage.org/cholesterol.php

[2] Bae HR, Kim DH, Park MH, et al. β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget. 2016;7(41):66444-66454. doi:10.18632/oncotarget.12119.

[3] Gylling H, Hallikainen M, Pihlajamäki J, et al. Insulin sensitivity regulates cholesterol metabolism to a greater extent than obesity: lessons from the METSIM Study. Journal of Lipid Research. 2010;51(8):2422-2427. doi:10.1194/jlr.P006619.

[4] Regulation of hepatic LDL metabolism in the guinea pig by dietary fat and cholesterol.
Lin ECK, Fernandez ML, Tosca MA, McNamara DJ. Journal of Lipid Research. 1994; 35:446-457

[5] Stamler J, Pick R, Katz LN. Effect of Insulin in the Induction and Regression of Atherosclerosis in the Chick. Circulation Research. 1960; 8:572-576.
Stamler Chick

[6] Brown MS, Goldstein JL. Lipoprotein Metabolism in the Macrophage: Implications for Cholesterol Deposition in Atherosclerosis. Annual Review of Biochemistry 1983 52:1, 223-261

[7] Kopprasch S, Pietzsch J, Kuhlisch E et al. In Vivo Evidence for Increased Oxidation of Circulating LDL in Impaired Glucose Tolerance. Diabetes 2002; 51(10): 3102-3106. https://doi.org/10.2337/diabetes.51.10.3102

[8] Vos MB, Weber MB, Welsh J et al. Fructose and Oxidized LDL in Pediatric Nonalcoholic Fatty Liver Disease: A Pilot Study. Archives of pediatrics & adolescent medicine. 2009;163(7):674-675. doi:10.1001/archpediatrics.2009.93.

[9] Medina-Navarro R, Durán-Reyes G, Díaz-Flores M, Kumate Rodríguez J, Hicks JJ. Glucose autoxidation produces acrolein from lipid peroxidation in vitro. Clin Chim Acta. 2003; 337(1-2):183-5.. PMID: 14568199

[10] Park YM, Sangeeta R Kashyap SR, Major JA, Silverstein RL. Insulin promotes macrophage foam cell formation: potential implications in diabetes-related atherosclerosis. Laboratory Investigation. 2012; 92, 1171-1780.

[11] Andersen CJ, Blesso CN, Lee J, et al. Egg Consumption Modulates HDL Lipid Composition and Increases the Cholesterol-Accepting Capacity of Serum in Metabolic Syndrome. Lipids. 2013;48(6):10.1007/s11745-013-3780-8. doi:10.1007/s11745-013-3780-8.

[12] Welty FK. How Do Elevated Triglycerides and Low HDL-Cholesterol Affect Inflammation and Atherothrombosis? Current cardiology reports. 2013;15(9):400. doi:10.1007/s11886-013-0400-4.

[13] Bertsch RA, Merchant MA. Study of the Use of Lipid Panels as a Marker of Insulin Resistance to Determine Cardiovascular Risk. The Permanente Journal. 2015;19(4):4-10. doi:10.7812/TPP/14-237.

[14] Sävendahl L, Underwood LE. Fasting increases serum total cholesterol, LDL cholesterol and apolipoprotein B in healthy, nonobese humans. J Nutr. 1999 Nov;129(11):2005-8.

[15] Ende N. Starvation studies with special reference to cholesterol. Am. J. Clin. Nutr. 1962. 11:270-280.

[16] Phinney SD, Tang AB, Waggoner CR, Tezanos-Pinto RG, Davis PA. The transient hypercholesterolemia of major weight loss. Am J Clin Nutr. 1991 Jun;53(6):1404-10.

[17] da Luz PL, Favarato D, Faria-Neto JR Jr, Lemos P, Chagas ACP. High ratio of triglycerides to HDL-cholesterol predicts extensive coronary disease. Clinics. 2008; 64:427-32

[18] Ramsamy TA, Boucher J, Brown RJ et al. HDL regulates the displacement of hepatic lipase from cell surface proteoglycans and the hydrolysis of VLDL triacylglycerol. The Journal of Lipid Research. 2003; 44: 733-741.

[19] Chatterjee C, Sparks DL. Hepatic Lipase, High Density Lipoproteins, and Hypertriglyceridemia. The American Journal of Pathology. 2011;178(4):1429-1433. doi:10.1016/j.ajpath.2010.12.050.

[20] Tiainen S, Ahotupa M, Ylinen P, Vasankari T. High density lipoprotein level is negatively associated with the increase of oxidized low density lipoprotein lipids after a fatty meal. Lipids. 2014; 49(12): 1225-32. doi: 10.1007/s11745-014-3963-y. Epub 2014 Oct 31.

[21] Rueda CM, Rodríguez-Perea AL, Moreno-Fernandez M et al. High density lipoproteins selectively promote the survival of human regulatory T cells. J Lipid Res. 2017 Aug;58(8):1514-1523. doi: 10.1194/jlr.M072835. Epub 2017 Apr 4.

[22] da Silvaa JL, Vinagrea CGCM, Morikawa AT et al. Resistance training changes LDL metabolism in normolipidemic subjects: A study with a nanoemulsion mimetic of LDL.
Atherosclerosis. 2011; 219(2): 532-537.

[23] Mukamal KJ, Clowry CM, Murray MM, et al. Moderate Alcohol Consumption and Chronic Disease: The Case for a Long-Term Trial. Alcohol Clin Exp Res. 2016 Nov;40(11):2283-2291. doi: 10.1111/acer.13231. Epub 2016 Sep 30. Review.

[24] Moderate Alcohol and Cardiovascular Health Trial (MACH15) . https://clinicaltrials.gov/ct2/show/NCT03169530

[25] Leite JO, Fernandez ML. Should we take high-density lipoprotein cholesterol levels at face value? Am J Cardiovasc Drugs. 2010; 10(1):1-3. doi: 10.2165/11319590-000000000-00000.

[26] Zaratin AC, Quintão EC, Sposito AC et al. Smoking prevents the intravascular remodeling of high-density lipoprotein particles: implications for reverse cholesterol transport. Metabolism. 2004 Jul;53(7):858-62.

[27] Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. European Heart Journal,. 2017; 38(32): 2478–2486, https://doi.org/10.1093/eurheartj/ehx163

[28] Devenyi P, Robinson GM, Roncari DA. Alcohol and high-density lipoproteins. Canadian Medical Association Journal. 1980;123(10):981-984.

[29] Volcik K, Ballantyne CM, Pownall HJ, Sharrett AR, Eric Boerwinkle E. Interaction Effects of High-Density Lipoprotein Metabolism Gene Variation and Alcohol Consumption on Coronary Heart Disease Risk: The Atherosclerosis Risk in Communities Study. Journal of Studies on Alcohol and Drugs, 68(4), 485–492 (2007).

[30] Barter PJ, Rye K-A. HDL cholesterol concentration or HDL function: which matters? European Heart Journal. 2017; 0: 1–3

[31] Bathum L, Depont Christensen R, Engers Pedersen L, Lyngsie Pedersen P, Larsen J, Nexøe J. Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: A population-based register study. Scandinavian Journal of Primary Health Care. 2013;31(3):172-180. doi:10.3109/02813432.2013.824157.

[32] Mente A, Dehghan M, Rangarajan S et al. Association of dietary nutrients with blood lipids and blood pressure in 18 countries: a cross-sectional analysis from the PURE study.
Lancet Diabetes Endocrinol 2017 Published Online August 29, 2017 http://dx.doi.org/10.1016/S2213-8587(17)30283-8
PURE lipids and BP

Glucose Ketone Index (GKI) – What Ratio Do I need for Nutritional Ketosis Benefits?

Generally these blog posts are a result of scratching my own itch (answering my own question), and this post is no different.

At the time of writing this, I’m doing a 5-day fast, and wanted to understand the readings I’m getting for my blood glucose and blood ketone levels.

Initially I thought that blood ketones were all that mattered, and certainly a lot of people only talk about that reading. But looking at Dr Thomas Seyfried’s paper on treating brain cancer (glioblastomas).  It suggests that its important to take into account blood glucose also. In their study, they acheieved optimal results when their patients maintained what they called ‘nutritional ketosis’. And as part of the paper, they included a formula for what this means.

The chart below describes visually what they mean by nutritional ketosis, and how it affected the tumour growth. The red is an increase in ketones as a fictional patient goes deeper into ketosis. The black line represents blood glucose, that decreases to a plateau, as carbohydrate sources are removed from the diet, and glycogen stores decrease.

So that sweet spot they reach at the end is an optimum level of nutritional ketosis. Now… obviously in our case we are (hopefully) not trying to slow the growth of a glioblastoma. But by getting into ketosis we’re hoping to achieve a number of benefits including:

  • Reduced IGF-1
  • Immune system rejuvenation (perhaps mainly lymphocytes)
  • Increased cellular autophagy
  • Reduced inflammation (often measured by improved C-reactive protein levels)

The extent of these benefits will depend if you’re eating a keto diet, or doing a water fast/fast mimicking diet. But all 3 should improve the biomarkers such that you have a reduced risk of major diseases such as diabetes, cancer and cardiovascular disease.

And studies like this one indicate that the optimal benefits from ketosis lie in maintaining  a 1:1 or lower ratio of glucose to ketones.

So on to the crux of this post, how to calculate GKI. What you’re trying to do is compare apples with apples, you really really want both readings in mmol/L. In my case, having a meter sourced from the UK, that’s how they came, so I simply do:

Glucose Reading (mmol/L) ÷ Ketone Reading (mmol/L)

However, if you’re in the USA, your blood glucose reading will be in mg/dL. You’ll know, because the meter should say mg/dL. But to be sure, if you blood glucose is in the 100s as a score, rather than single digits, that’s likely mg/dL.

So you’ll want to convert that glucose reading into mmol/L by doing:

Your Glucose Reading (mg/dL) ÷ 18.02

This converts your reading from mg/dL into mmol/L, and then you can do the above calculation (glucose reading divided by ketone reading) to get your glucose ketone index score.

So that’s it really, pretty simple.

Links that may be of use:

1 – Thomas Seyfried et al’s paper on using the glucose ketone index to treat brain cancer:
The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer

2 – An excel calculator for the GKI, developed by Dr Seyfried’s colleague Joshua Meidenbauer:
Glucose Ketone Index Calculator

What sticks out for me with all this stuff, is how amazingly valuable it can be in our treatment (and prevention of cancer), and yet in 2017 an incredibly small number of people (& physicians!) know and understand this work. For those with cancer, if its combined with other treatments, its even better. Its 5 years since Thomas Seyfried published his book ‘Cancer as a Metabolic Disease’. Time will tell how fast we are able to communicate this “meme” to a wider audience.

Time Restricted Feeding: Your Solution to Longevity and Shredding Fat

Why do we eat the way we eat? For health? Marketing? Societal standards? Or just because that’s the way we have always done it? If your answer is the last one, please never use that as a reason ever again.

With breakfast, lunch, dinner and grazing for snacks throughout the day; we could be eating for a 16 hour window. Increasing research is showing that we should narrow that window and give our body a chance to reset and cleanse itself. Let’s introduce time restricted feeding.

What is Time Restricted Feeding?

Time restricted feeding is not a way of telling you WHAT to eat, but a system of telling yourself WHEN to eat. Some people have referred to this as intermittent fasting, but the researchers who coined TRF thought feedingwould seem more inviting than the scary fasting word.

The time constraints of Time Restricted Feeding vary anywhere from a 12 hour eating window, an 8 hour eating window, all the way to 4 hours and fasting for 24 hours. The window starts when you first ingest something that isn’t toothpaste and ends when you have your last bite or sip of beverage that isn’t water at the end of your day. We will touch on those basic time frames further down, but the minimum effective dose is usually between 12 and 10 hours of eating per day.

Matching this time with your circadian rhythm and internal clock also looks to be beneficial. Your eating clock starts the moment you ingest something that isn’t water. For most of us, that would be our first cup of coffee in the morning. Holding off on that first bite, or sip allows you to start your feeding segment a bit later in the day.

It is suggested to try your best to halt your eating window before 7pm, so that your body can properly digest your food before entering your sleeping and fasted state. In all reality, do we want to eat a huge meal and then lie down for 7–8 hours? How silly does that sound?

What Are the Benefits?

1. Easier Implementation

Once we get over the idea that we need to eat every three hours, adapting to this schedule of eating overshadows any other diet or routine. This is a behavior based adjustment, not a complete overhaul of your eating or physical activity habits. Just do what you normally do and shorten the window.

“Diets are easy in the contemplation, difficult in the execution. Intermittent fasting is just the opposite — it’s difficult in the contemplation but easy in the execution.

Most of us have contemplated going on a diet. When we find a diet that appeals to us, it seems as if it will be a breeze to do. But when we get into the nitty gritty of it, it becomes tough. For example, I stay on a low–carb diet almost all the time. But if I think about going on a low–fat diet, it looks easy. I think about bagels, whole wheat bread and jelly, mashed potatoes, corn, bananas by the dozen, etc. — all of which sound appealing. But were I to embark on such a low–fat diet I would soon tire of it and wish I could have meat and eggs. So a diet is easy in contemplation, but not so easy in the long–term execution.

Intermittent fasting is hard in the contemplation, of that there is no doubt. “You go without food for 24 hours?” people would ask, incredulously when we explained what we were doing. “I could never do that.” But once started, it’s a snap. No worries about what and where to eat for one or two out of the three meals per day. It’s a great liberation. Your food expenditures plummet. And you’re not particularly hungry. … Although it’s tough to overcome the idea of going without food, once you begin the regimen, nothing could be easier.”

— Dr. Michael Eades

2. Decrease Body Fat

In it’s simplest description, TRF keeps the bad weight off and keeps the good weight on. While using an eating schedule, it is much easier to decrease body fat and maintain or increase lean muscle mass.

This all plays on our insulin levels. After you eat something, your insulin levels rise. Insulin is a hormone that’s made by the pancreas, which is used to regulate your blood sugar. It’s job is to take up the glucose that comes from sugar or carbs and either use it for energy or store it for later use. When you don’t eat for an extended period of time, say 8 to 12 hours or so, you enter a fasted state, your insulin levels are low, and your body starts to use fat as it’s source of energy.

Most people who only implement this schedule, with no other change to diet or exercise, tend to lose body fat because of this timing.

3. Reduces Chance of Cancer and Metabolic Disease

Occasional caloric restriction and fasting have been key weapons in the fight against cancer and metabolic disease. There hasn’t been tons of research on these issues, but the future looks bright.

One study fed rats a high fat diet, put them on a time restricted feeding program, and didn’t reduce calories. This protocol helped to prevent metabolic disease in this group versus the control group.

Dr. Dom D’Agostino, a researcher and professor at USF, focuses on the ketogenic diet and metabolic therapies. One of his suggestions for those heading to chemotherapy is to implement a fast beforehand to increase the benefits and help ward off the crappy after-effects.

4. Increases Lifespan

We can mention again, caloric restriction has been shown to increase the years of your life. When you are in a fasted state, your body looks for ways to keep you alive.

I don’t think many of us want to go on week long fasts to live a couple years longer. Let’s enjoy the years we have on this earth while lengthening when we can.

Good news for us is that time restricted feeding activates many of the same mechanisms that caloric restriction activates. We can have our cake and eat it too, within proper time frames…

5. Increases money in your wallet and time in your day

When I first implemented TRF into my lifestyle, I found so much more time and dollars lying around. You are essentially wiping out one meal from your old schedule. Gone were the Cheerios in the morning or the late night pizza. Want to be creative? Need more hours? Implement a time restricted feeding schedule and watch yourself come alive.

Popular Eating Schedules

16:8 This is quite possibly the most popular eating schedule in the intermittent fasting world. It allows for an 8 hour eating window usually starting with a late lunch and dinner. Skipping breakfast is easier for most because lunch and dinners seem to be the most social times for meeting up and eating together.

14:10 This is the window prescribed by Dr. Rhonda Patrick and the one she utilizes on most days. It’s essentially the largest feeding window you can get away with to realize the benefits. It accounts for 10 hours of eating and 14 hours of fasting. She wakes up and starts her window while ending with an early dinner or late lunch.

18:6 Want to one up the 16:8 community, here you go.

20:4 Some folks go for one BIG meal, usually dinner, and opt for FEASTING during this time.

24:0 or 24 Hour Fast You can implement a 24 hour fast once or twice a week to see benefits of decreasing your insulin levels for extended time. This usually can be done by eating dinner, then fasting until dinner the next day. Just make sure your time is used up and you’re not sitting around all day thinking about eating…

You Are an Experiment of 1, See What Works for You

The biggest takeaway anyone can glean from this post, I hope, is that you are your own experiment. Don’t let society, your family, or anyone else tell you what is right FOR YOU. Time Restricted Feeding has more and more research showing the positive effects, but it might not be right for you. Maybe you think you can get into 14:10 or 16:8 eating windows, GREAT! Maybe you want to try a 24 hour fast, that’s awesome. Lean into the edges of your comfort zone and see what happens. Many people are reaping the benefits of TRF, and you could be the next.

Why fasting matters: IGF-1 and inflammation

A very interesting and well designed intermittent fasting (IF) study published last year (hereafter denoted as “this study”) has been widely discussed because of its results on body composition. However, the data in this study shows a lot more if you are interested in health and longevity.

There is some debate in the calorie restriction (CR) community about the effects of IF in humans (as rodent data is mostly supportive of an independent effect). Overall, and currently, there are some major points that are thought responsible for the beneficial effects of CR, besides energy restriction per se. One of the most important ones is protein intake. There was a shift in the average thinking on dietary protein for some long-term CRONers over the years as to what the optimal intake of dietary protein is.

This is based mainly on the effect of protein (specially from animal origin) on IGF-1 levels, as high IGF-1 levels have been associated with increased risk of cancer. This was particularly troubling considering that protein intake directly regulates IGF-1 levels: in long term CRONers, a reduction of protein intake was necessary to lower serum IGF-1 levels.

This means that, in contrast to rodents, energy restriction was not sufficient to lower IGF-1. Further evidence of the effects of dietary protein come from studies done on Drosophila, which show that protein (but not energy) restriction was critical for the beneficial effects on longevity. Similar findings in rodents have also been published. I think there are some caveats and nuances to take into account, but that is a topic for another day.

So, in humans, long term CR appears to show most of the health benefits observed in other species, with the exception of lower IGF-1 levels. Thus, the current trend is to restrict protein intake to up to 0.8g/kg of body weight.

To quote Fontana et al., 2008 (my emphasis):

(…) our findings demonstrate that, unlike in rodents, long-term severe CR does not reduce total and free IGF-1 levels in healthy humans if protein intake is high. In addition, our data suggest that chronic protein intake is more powerful than calorie intake in modulating circulating IGF-1 concentration in humans. (…) these findings underscore the importance of dietary macronutrient intake in regulating metabolic events, and suggest that reduced protein intake may become an important component of anti-aging and anticancer dietary interventions, due to the importance of IGF-1 in the biology of aging (…) and in the pathogenesis of many human tumors.

Moro et al. studied the effects of an IF 16/8 schedule (16h fast, 8h eating window) or 3-meals-per-day (control) in resistance-trained subjects for 8 weeks. Although the IF group lost body fat and gained fat-free mass, the most interesting bit is in the blood markers measured. I will focus mainly on IGF-1, but it is worth mentioning that overall, markers improved dramatically in the IF group.

As the IF group consumed 1.93g of protein per kg of body weight and total calories were not restricted (they were around maintenance with approximately 14.97 kcal/lb of body weight and were not statistically different than in the 3-meals-per-day group), one can assume that the changes in several parameters are the result of the restriction of calories to a shorter window of time during the day. In other words, the design of this study helps us dissociate the effects of CR and protein intake from that of fasting or time-restricted feeding.

What happened with IGF-1 levels? They went down significantly, despite consuming a high protein and a normocaloric diet. In the IF group, IGF-1 levels (ng/mL) fell from 216.94 ± 49.55 to 188.90 ± 31.48, while in the control group (shown as “No IF” below) it didn’t change much (from 215.59 ± 56.25 to 218.41 ± 42,24). Just restricting calories to an 8 hour window reduced serum IGF-1 levels by 13% in 8 weeks despite consuming maintenance calories and high protein.

IGF-1 levels pre and post intervention in the 16/8 group (IF) and normal 3-meal per day pattern (No IF).

If we consider the proposed cancer risk that carries consuming a high protein diet (which in itself is controversial but not far-fetched in certain contexts), IF seems to promote “healthier” IGF-1 levels than spreading calories throughout the day.

We can also compare the effect of IF + resistance exercise + high protein/normocaloric diet (IF+EX) to the effect of CR without IF* on IGF-1 levels. After 8 weeks of IF + EX, IGF-1 levels were around 188.90 ng/mL, while after 6 years of CR, levels are around 194 ng/mL. I would argue that the difference is neither significant nor meaningful. But it shows that in humans, IF might be a more viable way of reducing high serum IGF-1 levels than CR (without protein restriction).

IGF-1 levels have also been shown to be responsive to a low calorie, low protein fasting-mimicking diet (FMD). The last study showed a 13% reduction after 3 months (or 3 cycles of 5 days of FMD), whereas a previous pilot studyshowed a reduction of 15%. Overall, reduction either by a 5-day per month FMD or by a 16/8 IF-high protein protocol seem to be comparable. Whether a larger fasting window (or a shorter eating window) promotes additional reductions is unknown. Probably combining IF + CR is synergistic.

An important point to mention is that its not a matter of “how low” you can go: low and high IGF-1 levels are both detrimental. One should look for the optimal serum level. Unfortunately, there is no consensus and the “optimal” level is unknown. Sufficient to say that IGF-1 levels per se are meaningless if not coupled to optimization of other markers (ie. insulin), but that is beyond the scope of this post.

Finally, concerns about lower serum IGF-1 levels being detrimental for muscle mass gains are based on a misunderstanding of physiology (which goes in line with the “more is better” mentality of some). Serum IGF-1 levels are not correlated with skeletal muscle hypertrophy (see also here), which is also exemplified in the study discussed here (no difference in muscle mass gains between groups despite lower serum IGF-1 levels).

This is because of differential expression and protein content/signaling in muscle vs liver (the latter is reflected in serum). Simply put: what matters for muscle hypertrophy is the IGF-1 available in muscle (not correlated to serum IGF-1), which is mostly produced locally and acting in an autocrine/paracrine manner.

*It is not stated whether CRONers in the Fontana, et al. study also fasted regularly, but based on most plans I’ve seen (and guides by the CR Society), food is spread during the day, in contrast to what happens in mice undergoing CR.


Initially I was going to make a different post about it, but it made sense to just add it to this one. Besides significant reductions in glucose and insulin levels, all markers of inflammation (IL-6, IL-1b, TNF-a, leptin) went down and adiponectin (anti-inflammatory) went up. You can see the values compared to the 3-meals-per-day group below:

Levels before the intervention are shown as black bars, while post-intervention, in white bars.

As these are markers associated with inflammation but also adiposity, can’t these results be explained by the loss of bodyfat in the IF group?

Unfortunately there is not much information on adipocytokines in lean populations in the absence of weight loss. But we can compare the magnitude of change with respect to body fat loss in obese subjects after a weight loss diet. In obese women, 3 weeks of a very-low calorie diet which reduced bodyfat by 3 kg, decreased IL-6 and leptin but no change was seen for TNF-a (and there are mixed results on the effect of weight loss on the latter). A reduction of TNF-a has been seen in obese subjects with a calorie restricted diet (-500 kcal), sibutramine and exercise. Achieving 10% of weight loss through an aggressive weight loss program (500–1000 kcal of restriction) in obese women decreased IL-6 by 27%, compared to around 19% observed for IF subjects. Overall, it looks like the reduction in inflammatory markers is not proportional to the amount of body fat lost (1.6 kg) in this study. This suggests a different effect of IF per se.

As before, the most relevant comparison could be to long-term CRONers. Adiponectin levels in people practicing sever CR for approximately 7 years have been shown to be around 15.7 ug/mL, compared to 13.9 ug/mL seen after 8 weeks of IF. In comparison, long-term endurance runners had lower levels (11.1 ug/mL) which is more or less the values observed for the No IF group in this study (10.9 ug/mL) (which can also serve as a resistance-trained control group, as they were experienced lifters). Importantly, these levels are comparable to those of matched sedentary controls consuming a typical Western diet (WD) (9.5 ug/mL). This suggests that fasting and CR are better for increasing serum adiponectin levels than exercise (endurance or resistance), being CR the most efficient. The lack of effect of exercise on adiponectin levels has been shown before. There is also some evidence that moderate weight loss does not result in higher adiponectin levels in obese subjects (see also here).

On the other hand, we can also compare the effect of IF or CR on IL-6 levels: CRONers showed significantly lower levels of serum IL-6 (0.73 ng/L) compared to IF subjects in this study (1.08 ng/L). Endurance runners also showed lower IL-6 levels (0.71 ng/L) than IF subjects. Disturbingly, those sedentary on a WD had almost the same levels (1.21 ng/L) as resistance-trained subjects in this study (1.33 and 1.24 ng/L before the intervention).

Chronic low-grade inflammation has been implicated in several diseases related to obesity and insulin resistance, in which adipocytokines play a major role. As described here, levels of these pro-inflammatory cytokines are related to cardiovascular disease:

Interleukin‐6 (IL‐6), interleukin 1b (IL‐1b) and tumour necrosis factor α (TNFα) are the principal pro‐atherogenic cytokines,1 which are also produced in tissues other than the vascular wall and immune system, such as adipose tissue, myocardium, intestine, etc.1 They upregulate the expression of adhesion molecules on vascular endothelium, depress nitric oxide synthesis and promote the subendothelial migration of leucocytes. Further to their local regulatory role at a vascular level, these cytokines induce the liver‐derived synthesis of acute phase proteins, such as fibrinogen, plasminogen, C‐reactive protein (CRP) and serum amyloid α (SAA), which amplify inflammatory and pro‐coagulant responses.

The importance of the molecules described above can be further seen in this review. Some extracts below (my emphasis):


Adiponectin has also been reported to have antiatherogenic effects (Funahashi et al. 1999, Ouchi et al. 1999). In addition, adiponectin exhibits cardioprotective activity in ischemic heart disease through AMPK and cyclooxygenase 2 pathways (Shibata et al. 2005). (…) Adiponectin also has anti-inflammatory effects that contribute to its protective role against metabolic stress in obesity. Adiponectin suppresses TNFα production in obese mice (Xu et al. 2003a), and adiponectin-deficient mice have high levels of TNFα in adipose tissue (Maeda et al. 2002). Low levels of plasma adiponectin are associated with C-reactive protein in humans (Ouchi et al. 2003). Adiponectin enhances the clearance of apoptotic cells by facilitating their opsonization and uptake by macrophages (Takemura et al. 2007). Some of the anti-atherogenic effects of adiponectin are also mediated by its role in the suppression of inflammatory responses. Adiponectin inhibits nuclear factor-κB (NFκB) activity and its downstream adhesion molecules leading to reduced monocyte adhesion to endothelial cells (Ouchi et al. 1999, Okamoto et al. 2002). In addition, adiponectin confers vascular-protective activities by suppressing the apoptosis of endothelial cell (Kobayashi et al. 2004).


Leptin is structurally similar to Class I helical cytokines and shares the same JAK–STAT pathway downstream of its receptor. Leptin expression can be induced by endotoxin or cytokine TNFα (Grunfeld et al. 1996). Conversely, leptin increases thymic secretion of acute-phase reactants and TNFα and promotes T helper 1 cell differentiation (La Cava & Matarese 2004). Leptin acts on T cell, macrophages, and other immune cells to stimulate the production of a wide spectrum of cytokines (La Cava & Matarese 2004). In light of the role of several cytokines in enhancing energy expenditure and suppressing food intake (Ye & Keller 2010), this proinflammatory action of leptin might contribute to its overall effects in body weight regulation.


TNFα was the first cytokine identified in the adipose tissue of obese mice, marking the start of the metabolic inflammation concept (Hotamisligil et al. 1993). The direct involvement of TNFα in obesity-induced insulin resistance was confirmed by observations that TNFα treatment interferes with insulin signaling and blocks insulin actions (Hotamisligil et al. 1994). Mice lacking the functions of TNFα or its receptors are protected from obesity-induced insulin resistance and hyperglycemia (Uysal et al. 1997, 1998). It was initially thought that adipose-derived TNFα was produced mainly by adipocytes, but the parallel trend of macrophage infiltration and TNFα expression in adipose tissue of obese mice suggests that a significant portion of the adipose TNFα pool might be derived from macrophages and other immune cells. Interesting, FFA strongly stimulates TNFα production in macrophages (Nguyen et al. 2005) and in turn, TNFα stimulates lipolysis to increase fatty acid release from adipocytes (Wang et al. 2008). This FFA-cytokine cycle suggests that metabolic inflammation, once started, can use this self-perpetuating mechanism to further its inhibitory effects on insulin signaling and energy metabolism. In addition, TNFα directly stimulates hepatic lipogenesis in vivo (Feingold & Grunfeld 1987), and adipose-derived TNFα is also a major mechanistic link between obesity and cancer (Park et al. 2010).


IL6 is one of the major pro-inflammatory cytokines whose expression level increases in the adipose tissue of obese mice and patients, but its role in glucose metabolism has not been fully resolved. (…) There are several potential explanations for the seemingly contradictory data regarding IL6 in insulin action and glucose metabolism. Effects of acute vs chronic treatments need to be differentiated and dose and site of action of IL6 need to be carefully considered. In addition, IL6 produced by different organs might also contribute to its complex effects on metabolic regulation.

From an in-depth review of IL-6 and metabolic inflammation, please read here. Although its not clear if IL-6 has a direct causative effect (it can have pro and anti-inflammatory effects), it has been associated with the T2DM, CVD and inflammation:

Low-grade chronic inflammation in obesity, reflected by a two- to threefold increase in the systemic level of cytokines including IL-6, appears to precede and is a risk factor of the subsequent development of insulin resistance and T2DM (Spranger et al., 2003; Wang et al., 2013; Lowe et al., 2014). (…) IL-6 has been identified as an independent predictor of T2DM and associated cardiovascular events (Spranger et al., 2003; Lowe et al., 2014). Adipocytes and macrophages residing in adipose tissue are the major sources for the elevated plasma IL-6 concentration up to 2–3 pg·mL−1 in patients with obesity and T2DM (Pradhan et al., 2001; Spranger et al., 2003). Nevertheless, the existing evidence is not enough to establish a causal association between IL-6 levels and the progression to metabolic and cardiovascular disorders. Due to its pleiotropic actions in various tissues and organs, the exact role of IL-6 in the pathogenesis of diabetes must be examined carefully in a cell- and tissue-specific manner, but allowing for the possibility of crosstalk between affected tissues and organs.

Overall, it seems that restricting calories daily to a short window of time might be metabolically beneficial in the absence of significant calorie or protein restriction. In combination with a diet with adequate protein and resistance exercise, it seems to promote favorable changes in body composition and improve metabolic markers related to inflammation. The combination of IF and CR might be synergistic, while the effects of longer daily fasting periods with a shorter eating window is unknown.

Let’s see at the body composition data from the study.

  • The IF group lost 0.9 kg in 8 weeks. This represents 1% of body weight. They lost 15% of body fat mass.
  • In kcal/lb (a rough measure of energy intake level), at the end of the study, the IF group was consuming around 14.97 kcal/lb, while the control group was consuming 15.47 kcal/lb. Generally, a good estimate for maintenance calories is between 14–16 kcal/lb.
  • In the IF group, subjects went from consuming 2826 to 2735 kcal/day. In the control group, it went from 3007 to 2910 kcal/day. There was no significant difference between calorie intake between groups. But for the sake of the argument, lets say that they were in calorie deficit. Energy restriction was thus 3% from baseline in both groups. This level of restriction is well within errors in estimation and in all practical purposes, not considered as “energy restriction”. However, if we assume that it indeed is considered an energy restricted diet, then no one can argue that the deficit was small and almost non-significant. This also agrees with the small amount of weight loss, which is well within normal daily variation.
  • Protein intake was increased compared to baseline and not significantly different between groups (1.93 g/kg in the IF group vs. 1.89 g/kg in the control group).

Based on the above, one can rely on the lack of statistical significance in energy intake between groups and mean calorie intake per day to assume that both groups consumed the same number of calories, which were around maintenance. However, the calorie difference might be biologically significant as suggested by the greater loss of body fat in the IF group. Given that the focus of the criticism is in the latter, I will consider the IF group to be in a slight calorie deficit and show how it doesn’t change the main argument of the original post.

What we know about IGF-1, calorie restriction (CR) and weight/fat loss

As mentioned in the other post, it is well established than in humans, dietary protein intake is the main determinant of serum IGF-1 levels. So in theory, the higher the protein intake, the higher the IGF-1 levels. CR has a modest effect. On the other hand, CR, by definition, will result in weight loss, which could also modulate IGF-1. Thus, the significant reduction of IGF-1 in the IF group, if not because of the temporal restriction of food to a short window, could be due to:

a) Lower protein intake than the control group.

b) Lower caloric intake or greater CR than the control group.

b) Greater weight/fat loss than the control group.

Protein intake was not different between groups and was high, so if anything, it should have increased IGF-1 levels.

The CR level in both groups was 3%, so the level of restriction for both was the same (the absolute level of restriction was 91 kcal for the IF group and 97 kcal for the control group). The difference in basal energy intake between groups was due to different initial mean body weight, which was not statistically significant (83.9 kg in the IF group vs. 85.3 kg in the control group), but at the end of the study was 175 kcal. Again, the difference was not statistically significant, both diets were on maintenance levels and restricted from basal levels by the same amount. But for the sake of the argument, we will assume that this difference could account for the change in IGF-1.

The IF group lost significantly more body fat than the control group. Thus, it could also be that this loss of body fat explains the difference in IGF-1 between groups.

In summary and for further comparisons, the IF group was 3% CR, lost 1% of body weight and lost 15% of body fat mass in 8 weeks. The appropriate way to calculate the calorie deficit should be to subtract the intervention calories from basal calories (which is 91 kcal), but as people have focused on the 175 kcal difference with the control group, we will use this number as the calorie deficit (-175 kcal).

Because CR and weight loss are invariably linked, I will discuss them together.

I already mentioned that long-term (6 years) CRON results in a modest decrease in IGF-1, with average levels compared to what achieved in 8 weeks in the IF group. This population is the most relevant for discussion of independent effects of CR on metabolic markers as they are weight-stable (so no confounding due to weight loss).

There is also data from the CALERIE study, at 1 and 2 years. In this intervention, normal weight subjects were calorie restricted for 2 years to a goal of 20% CR. After 1 year, subjects achieved only 12% of CR (-279.5 kcal), reduced body weight by 10.7%, fat mass by 24%, improved insulin sensitivity and some inflammatory markers, but didn’t reduce IGF-1 significantly. The same results were seen after 2 years: body weight was reduced by 10.4%, fat mass by 22.5% with a similar CR level (-216.3 kcal), but IGF-1 levels were only reduced by 8.6%. Importantly, protein intake increased in this period to 1.28 g/kg.

I have put these differences in a table to make it easier to compare:

All changes are with respect to baseline values and just a rough difference between means.

Achieving 10% of weight loss, 22.5% of fat loss and 10% CR in 2 years didn’t produce the same reduction in IGF-1 as 8 weeks with IF with 3% CR, despite higher weight/fat loss and lower protein and calorie intake. Even if we consider that the calorie reduction was 175 kcal (which was not), it still falls short compared to that in Fontana et al., 2016 (175 kcal vs 216 kcal, or 6% CR vs 10% CR).

I believe the most adequate comparison is the one above, because it compares normal weight subjects. But there is also data from obese subjects undergoing weight loss.

In overweight women, 25% of energy restriction either continuously (CER, 1500 kcal daily) or intermittently (IER, 647 kcal for 2 days per week) resulted in similar body weight loss after 6 months. Neither of the interventions reduced significantly IGF-1. However, there is a clear trend in the IER group for reducing IGF-1 levels (baseline=201.3; 6 months=191.6 ng/mL) that was not seen in the CER (baseline=202.9; 6 months= 203.7 ng/mL) and didn’t appear to correlate with weight or fat loss.

But the IER protocol is more similar to the 5:2 diet than to a 16/8 IF protocol (and it involves less overall fasting period). Nevertheless, it shows that 6 months of 25% CR that produced significant changes in body weight and fat loss didn’t reduce IGF-1 levels. Similar results have been observed by the same authors: no change in IGF-1 with 25% daily or intermittent energy restriction despite significant weight/fat loss.

In other group of obese subjects, dietary restriction (1200 kcal/day) increased IGF-1 levels after 8 weeks but returned to baseline after 16 weeks, despite 5.8 and 8.1 kg of body weight lost (8 vs. 16 weeks, respectively). A similar increase in IGF-1 after weight loss has been observed in other study with obese women, as well as in an intervention with or without orlistat.

As described, there is no clear relationship between body weight/fat loss and degree of CR on serum IGF-1 levels in normal or obese subjects. Only after a long period of time (2 years) and constant, significant CR (10–12%) a small change in IGF-1 is observed. Thus, it is highly unlikely that the change seen in the IF group is due to either CR or weight/fat loss, specially with a high protein intake, almost no CR and short duration of the intervention (8 weeks).

Even if one assumes that the IF group was in significant calorie deficit, the degree of IGF-1 reduction in such a short time and with the amount of protein is remarkable. As mentioned in the other post, comparable reductions have only been observed after 3 cycles of a Fasting-Mimicking Diet(13%) or reducing protein from 1.67 g/kg to 0.95 g/kg for 3 weeks (22%), the latter being the most effective.

Finally, I want to mention something important that was not part of the original post as the study didn’t measure it: IGFBP (IGF-binding proteins). The activity of IGF-1 depends on its bioavailability, which in turn is determined by the ratio of IGF-1 to IGFBP (IGF-1:IGFBP ratio).

Simply put, the concentration of IGFBP determines the amount of free serum IGF-1, which in the end is the available hormone in circulation. 2 years of CRincreased IGFBP-1 (one isoform of IGFBP that is regulated by metabolic status) by 20–25%, which in turn reduced the IGF-1:IGFBP-1 ratio by 42%. So even though CR didn’t reduce IGF-1 significantly, it did reduce the amount of free IGF-1.

Why it makes sense

Quoting Fontana et al., 2016 (my emphasis):

In fact, serum concentration of IGFBP-1, unlike IGFBP-3 which binds 75–90% of circulating IGF-I, is heavily influenced by the metabolic (i.e., insulin resistance, and insulin and glucagon levels) and nutritional (fasting and refeeding) state of the individual. Excessive adiposity-induced insulin resistance and compensatory hyperinsulinemia have been shown to decrease hepatic synthesis of IGFBP-1, which translates into increased concentrations of bioavailable IGF-1, without modifications in serum total IGF-1 levels (Lukanova et al., 2001; Maddux et al., 2006).

Patients with type 1 diabetes have higher serum IGFBP-1 concentrations than normoglycemic controls (Suikkari et al., 1988), and acute steady state hyperinsulinemia lowers serum IGFBP-1 levels by 40–70% in normal individuals (Yeoh & Baxter, 1988; Snyder & Clemmons, 1990). Moreover, it has been shown that circulating levels of IGFBP-1 are acutely increased by 3–4 fold in response to overnight fasting and decline rapidly after a meal (Busby et al., 1988; Smith et al., 1995).

Indeed, IGFBP-1 has been proposed as a marker of hepatic insulin sensitivity. While IGF-1 levels are primarily determined by dietary protein intake, IGFBP-1 levels are regulated by insulin secretion. It appears that fasting decreases IGF-1 and increases IGFBP-1, effectively reducing IGF-1 bioavailability. In normal subjects after 36 hours of fasting, IGF-1 levels are reduced from 249.5 to 219.4 ng/mL (-12%) and IGFBP-1 levels are increased from 27.4 to 205.2 ng/mL (+649%).

A note on adipocytokines

In the previous post I presented evidence that the relationship between weight loss and levels of adipocytokines is equivocal. However, I found information on TNF-a in non-obese subjects. From the same CALERIE study, TNF-a was reduced by 22% after 2 years, compared to only 8% in the IF group, which is almost the same reduction observed for the CR subjects in CALERIE after 1 year (8.5%) with a higher CR level. Still, absolute values are significantly lower in long-term CRONers.

Low Carb Best for health and weight loss

High-Fat Diet Doesn’t Cause Obesity

I wrote the other day about the less-than-optimal control animals and humans used in fasting and calorie-restriction studies. Partly this is due to the bad food that most people eat, as well as the substandard lab food that rats and mice eat. A similar problem exists in other diet experiments on lab animals. Here I’ll show that a high-fat diet doesn’t cause obesity – in lab animals anyway.

High-fat lab diets

If you read much of the scientific literature, you’ll come across lots of studies using lab rats and mice that were fed “high-fat” diets. Usually they produce ghastly results, like obesity, diabetes, cancer, cognitive deficits, and so on. Then the mainstream media trumpets these as meaning that you are going to get sick and die if you eat a high-fat diet.

Just to pull one more or less at random, “High-Fat Diet Disrupts Behavioral and Molecular Circadian Rhythms in Mice“. Control mice ate the Harlan Teklad 7012 diet of standard lab chow. It’s 25% protein, 17% fat, and 58% carbohydrate. Importantly, it contains no sugar and has high-quality, natural ingredients.

The high-fat group ate Research Diet 12451. Here are the ingredients:

This diet is 35% carbohydrate, 20% protein, and 45% fat. It contains sucrose – table sugar – as 17% of calories, as well as soybean oil, maltodextrin, and casein.

High fat? It’s more like dessert for rodents.

That amount of sugar is comparable to what the typical obese and heart-disease-prone American eats. Soybean oil has a high omega-6 content. Maltodextrin is a simple carbohydrate that turns to maltose and then glucose when absorbed, spiking blood sugar and insulin. Casein supplies all the protein, whereas the standard lab chow has no animal protein.

Yes, of course animals eating this garbage get sick.

Healthy high-fat diets

In contrast, look at another paper: A high-fat, ketogenic diet induces a unique metabolic state in mice. The animals on the ketogenic diet had lower body weight, lower glucose and insulin, and higher AMPK activity, a pro-longevity mechanism. When animals were switched to this diet, they lost weight. All very healthy, yet it was a high-fat diet, with 95% fat, 5% protein, and 0% carbohydrate. A very high-fat diet.

One of the experimental arms in this experiment was on the Research Diet 12451, as illustrated above. They got fat and sick.

Conclusion: Don’t believe everything you read

The animals on the “high-fat” diet in the first study were in reality eating a high-sugar, moderate-fat diet. Very misleading, if you ask me.

The animals in the second study ate a very high fat, no carb and sugar diet, and were healthy.

So next time you read about a high-fat diet making animals sick, diabetic, obese, or whatever, you can’t take it at face value.

Are carbohydrates needed to build muscle?

Lots of bodybuilders, most of them I would say, emphasize the need for a substantial amount of dietary carbohydrates to build muscle. The argument takes one or both of two forms; 1) that you need carbs to perform more intense exercise in the gym; and 2) carbs are needed to raise insulin and stimulate muscle growth. I’ve never found the arguments all that compelling, but then I’m just an average gym rat, not a bodybuilder extraordinaire. So how much truth is there in these statements?

First, as for intensity of workouts. A study was recently published in the Journal of the International Society of Sports Nutrition  – which looked at elite level gymnasts. After 30 days on a ketogenic diet, i.e one with a very low carbohydrate content, probably under 50 grams a day, the athletes’ strength and power had not diminished. However, even these elite athletes, who one would presume were already in terrific shape, lost about 2 kg of fat, with a “non-significant” increase in muscle. This shows that if anything, at least for gymnasts, who require a high level of strength, the ketogenic diet was better than their regular diets. The authors conclude:

Despite concerns of coaches and doctors about the possible detrimental effects of low carbohydrate diets on athletic performance and the well known importance of carbohydrates there are no data about VLCKD and strength performance. The undeniable and sudden effect of VLCKD on fat loss may be useful for those athletes who compete in sports based on weight class. We have demonstrated that using VLCKD for a relatively short time period (i.e. 30 days) can decrease body weight and body fat without negative effects on strength performance in high level athletes.

Assuming that the same holds for bodybuilders, let’s move on to muscle hypertrophy. Another recent study found that carbohydrate does not augment exercise-induced protein accretion versus protein alone. In this study there were two conditions: young men performed resistance training followed by ingestion of either 25 grams of whey protein, or 25 grams of whey plus 50 grams of carbohydrate (maltodextrin). Despite the fact that the extra carbohydrate raised blood glucose levels 17.5 times higher and insulin levels 5 times higher (that is, area under the curve) than protein alone, no difference was found in either muscle protein synthesis or muscle protein breakdown.

So as long as you get adequate protein, you’ve maximized the amount of hypertrophy you can get out of resistance training. Protein raises insulin, which is required for hypertrophy, but raising insulin further does nothing.

Finally there’s an interesting new study, one the co-authors of which is Jeff Volek, who’s done so much great work in this area. The effects of ketogenic dieting on skeletal muscle and fat mass. One reason why it’s interesting is that the men in the study were already resistance-trained. Normally in studies like this they like to use newbies, as you see greater results in them; if already trained subjects are used, and there’s a difference between groups, then you know it really worked well.

Twenty-six college aged resistance trained men volunteered to participate in this study and were divided into VLCKD (5 % CHO, 75 % Fat, 20 % Pro) or a traditional western diet (55 % CHO, 25 % fat, 20 % pro). All subjects participated in a periodized resistance-training program three times per week….

Results: the ketogenic diet group gained 4.3 kg lean mass (muscle) compared to only 2.2 kg for the traditional diet group; the ketogenic group lost 2.2 kg of fat, compared to 1.5 kg in the traditional group.

I’d say this last study puts to rest any argument for lots of carbohydrates in weightlifting. The very low carbohydrate ketogenic diet was superior to a diet with 55% carbohydrate. Note that protein percent was the same for both groups.

Finally, there’s a very good book I recommend by the above-mentioned Jeff Volek and co-author Stephen Phinney, The Art and Science of Low Carbohydrate Performance.

So, no, carbohydrates are not needed to build muscle, and in fact muscle building might be even better without them.



Low-Carbohydrate Diet Beats Others for Weight Loss



Low-carbohydrate food pyramid.

Low-carbohydrate food pyramid.

Weight loss and the myth of saturated fat


What’s the best diet for weight loss? Much controversy swirls around this question because although diets like the low-carb Atkins diet have had great success, we don’t know whether they’re more effective, and besides we’ve been told for years that too much saturated fat in the diet may be bad for our health.

The “fact” that saturated fat may cause heart disease and be bad for our health generally has finally, and I believe definitively, been shown to be a myth. A meta-analysis from a few years ago, one of whose co-authors was Dr. Ronald Krauss, than whom it would be impossible to be more mainstream, showed that “there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD [coronary heart disease] or CVD [cardiovascular disease].” The myth of dietary fat and health risks has been expounded upon at length in the recent book by Nina Teicholz, The Big Fat Surprise, which I highly recommend.

As the myth of saturated fat has been debunked, we’re left with which diets are better for weight loss. One factor in that analysis is compliance, that is, to what extent dieters will stay on a diet. In compliance, there are basically two things to consider: 1) whether the food taste good; and 2) whether hunger can be kept under control.

Diets must control hunger


Food doesn’t just supply us with nutrients; it’s pleasant and the occasion for social interaction, and a diet depriving people of these will generally make them unhappy and unwilling to continue.

And if dieters are hungry, they are much more likely to break their diets and revert to their old, weight-gaining ways.

Low-fat diets, the kind prescribed over the past few decades, generally deprive dieters of foods that humans find naturally satisfying and that taste good, fatty foods like steak and all kinds of meats, butter, cream, cheese, eggs, even olive oil. Many or most people find that they feel deprived on such a diet – I would anyway.

On the other hand, low-carbohydrate diets deprive dieters of or severely limit sugar, bread, rolls, pasta, tortillas, candy, pastries, and any number of other things. However, on a calorically restricted low-fat diet, you can’t really eat your fill of these foods either.

So, as far as taste goes, a low-carbohydrate diet would seem to offer a better choice, being able to eat one’s fill of “main meal” type, satisfying foods, while limiting anything made with flour or sugar. Low-fat diets, if calorically restricted, limit these foods anyway.

What about hunger? Most people report less hunger on a low-carbohydrate diet, so they’re more likely to stay on it. But the kicker is that most low-carbohydrate diets do not restrict calories, while low-fat or conventional diets do. So even if low-carbohydrate, high-fat foods didn’t satisfy hunger more, the fact that one can just eat more of them would seem to make up for it. But all the evidence points to low-carb, high-fat foods as better able to eliminate hunger – in fact, that’s part of the mechanism that makes them work.


A head-to-head comparison of low-carbohydrate, low-fat, and Mediterranean diets


A study from a few years ago directly compared three different diets for weight loss: Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet. (New England Journal of Medicine.)

The low-fat diet was calorically restricted, with a target 1800 calories a day for men, 1500 for women. (Editorial comment: I’d be hungry on that amount of calories.) It was 30% of calories from fat, and “participants were counseled to consume low-fat grains, vegetables, fruits, and legumes and to limit their consumption of additional fats, sweets, and high-fat snacks”. (Editorial comment: even on this diet, sweets are limited.)

The Mediterranean diet’s target calorie intake was the same as for the low-fat, but with a goal of 35% calories from fat, “the main sources of added fat were 30 to 45 g of olive oil and a handful of nuts (five to seven nuts, that’s it).

The low-carbohydrate diet was not restricted in calories; it was all you can eat. (Now we’re talking.) It provided “20 g of carbohydrates per day for the 2-month induction phase…, with a gradual increase to a maximum of 120 g per day to maintain the weight loss. The intakes of total calories, protein, and fat were not limited. However, the participants were counseled to choose vegetarian sources of fat and protein and to avoid trans fat. The diet was based on the Atkins diet.” Unfortunately, we see the fear of saturated fat loom here, with “vegetarian sources of fat and protein”. At the beginning, the diet amounts to a ketogenic diet; it’s unclear why they felt the need to increase carbohydrates from the original to 120 grams. Possibly they think better compliance would result.

The study lasted for 2 years; all participants were either overweight (BMI ≥27), or with diabetes or coronary heart disease.

So, what happened? Drum roll, please…

Weight loss on low-carbohydrate, low-fat, and Mediterranean diets. Low-carb for the win.


Low-carbohydrate diet resulted in more weight loss


For participants who completed the entire 24-month program, weight loss was 3.3 kg (7.3 lbs.) on low-fat, 4.6 kg (10.1 lbs.) on the Mediterranean diet, and 5.5 kg (12.1 lbs.) on the low-carbohydrate diet. Low-carb was the clear winner.

Note from the above graph that with all diets, most weight loss occurred in the first 6 months, with either a plateau (Mediterranean) or a gradual weight regain. This pattern is often seen in diet studies and, no doubt, in real-world dieters.

The reasons for that are at least two or three. One is that dieters lose their initial enthusiasm and start to cheat. Another is a decrease in metabolism that follows weight loss; although this occurs with all weight loss, the low-carbohydrate diet appears to have a better record of maintaining metabolism, one reason being that it’s not calorically restricted. Finally, the low-carb diet had “cheating” built into it, with a beginning carbohydrate allocation of 20 grams a day, but rising to 120 grams a day later. That alone could easily account for weight regain.

The low-carbohydrate diet reduced disease risk more


The researchers wanted to know how each of these diets affected heart disease risk, and thus looked at lipid profiles. Results below.

The low-carbohydrate diet had the best lipid profile results.

We know that in lipid profiles, triglycerides (lower is better), HDL cholesterol (higher is better), and the ratio between the two have the most significance for heart disease risk. The low-carbohydrate diet trounced the others in this category.

Fasting glucose (chart not shown) remained about the same for all groups, although in diabetics, the Mediterranean diet group showed the greatest improvement.

Also in non-diabetics, the low-carbohydrate group showed the greatest decrease in fasting insulin levels. Since insulin is a pro-growth, anabolic hormone, and is implicated in aging, this gives further backing to the fact that a low-carbohydrate diet is an anti-aging diet. Of great interest, the level of C-reactive protein, which is a measure of inflammation, dropped the most on the low-carb diet. Again, since increasing inflammation is associated with aging, the low-carb diet can potentially slow the aging process.

The results show that the low-carbohydrate diet was the clear winner for weight loss. (Diabetics had somewhat better results with the Mediterranean diet, although not for weight loss.)

The better results on low-carb were likely due to two things, in my opinion. One is that insulin levels dropped. Insulin helps drive fat into cells, and lower insulin levels allow fat cells to release fat to be burned. The other reason is probably better compliance. This low-carbohydrate diet was unrestricted in calories, i.e. all-you-can-eat, therefore the participants on this diet were unlikely to get hungry and grab the nearest food available. The participants on the other, calorically restricted diets may have been much more likely to get hungry and cheat.

If weight loss is your goal, the choice seems clear enough. The addition of weight training and adequate protein intake to a low-carb diet will make the retention and even gaining of muscle possible, even while losing fat. (Annals of Nutrition and Metabolism.)

A couple of books that I like that thoroughly explain the low-carbohydrate diet, both by the same authors, Jeff Volek and Stephen Phinney, are The Art and Science of Low Carbohydrate Living, and for athletes, The Art and Science of Low Carbohydrate Performance.



Why a Low-Carb Diet Is Best for Weight Loss

If you want to lose weight, you have a number of choices. The most popular is to cut calories and eat a low-fat diet. A way that’s becoming more popular, because it works much better, is to cut carbohydrates. Here we’ll take a look at scientific proof that a low-carb diet is best for weight loss.

No calorie counting

The biggest impediment to losing weight on a low-calorie diet is hunger. If you voluntarily reduce calories while eating the same foods, you get hungry, as is to be expected. Your body defends its weight, i.e. it has a set point, and makes you hungry if your weight moves away from the set point.

On a low-carbohydrate diet, you merely cut the amount of carbohydrates in the diet, and in most studies looking at low-carb diets, the dieters ate as much as they wanted. Only carbohydrates were restricted. Cutting carbohydrates lowers levels of the hormone insulin, which signals the body to store fat, and which is responsible for setting the body weight set point. The result is nearly effortless weight loss.

In the first study we’ll look at, a group of obese women were randomized to either a low-fat, low-calorie diet, or a low-carbohydrate diet that was not restricted in calories, and followed for 6 months. Weight loss result in the chart below.

low carb weight loss

The low-carb group ate 20 g of carbohydrate daily, but were allowed to increase this to 40 to 60 g after 2 weeks, so long as they remained in ketosis as shown by urinary testing. The low-fat group was restricted in calories by 30% and ate about 55% of their calories as carbohydrates.

Despite the fact that the low-carb group could eat as much as they wanted, they spontaneously reduced their calorie intake to about the same as the low-fat group. That shows the power of low-carb in reducing hunger and changing the body’s weight set point. And they still lost more weight, an average of 7.6 kg, than the low-fat group, at an average of 4.2 kg.

You can even eat more calories and still lose weight

The second study concerns weight loss in obese teenagers. A group of adolescents, average age 14, were assigned to either a low-carb diet or a low-fat diet.

The low-carb group was instructed to keep carbohydrates at less than 20 g a day for the first 2 weeks, but increasing to 40 g a day in weeks 3 through 12. They could eat as musch as they wanted.

The low-fat group was instructed to keep fat at <40 g a day. They also could eat as much as they wanted.

Here are the results.

low carb weight loss 2

The low-carb teenagers averaged 9.9 kg of weight loss, compared to 4.9 kg in the low fat group. (That’s 22 pounds vs 11 pounds.) That was despite the fact that the low-carb group ate over 1800 calories a day, while the low-fat group ate 1100 calories a day. That’s the power of lowering carbohydrate intake. Also it’s guaranteed that the low-carb group was less hungry.

You don’t even need to reduce carbohydrates much

The third study compared a low-carbohydrate to a low-fat diet in severe obesity. These people had a high prevalence diabetes or metabolic syndrome.

The low-carbohydrate group was instructed to keep carbs at <30 g a day. However, they didn’t. They could eat as much as they wanted.

The low-fat group was instructed to keep fat  at <30% of calories, and to reduce their calorie intake by 30%.

low carb weight loss 3

The low-carb group lost 5.8 kg after 6 months, the low-fat group 1.9 kg. (13 pounds vs 4 pounds.) The low-carb group spontaneously reduced their calorie intake, so that the 2 groups ate about the same number of calories, again showing the power of reducing hunger and body weight set point.

Notably, the low-carb group wasn’t very compliant, and they only reduced their carb intake to 37% of calories at 6 months, vs 51% for the low-fat group. Yet they still lost more weight.

Low-carb vs low fat and Mediterranean diets

The fourth study was a three-way comparison between a low-carb, low-fat, and Mediterranean diets. The low-fat and Mediterranean diets were restricted in calories, with limits of 1500 calories daily for women, and 1800 for men.

The low-carb dieters could eat as much as they wanted, so long as they restricted carbohydrates to 20 grams daily initially, but increasing to a maximum of 120 grams.

Here’s what happened:

low carb weight loss 4

Once again, low-carb is a clear winner. Low-fat lost 2.9 kg, Mediterranean 4.4 kg, and low-carb 4.7 kg. The low-carb group still ate a whopping 40% of calories as carbohydrates, although that was down from 51% at baseline, representing a drop of 120 grams of carbs daily.

Noteworthy is the increase in weight after the first few months of weight loss, which was greatest in the low-carb group. That group actually increased its carb intake slightly. Another explanation might be a lower metabolic rate and/or less exercise. the low-carb group did decrease the amount of exercise between 6 and 24 months; the low-fat group increased exercise.

Reviews of low-carb diets

We’ve seen above that several studies have found that low-carbohydrate diets are superior for weight loss. have I cherry-picked the studies? Nope.

Several meta-analyses (reviews of studies) have found that low-carb diets beat calorie-restricted low-fat diets.

Dietary Intervention for Overweight and Obese Adults: Comparison of Low-Carbohydrate and Low-Fat Diets. A Meta-Analysis. This study concluded:

This trial-level meta-analysis of randomized controlled trials comparing LoCHO diets with LoFAT diets in strictly adherent populations demonstrates that each diet was associated with significant weight loss and reduction in predicted risk of ASCVD events. However, LoCHO diet was associated with modest but significantly greater improvements in weight loss and predicted ASCVD risk in studies from 8 weeks to 24 months in duration. These results suggest that future evaluations of dietary guidelines should consider low carbohydrate diets as effective and safe intervention for weight management in the overweight and obese, although long-term effects require further investigation.

Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials. This study concluded:

Compared with participants on LF diets, participants on LC diets experienced a greater reduction in body weight.

What to eat on a low-carb diet

Low-carb diets vary in the degree of carbohydrate restriction. One scheme that I used in my book Stop the Clock was the following:

  • moderately low-carb: <130 grams of carbohydrate daily
  • low-carb: 50 to <130 grams daily
  • very low-carb ketogenic: <50 grams daily.

As we saw in this article, virtually any degree of carbohydrate restriction is beneficial. But, the more you restrict carbs, the better your weight loss is likely to be.

Timothy Noakes, M.D., a noted advocate of low-carb diets, recently published an article, Evidence that supports the prescription of low-carbohydrate high-fat diets: a narrative review. In it, he listed the following foods as being “green-lighted” for a low-carbohydrate diet:


This list is meant for people who are insulin-resistant. If trying to lose weight, it would be a good idea to go easy on the added oils and nuts.

You should omit the following foods entirely:

  • anything made with flour: bread, pasta, tortillas, pastries
  • anything with added sugar: soft drinks, fruit juice, candy, cookies
  • starch: potatoes, sweet potatoes

Did I miss anything? It’s easy, just eat plenty of meat, eggs, vegetables, cheese. Don’t go hungry.

For what it’s worth, I eat this way all the time. Most days my carb intake is probably 20 to 60 grams, some days rising to 100.

Keto-Fasting and life extension

The starvation hormone increases lifespan


In the last post, I discussed the growth-longevity trade-off in the context of intermittent fasting. In this post, I’ll discuss some further evidence for the connection between growth and lifespan.

A very neat paper shows that transgenic mice made to overexpress a certain hormone live much longer than wild type mice: The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. First of all, I’ll just emphasize something from the title of the paper, namely that fibroblast growth factor, or FGF-21, is the starvation hormone.

In mice, FGF21 is strongly induced in liver in response to prolonged fasts… FGF21 in turn elicits diverse aspects of the adaptive starvation response. Among these, FGF21 increases insulin sensitivity and causes a corresponding decrease in basal insulin concentrations; FGF21 increases hepatic fatty acid oxidation, ketogenesis and gluconeogenesis; and, FGF21 sensitizes mice to torpor, a hibernation-like state of reduced body temperature and physical activity. FGF21 also blocks somatic growth by causing GH resistance, a phenomenon associated with starvation. Transgenic (Tg) mice overexpressing FGF21 are markedly smaller than wild-type mice and have a corresponding decrease in circulating IGF-1 concentrations despite having elevated growth hormone (GH) levels…. In liver, FGF21 inhibits the GH signaling pathway… Thus, FGF21-mediated repression of the GH/IGF-1 axis provides a mechanism for blocking growth and conserving energy under starvation conditions. [my emphases]

So, it can be seen from this passage how growth and lifespan are opposed. FGF-21 causes better insulin sensitivity and increased fat burning, both known to be associated with better health and longevity, and it interferes with the growth hormone signaling pathway.

Here are the survival curves for the mice, transgenic vs. wild type:

Median survival time in the mice was increased by 36%, and maximum survival was even longer, as around 30% of the transgenic mice were still alive at the time the paper was written.

According to an accompanying article written by one of the most prominent aging researchers around, Cynthia Kenyon, FGF-21 is produced by the liver after 12 hours of fasting.

All in all, we see that a hormone produced by fasting inhibits growth pathways and extends lifespan. Worth noting also is that FGF-21 also increases insulin sensitivity and promotes the production of ketones. Low-carbohydrate diets do this also, suggesting that they may promote longevity as well. And exercise, especially resistance exercise, strongly increases insulin sensitivity.

Could regular use of intermittent fasting increase longevity in humans? In my opinion, very likely it will. What is needed now are studies to see how and to what extent FGF-21 is increased in humans in response to fasting.

Finally, as further evidence of the growth-longevity trade-off, we should note that, in humans, growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes. Also in humans, functionally significant mutations in the insulin-like growth factor receptor are more common in centenarians.

How to Fast Without Fasting

Intermittent fasting, discussed many times on this site, is a potent anti-aging and health-promoting intervention. It lowers insulin and glucose levels, and therefore can be used to treat diabetes and for fat loss. Nevertheless, fasting requires going without food, which many people are unwilling — or possibly unable, in some cases — to do.  Is there a workaround? Yes… here’s how to fast without fasting.

The effects of fasting

What does intermittent fasting do that’s so beneficial? It appears that the main way that short-term fasting benefits health is by lowering insulin levels. The mobilization of fat stores — lipolysis — that greatly accelerates during fasting appears to be due to lower insulin levels, and not to changes in blood glucose (sugar) levels.

Besides increasing lipolysis or fat-burning, lowering insulin levels also greatly increases the rate of autophagy, the cellular self-cleansing process that rids cells of junk and that is so important to fighting aging.

Fasting also increases the production of ketones, which benefit metabolic and brain health.

So how can you get these effects of fasting without fasting?

You do this through restricting carbohydrates.

Carbohydrate restriction gives many of the benefits of fasting

Carbohydrate restriction, i.e. a very low carbohydrate ketogenic diet (VLCKD), or in this case, a zero-carbohydrate diet, was found to account for about 70% of the metabolic response to fasting. That is, merely refraining from eating carbohydrates gives most of the benefits of fasting in terms of lower glucose and insulin.

In another study, a group of volunteers fasted for 84 hours (3.5 days), or fasted for that length of time and received a lipid infusion such that they got all the calories they needed. The scientists found that there were no differences in “plasma glucose, free fatty acids, ketone bodies, insulin, and epinephrine concentrations” between fasting and non-fasting conditions.

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.” [My emphasis.]

Now, I might not go so far as these scientists as to say that the entire response to intermittent fasting is due to absence of dietary carbohydrate. Another study cited above found that carbohydrate restriction accounted for about 70% of the response to fasting, not 100%.

There may be other parameters that the study didn’t observe, IGF-1 for example, or increased rates of autophagy. But it’s clear that restricting carbohydrates accounts for a lot of the changes seen in intermittent fasting.

I suspect that the additional benefits of fasting come from lack of protein intake.

Radically restricting carbohydrates results in the production of ketones, and ketones stimulate autophagy, which is one of the important benefits of fasting. So here’s another way that reducing carbs effectively imitates fasting.

Intermittent fasting also works by reproducing many of the effects of calorie restriction, the most robust life-extending intervention known.

And in turn, restriction of carbohydrates is the most effective way to mimic calorie restriction.

The conclusion must be that carbohydrate restriction confers most of the benefits of intermittent fasting.

What if you combine a very-low carbohydrate diet with bouts of intermittent fasting? That’s exactly what I do, and it should give synergistic benefits.

If you start from a base of low-carb eating, and then fast for a period of time, this should more strongly induce ketosis and lower insulin levels, and more strongly increase the rate of autophagy and lipolysis (fat-burning).

How to implement a low-carbohydrate diet + intermittent fasting

The main source of dietary carbohydrates are refined grains and starches. These should be omitted entirely, so that means no bread, tortillas, pasta, breakfast cereal, rice, anything with sugar such as soda.

Large sources of carbohydrates are also found in starches such as potatoes.

Green leafy vegetables, while they contain carbohydrates, are such poor sources of them and so high in fiber that they may be eaten freely.

The main source of calories would consist of meat, eggs, cheese, cream, butter, yogurt (unsweetened, natch). If you drink alcohol, be moderate and stay with red wine and plain highballs, which have no sugar.

Don’t eat anything after dinner, and then again not until 16 to 18 hours have passed, say until 10 A.M. to noon the following day.  That’s your fast.

You could do that daily, although if you lift weights, don’t begin a fast until at least 24 hours after your workout. When you lift weights, muscles are primed for growth, and need nutrients to do so. If you want to get those gains, you must feed your muscles.

On my current schedule of approximately twice a week workouts, I can still manage several 16-hour fasts a week.

Hopefully, I’m getting potent anti-aging and health-giving synergy between my low-carbohydrate way of eating and intermittent fasting.

Keto diet creates beta hydroxybutyrate (BHB) that extends health and lifespan

Eating a very low-carbohydrate diet results in the production of ketones, which the body uses as an alternative fuel source; hence very low-carbohydrate diets (VLCKD) diets are called ketogenic.

The liver makes ketones from fatty acids when glycogen (the storage form of carbohydrate) has been depleted, hence going without carbohydrates, or fasting altogether (for around 16 hours or more), ramps up ketone production, and it does this to spare glucose so that the brain can use it. While it’s been known for a long time that ketogenic diets have therapeutic uses, such as for weight loss and in epilepsy, new research is showing the relation between ketones, longevity, and cancer.

Ketone supplements extend lifespan

The ketones, often referred to as ketone bodies, are beta hydroxybutyrate (BHB), acetoacetate, and acetone.

Ketogenic diets are therapeutic for several reasons, one of the most important being a decrease in levels of the hormone insulin. Low insulin allows fat to be released from fat (adipose) tissue, hence a ketogenic diet speeds weight loss.

One of the main benefits of ketogenic diets may be the production of ketone bodies themselves. Ketones mimic many of the changes that calorie restriction causes, and ketones have been found to extend lifespan in C. elegans.

Scientists believe ketones should also extend human lifespan.

Calorie restriction works via ketones


Calorie restriction as a method of extending lifespan in animals has been known or a long time, maybe 80 years or so, but the concept goes back much further. Luigi Cornaro (1464-1566) sought the advice of physicians when he was in his 30s (placing the time at about 1500) when he was so sick that he felt he was going to die; Cornaro may have been diabetic. One of the doctors advised him to cut back his food intake radically, which he did, eating only one meal a day, including a half a bottle of wine.  Cornaro returned to health, lived to over 100 years of age, and wrote about his experiences in his book, On the Temperate Life.

Since one of the physicians knew that cutting food meant better health, that knowledge must have been around long before Cornaro’s time and passed down among physicians.

In modern times, scientists discovered that restricting rats’ food by 10% or more made them live longer, contrary to expectations. It is counter-intuitive, as one might think that more food means the body can repair itself better, but that’s not the case; excess food drives aging faster. Since calorie restriction (CR) is one of the very few interventions that extends lifespan, we’d like to know how it works. If we could discover that, we could intervene in other ways, for example with CR mimetics such as resveratrol.

Many theories have sought to explain CR, e.g.

  • it results in less fat mass
  • less oxidative stress and inflammation
  • beneficial changes in the gut microbiome
  • lower insulin, growth hormone, and IGF-1
  • a lower metabolic rate
  • less iron accumulation
  • others.

But what may have escaped notice is that CR reliably produces ketones in virtually every species.

The production of ketone bodies could account for the life-extension effects of calorie restriction, at least in part.

Maybe just as important, exogenous ketones could extend human lifespan. No need for calorie restriction or very low carbohydrate ketogenic diets (VLCKD), although the benefits of a VLCKD likely go far beyond just the production of ketones.

Giving exogenous (from outside the body) ketones to rats decreases blood glucose and insulin. When rats were given 30% of their calories as corn starch, palm oil, or beta hydroxybutyrate (BHB, the most quantitatively important ketone body), those that got the ketones had about half the glucose and insulin levels of the group given starch. Their food intake also dropped by about half. The experiment lasted only 6 days, so no weight loss, which probably would have happened if it had gone on longer.

MCT oil, which produces ketones in humans, results in better weight loss than an equal amount of olive oil.

Exogenous ketones may extend lifespan partially by lowering glucose and insulin.  But they also increase antioxidant defense mechanisms.

As humans age, blood glucose and insulin increase, possibly as a result of decreased muscle mass and increased fat mass. Exogenous ketones (a ketone supplement) could improve these. Alzheimer’s, which has lately come to be called type 3 diabetes, could possibly be treated with exogenous ketones. (Recall the well-known N=1 study in which a doctor treated her husband’s Alzheimer’s with coconut oil.)

Ketones can treat cancer

In mice who that had metastatic cancer, exogenous ketones increased survival time by 70%. That survival time was independent of glucose level or calorie restriction. This effect looks like a direct targeting of the Warburg effect, i.e. it’s a treatment based on the metabolic theory of cancer.

Many people, even cancer patients, won’t cut their carbohydrates to get into ketosis. Exogenous ketones could help.

For anti-aging purposes also, ketone supplements could work; MCT oil probably would as well. I regularly eat a very low carbohydrate diet, but even here, boosting ketones with a supplement might be advantageous.

Ketone supplements

I’ve tried KetoCaNa, a ketone supplement, and it works; killed my appetite when I took it. Currently, I occasionally use MCT oil, since it’s a lot cheaper than exogenous ketones. You can put a tablespoon or more in your coffee in the morning instead of breakfast, get those ketones going.