Keto Diet fights cancer and heart disease for longer and healthier life

 

Health Benefits of Ketones

A ketogenic diet is characterized by the production of ketones, small molecules that the body can use as alternative energy sources. These molecules — beta hydroxybutyrate, acetoacetate, and acetone — are produced when carbohydrate consumption is very low. Depletion of glycogen, the storage form of carbohydrate, results in the production of ketones from fatty acids.

Intermittent fasting also causes the production of ketones, since if you’re not eating anything, you’re not eating carbohydrates either.

How low does carbohydrate consumption need to be to cause the production of ketones? The amount varies, and most people will need to eat 50 grams or fewer carbohydrate daily to see a rise in ketones. People who are very physically active, such as through daily strenuous exercise, may be able to eat 100 grams or more and still be in ketosis.

Ketones are used as an alternative to glucose. The body only carries about a 24-hour supply of glycogen — which is broken down to glucose — but the supply of fat is enough to last for weeks or months, depending on how much fat the person has. So after a period of about 24 hours with minimal carbohydrate intake, the production of ketones ramps up.

Just to be clear, the ketones under discussion here have nothing to do with raspberry ketones, which are a current weight-loss fad and appear to be ineffective for that purpose.

Health benefits of ketogenic diets

Ketones and the ketogenic diet have a number of health benefits.

  1. The ketogenic diet has strong anti-seizure properties. Many children and adults with epilepsy, whose condition cannot be treated with drugs, become seizure-free with a ketogenic diet.(1) The effect may be due to increased mitochondrial energy production in the brain.
  2. Ketones and the ketogenic diet may be useful in the treatment of Alzheimer’s disease.(2) A case that was in the news not long ago was of a doctor who treated her husband’s Alzheimer’s disease with coconut oil, which metabolizes to ketones. The treatment was quite successful.(3)
  3. The ketogenic diet may be useful for insulin resistance.(4)
  4. The ketogenic diet may help treat cancer.(5) Cancer cells thrive on glucose, so keeping blood sugar low may be therapeutic.
  5. Finally, the ketogenic diet can be used for fat loss, the Atkins diet being a notable example.(6)

The benefits of the ketogenic diet could be due to several things, for example to the absence of carbohydrate, to the presence of ketones, a decrease in insulin, or even increased consumption of fat. Or possibly to all of these.

The absence of carbohydrate in the diet leads to lower insulin levels, and this in turn allows fat to leave fat cells and be burned as energy. Hence the fat-loss effect of low-carbohydrate diets.

As noted, after 24 hours or more of carbohydrate restriction, ketones begin to be produced, and the presence of ketones and not the absence of carbohydrate seems to be the cause of the beneficial effects of the ketogenic diet in epilepsy and Alzheimer’s.

Ketones suppress hunger

It’s also widely suspected that ketones suppress hunger. They may be the cause of the absence of hunger during prolonged fasting. Many people report that as they begin to fast, they’re hungry, but their hunger goes away as they extend their fast.

The disappearance of hunger has certainly been my experience in fasting, especially if the fast lasts more than about 16 hours. What’s probably happening is that ketone levels increase in the bloodstream, and this suppresses hunger.

The fact that many of the benefits of the ketogenic diet may be due to the ketones themselves opens the way for exogenous ketone supplements. In theory, someone could take one of these supplements to get the benefits without even restricting their carbohydrate intake.

Exogenous ketone supplements

I recently received a sample of KetoCaNa, an exogenous ketone supplement.

KetoSports Keto CaNa

 

KetoCaNa contains beta hydroxybutyrate, one of the ketones normally produced by a ketogenic diet, and is flavored (“natural flavors”) and sweetened with stevia, a non-caloric sweetener.

I’ve used it several times now, and I can report that it works.

Works for what?

For one thing, it suppresses hunger, just as suspected. I’ve taken it several times in the morning during an intermittent fast. Hunger just goes away.

I’ve also taken it (twice) before lifting weights. Ketones may possibly be used as an alternative fuel during exercise, and thus may boost exercise performance.(7) My own experience here is less definite. Maybe it works. But the high-intensity protocol that I’ve begun practicing lately is so short — typically under 40 minutes — that I probably don’t need an alternative fuel source. I suspect that in a longer exercise bout, say cycling or running, ketones may make more of a difference. But I don’t know, since I don’t do those things.

By suppressing appetite, KetoCaNa could be useful for weight loss. Ketone supplements lead to lower body weight in rats.(8)

One drawback of KetoCaNa: the stuff is expensive. A full serving will run you over $4.00. However, half a serving seems to work well too.

The best way to use it is to take it during a fast, so ketone levels are increased. It will increase ketones if you’ve been eating as well, but that would negate many of the weight-loss benefits.

KetoCaNa may prove to be useful in treating Alzheimer’s, cancer, and epilepsy, but that remains to be seen. Most of those who take it now seem to be athletes.

There’s a newer entry into the ketone supplement line, Pruvit Keto // OS. I haven’t tried it.

MCT oil

Another, cheaper way to raise ketone levels is with MCT oil, which consists of medium-chain triglycerides which rapidly metabolize into ketones. MCTs seem to be difficult or impossible to store as fat, and a diet that included MCT oil resulted in significantly more fat loss than did a diet that contained olive oil, in humans.(9)

A tablespoon of MCT oil ought to do the job. Some people report stomach upset with MCT oil, but it’s never bothered me.

Another good reason to take exogenous ketones or MCT oil during an intermittent fast is because ketones stimulate autophagy, the cellular self-cleansing process.(10)

Increased autophagy is one of the main health benefits of intermittent fasting, and is mainly responsible for its longevity-promoting effect. Adding exogenous ketones while fasting ought to boost the autophagy process even more than fasting alone.

Conclusion

Many of the benefits of a very low carbohydrate ketogenic diet may be due to the presence of ketones. Exogenous ketone supplements can a) provide ketones even when not refraining from carbohydrates, and b) boost ketones even further when eating a ketogenic diet.

Lots of people who suffer from illnesses such as cancer or Alzheimer’s simply will not stop eating carbs. Crazy, I know, because if I had cancer I would do everything I could to treat it. But even a simple measure like cutting carbs seems beyond the reach of many. So ketone supplements may be able to fill in a gap in these cases.

Ketosis extends lifespan

 

ketosis extends lifespan

Ketosis and ketone bodies

Ketone bodies are the small molecules that are produced by the liver when the body is in a state of ketosis. These can be readily used by the body and, most notably, the nervous system, and one of their functions is to spare lean tissue during ketosis, since with the burning of ketones, the body does not have to break down muscle in order to make blood glucose.

The state of ketosis is readily entered when severely restricting carbohydrates in the diet for just a short while; for instance, if someone goes on the Atkins diet, or generally keeps carbs below 50 grams a day. (If one exercises a lot or is otherwise physically active, one can eat more carbs, say up to 100 grams, and remain in ketosis.)

Ketosis extends lifespan in C. elegans

It turns out that in the roundworm C. elegans, one of the ketone bodies, beta hydroxybutyrate, extends lifespan: D-beta-hydroxybutyrate extends lifespan in C. elegans.

βHB supplementation extended mean lifespan by approximately 20%. … βHB did not extend lifespan in a genetic model of dietary restriction indicating that βHB is likely functioning through a similar mechanism. βHB addition also upregulated ΒHB dehydrogenase activity and increased oxygen consumption in the worms.

So, the ketone functioned similarly to dietary restriction, increased lifespan by 20%, and caused increased metabolism.

It looks like being in ketosis much of the time could be, gasp, good for you.

The probable future Nobel Laureate Cynthia Kenyon discovered that a mutation in insulin signalling in C. elegans caused radically increased lifespan. When she made that discovery, she herself went on a low-carbohydrate diet.

So, add all this to the evidence for the healthiness of a low-carbohydrate diet.

 

 

 

Longer Life Through Lower Blood Sugar

Many experiments and studies on life extension have found the interesting and important result that lowering blood glucose (blood sugar) and/or restricting dietary carbohydrates means longer life. This has been found using several different lab animals and in humans as well. It’s possible to have longer life through lower blood sugar.

Acarbose

Acarbose is an anti-diabetic drug that works by inhibiting enzymes in the gut that break down carbohydrates to glucose, and therefore less glucose is absorbed.

Male mice that were fed acarbose lived 22% longer than controls, although the female mice lived only about 7% longer.

 

A lifespan increase of 22% is large, among the longer lifespan extensions seen with other interventions, comparable to rapamycin and a larger increase than fat-tissue insulin receptor knockout. Acarbose reduced fasting insulin in male mice but not in females, which may account for the difference in lifespan extension.

IGF-1 was decreased in both sexes, and fibroblast growth factor 21 (FGF21) was increased, and both of these hormonal changes could be involved in life extension.

In humans with type 2 diabetes, long-term acarbose treatment was associated with a huge 50% decrease in the risk of cardiovascular events such as heart attack and stroke. Importantly, the risk reduction was associated with a decrease in postprandial hyperglycemia, or a rise in blood sugar after eating.

A meta-analysis of acarbose found similar large reductions in CVD events.

Since dietary carbohydrates, especially grains, sugar, and starches, are the primary determinant of blood sugar, why not just cut carbohydrates instead?

Metformin

Metformin is the most prescribed anti-diabetic drug, and it lowers blood sugar and insulin. Similar large reductions in death rates have been found with metformin use, so much so that diabetics using metformin may outlive non-diabetics who don’t use it.

Would cutting carbohydrates cause the same life extension and anti-aging as metformin?

An argument against that is that diabetics taking metformin may live longer than non-diabetics who don’t take it. Therefore, metformin may be causing a real anti-aging effect.

An argument for it is that most non-diabetics eat large amounts of carbohydrates, with the average American eating about 50% of his or her calories as carbohydrate. And among average people, Dr. Joseph Kraft showed that large numbers, perhaps up to 80%, have some degree of impaired glucose tolerance, i.e. they’re insulin resistant.

If metformin increased lifespan in animals or people who ate little or no carbohydrates, that would be convincing, but to my knowledge, it has not.

Glucosamine

Glucosamine is an over-the-counter supplement commonly taken for arthritis and joint pain. Glucosamine extends lifespan in mice through

an induction of mitochondrial biogenesis, lowered blood glucose levels, enhanced expression of several murine amino-acid transporters, as well as increased amino-acid catabolism. Taken together, we provide evidence that GlcN [glucosamine] extends life span in evolutionary distinct species by mimicking a low-carbohydrate diet. [My emphasis.]

Glucosamine impairs glycolysis (glucose metabolism) and therefore lowers blood glucose levels.

Glucosamine also activates autophagy, the cellular self-cleansing process that retards aging, and inhibits mTOR, the cellular growth engine that accelerates aging.

In humans, use of glucosamine is associated with an 18% lower death rate.

Again, if glucosamine mimics a low-carbohydrate diet, why not just eliminate the middleman and refrain from eating carbohydrates?

Ketones

Fasting, eating a very low amount of carbohydrates (usually less than 50 grams daily), or taking ketone supplements or MCT oil raises the amount of molecules known as ketones in the bloodstream. Increased ketones mimic the effects of food restriction by lowering blood glucose and insulin.

While ketone supplements are generally beneficial in my opinion, if you cut the carbohydrates, albeit radically, you’re in ketosis (producing ketones) and presumably extending your lifespan and fighting aging by doing so.

Glucose

Feeding glucose to the worm C. elegans shortens its lifespan.

Restricting glucose extends its lifespan.

When carbohydrates are digested, they become glucose inside the body, since most carbohydrates are just long chains of glucose. (Sugars may incorporate other molecules, such as fructose and galactose.)

So why not just restrict carbohydrates?

Multiple lines of evidence lead to carbohydrate restriction

As we’ve seen from the studies above, multiple lines of evidence lead to the conclusion that restricting carbohydrates and thus preventing high blood glucose, whether spikes in it or a higher average glucose, leads to longer life.

These same lines of evidence lead to the conclusion that carbohydrates can promote aging and shorten life.

Note that some carbohydrates, namely complex carbohydrates found in non-starchy vegetables, don’t raise blood sugar much if at all.

The foods that contain abundant carbohydrates and increase blood glucose are the ones to restrict or eliminate, and they include grains (wheat, rice, corn, etc.), sugar, and starchy tubers such as potatoes.

Someone who is very insulin sensitive may not be harmed much by carbohydrates. These people include athletes and other lean people who exercise or labor at physically demanding jobs.

Anyone else, and that includes most people, would likely see a big improvement in health by restricting carbohydrates.

Keto Diet Stops Cancer

 

Cancer is the second leading cause of death in the U.S., and is one of the most dreaded diseases anywhere. It typically strikes older people more; some 90% of cancer is diagnosed in people over the age of 50, and incidence increases with age. Could we be looking at the end of cancer?

While many of the causes of cancer have been identified, the exact manner in which cancer starts and why it does so remains an open question in science. While the lay person may consider the origin of cancer to be of academic interest only, the way that cancer starts, and even precisely what cancer is, has great relevance to prevention and treatment. A new line of thought on cancer has emerged in recent years, backed by compelling evidence, that the prevalent theory of how cancer starts and what it is are wrong, at least in part.

This new way of looking at the problem is the metabolic theory of cancer.

Is cancer caused by genetic mutations?

The prevailing theory of cancer is that it’s caused by genetic mutations, which lead to uncontrolled growth, metastasis, and death. The Mayo Clinic flatly states, “Cancer is caused by changes (mutations) to the DNA within cells.” A scholarly review, The Hallmarks of Cancer, argues that the “enabling characteristic” for these hallmarks of cancer is “genome instability”, that is, the increased propensity of the cell’s genes to mutate.

But seemingly, there’s a paradoxically low rate of mutations together with a high rate of cancer. Even the authors of the review cited above state:

But mutation of specific genes is an inefficient process, reflecting the unceasing, fastidious maintenance of genomic integrity by a complex array of DNA monitoring and repair enzymes. These genome maintenance teams strive to ensure that DNA sequence information remains pristine… Yet cancers do appear at substantial frequency in the human population, causing some to argue that the genomes of tumor cells must acquire increased mutability in order for the process of tumor progression to reach completion in several decades time.

Mutations are rare, they say, because cells strive to repair their DNA, but cancer occurs frequently.

There are a number of other paradoxes of cancer.

The discovery that cancer cells collectively manifest millions of different types of gene mutationsled to the idea that all cancers were different, or different in type, and required complex treatment.

But what if cancer cells all had a remarkable similarity, one that had nothing to do with genetic mutations?

The Warburg effect

Otto Warburg, who won the Nobel Prize for Physiology or Medicine in 1931, first proposed that cancer is due to a metabolic defect.

Just as there are many remote causes of plague, heat, insects, rats, but only one common cause, the plague bacillus, there are a great many remote causes of cancer-tar, rays, arsenic, pressure, urethane- but there is only one common cause into which all other causes of cancer merge, the irreversible injuring of respiration.

In most normal cells, energy is burned in the mitochondria in the presence of oxygen to produce ATP, the currency of energy. Cancer cells have a severely diminished, or no, capacity to do this. Instead, they burn glucose for energy in a process known as aerobic glycolysis. The mitochondria of cancer cells appear to be severely damaged, so the only way they can obtain energy is through this alternative and relatively inefficient method.

Cancer cells burn glucose, as opposed to the mixture of fat and glucose burned by normal cells. Furthermore, non-cancerous normal cells can use ketone bodies for energy, and most cancer cells cannot.

Cancer as a metabolic disease

If genetic mutations don’t cause cancer, what does?

Thomas Seyfried, the most well-known scientist in this area, postulates that cancer is a metabolic disease.

In Seyfried’s view, metabolic dysfunction in the mitochondria of cancer cells is the initial event in cancer formation. The result is genomic instability, leading to the gene mutations seen in cancer; but the mutations are not causal, the metabolic dysfunction is.

Cancer cells burn sugar as a result of their dysfunction.

Therefore, treatment partially consists of depriving cancer cells of glucose. One way to do that is to lower blood glucose levels by the ketogenic diet. In fact, Seyfried has advocated just this approach. It appears to be effective, though much more clinical research would need to be done.

2-deoxyglucose, a compound that is taken up by cells but which cannot be metabolized, and which essentially jams up the metabolic machinery, inhibits cancer cells in vitro. So it appears that depriving cancer cells of glucose, their main fuel, inhibits their growth and may kill them.

Is there any other way to jam the molecular machinery of cancer cells?

Inhibiting cancer metabolism

Enter Dr. Laurent Schwartz, French physician and oncologist, who has been working on this problem for many years and treats patients using the metabolic theory of cancer. (In addition to conventional treatment.)

Schwartz and colleagues have developed a compound called Metabloc, which consists of two over-the-counter (in the U.S. at least) supplements, hydroxycitrate and alpha lipoic acid. These two compounds interfere with the metabolism of cancer cells, but have little effect on the metabolism of normal cells.  Below is a chart showing various strengths of both compounds either alone or in combination against cancer cells in vitro. The highest concentrations of the combination, though still in the micromolar range, reduced cancer cell viability to zero, i.e. no surviving cells.

This treatment, in contrast to standard cancer treatment, is non-toxic, with few side effects.

In vivo, in mice, the combination works too, greatly inhibiting tumor growth. Interestingly, adding another common compound, capsaicin, the substance that gives hot chili peppers their heat, inhibited cancer cells even more. The addition of a fourth compound, a peptide drug called octreotide, further diminished cancer cell viability. Octreotide is a potent inhibitor of growth hormone.

Schwartz has published several papers on the effects in actual patients; the most recent (as far as I know) is “Combination of Metabolic Treatment of Aggressive Primary Brain Tumour and Multiple Metastases of the Brain”.

Background: The combination of hydroxycitrate and lipoic acid has been demonstrated by several laboratories to be effective in reducing murine cancer growth. In previous article in 2014, we reported the fate of 11 patients treated for metastatic cancer unresponsive to chemotherapy. As of today, 32 months after inclusion, five of these patients (45%) are still alive.

Patients and Methods: We report the cases of 12 patients with advanced brain tumor. They were all treated with conventional treatment and a combination of sodium R lipoate (800 mg bid), hydroxycitrate at 500 mg tid and low-dose naltrexone at 5 mg at bedtime. Eight patients had primary brain tumour (n=8 including five glioblastomas) four patients had multiple brain metastases.

Results and Discussion: The combination of conventional and metabolic treatment was well tolerated. Four out of five patients with gliobastoma are still alive and well. The longest follow-up is 7 years.The four patients with disease widely metastatic to the brain have experienced long-term survival. A randomized clinical trial of metabolic treatment associated with conventional treatment is warranted.

The conclusion of the paper states:

To our knowledge, this is the first attempt to treat cancer using a combination of molecules targeting abnormal cancer metabolism. None of these patients experienced major side effects of metabolic treatment. At this stage of development, not a single case proves the efficacy of treatment. But at the time of writing, most patients were alive and well several months after having been sent home to await their death. Several months of life without symptoms strongly suggests that targeting cancer metabolism may be a reasonable option in therapy of advanced brain cancer. The role of metabolic treatment and its association with existing therapy remains to be explored in well-conducted trials.

The end of cancer?

It’s obviously too soon to say whether this new treatment for cancer will be so much of a success that the treatment becomes widely accepted and used. Apparently, Dr. Schwartz is the only oncologist in the world who is using it. His new book is “Cancer: Un Traitement Simple et Non Toxique.”

The number of cancers is increasing and, despite what we hear about medical progress, mortality has not dropped since 1960 , especially for tumors of the pancreas, lungs, liver, brain …

And if, instead of merely seeking to destroy cancer cells with aggressive treatments, they were also rendered functional again? This approach can improve the effectiveness of chemotherapy and the survival of patients.

This is the conviction of Dr. Laurent Schwartz, shared by many scientists around the world. This brilliant physician and researcher in cancer has spent his career gathering evidence that the mechanisms that cause cells to multiply in an anarchic way are essentially related to a sugar burning problem .

In this book written for patients and caregivers, he proposes to normalize the metabolism of cancer cells by a combination of non-toxic and inexpensive foods and supplements, or even a diet low in carbohydrates.

This metabolic treatment has already benefited many patients.

I can only say that if I had cancer, I would definitely seek out the expertise of Laurent Schwartz. He appears to be little known in the U.S., but his latest book will be translated into English and published here. It’s also being translated into Spanish and Italian.

 

Dr. Laurent Schwartz

While Dr. Schwartz has patented Metabloc, the fact that it’s comprised of two OTC supplements means it’s cheap and that huge pharmaceutical industry profits can’t be made on this treatment. That’s an obstacle to it becoming more widely adopted, since cancer treatment is big business

More Muscle Gains and Fat Loss on a Ketogenic Diet

What happens when you combine weight lifting with a very low carbohydrate ketogenic diet(VLCKD)? You get greater muscle gains and more fat loss than when compared to a conventional diet.

The study looked at a group of “college aged resistance trained men”, and put them on either a conventional Western diet or a VLCKD.

The conventional diet was 55% carbohydrate, 25% fat, and 20% protein, similar to what lots of people eat, though a bit higher in protein, a bit lower in fat.

The low-carb diet was 5% carbohydrate, 75% fat, and 20% protein.

Note that protein, the main macronutrient responsible for muscle growth, was the same in both groups. Both groups did resistance training three times a week for 11 weeks.

The very low carbohydrate group gained twice as much muscle as the conventional group, 4.3 kg vs 2.2 kg.

The very low carbohydrate group lost 50% more fat than the conventional group, -2.2 kg vs -1.5 kg.

It should be noted that this is from a “poster presentation” at a conference, and as such has not been peer-reviewed.

What could be going on here? The extra fat loss was not a surprise to me. Low-carbohydrate diets have a much better record at fat loss than do conventional diets. However, this was not a weight-loss trial, and presumably the participants ate as much as they wanted.

How ketogenic diets could increase muscle gains

There are several ways that muscle gains could be greater when a ketogenic diet is combined with weight training.

  1. Adrenergic stimulation. Lower blood glucose (sugar) stimulates adrenaline release, which inhibits muscle protein breakdown. Although this doesn’t directly relate to gains, the breakdown of muscle is a normal, daily occurrence in healthy people, for instance with overnight fasting. Inhibiting this could mean greater gains.
  2. Ketone bodies produced by the VLCKD inhibit muscle breakdown. However, carbohydrate ingestion does this also, so perhaps this aspect is a wash.
  3. Growth hormone. Lower blood glucose means an increase in growth hormone. As carbohydrate does not increase growth hormone, this could be a major factor in better gains and fat loss.
  4. Dietary protein. Generally, people ingest more protein on a low-carb diet, resulting in increased muscle mass. However, the protein consumption here was the same in both groups.

Most bodybuilders will tell you that you need carbohydrates to build muscle, or that it’s more effective with carbohydrates, but there are several reasons for thinking that is not the case

Protein alone and not carbohydrate is responsible for muscle growth and, once the metabolism is adapted to burning fat, intense exercise can be performed on a low-carb diet.

One reason for thinking that carbohydrates make for better gains, and this may be a real consideration, is that people often spontaneously decrease calorie intake on a very low-carbohydrate diet. This may account for much of this diet’s efficacy in fat loss. But if you’re looking for those gains, you need to eat enough, and it could be that many low-carb eaters do not.

But it seems for most people a VLCKD could be just the ticket for muscle gains and fat loss when combined with regular resistance training.

.

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:

low-carb-food-list

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.

Different Intermittent Fasting Protocols explained

Yes, you’ve heard of it, but have you experimented with an Intermittent Fasting Protocol to see how many pounds of body fat you can melt away? Here’s several to choose from, guided by doctors who walk their talk. And if none are for you, there’s always soups and smoothies.  Watch the videos!

Choose your Intermittent Fasting protocol and get lean!

[photo credit: PrecisionNutrition.com]

 

“Hi, My Name is John. And I Haven’t Eaten in 24 Hours.”

Actually, my name is Joe, not John, and I just ate bagels and lox an hour ago, which is now a lump lying in my stomach because I’m not used to eating that much bread stuff. That said, it’s John, not Joe, who’s the subject of this article, the first part anyway.

“Hi, my name is John…” is how Dr. John Berardi of Precision Nutrition fame began his detailed and informative guide, Experiments With Intermittent Fasting, which chronicles his experimentation with an eating regimen that shortens your feeding window, can melt away body fat and help you live healthier, if not longer.

I’m going to summarize John Berardi approach with, and benefits thereby derived by his experiment with Intermittent Fasting (IF). Then I’ll review the various IF methods you can try. Lastly, should no Intermittent Fasting protocol in any form be your thing, there’s always soups and smoothies – I’ll tell you why they can do lots to improve your overall nutrition and get you leaner.

In this article, you’ll discover:

  • How a guy already lean at 10% body fat used IF to drop it to 4%;
  • The three IF protocols most favored by Dr. Berardi;
  • Tips, strategies and outlines of an Intermittent Fasting protocol you can start right away;
  • A list of various intermittent fasts, time-restricted feeding and periodic fasting you can try to get lean and healthy fast;
  • Videos of Dr. Michael Mosley explaining his 5:2 Intermittent Fasting protocol; and
  • A video of Dr. Michael Greger showing the studies that indicate why soups and smoothies might be just good enough if you just don’t want to experience hunger.

Let’s dive in…

 

Your 10-Minute Intermittent Fasting Primer

Curious but only have 10 minutes to get to the gist of what the heck this Intermittent Fasting thing is all about?

Well, thankfully, Dr. Berardi’s got you covered. What follows in this section is his three favorite IF protocols and his key takeaways.  Perhaps one of this three favorite Intermittent Fasting protocols will become yours.

Dr. Berardi’s Approach

There are many different kinds of IF protocols, so Dr. Berardi tested six different methods over a six month period. He carefully took extensive notes on everything from scale weight, body-fat percentage, and blood/hormonal markers, to lifestyle markers like energy levels and cognitive thoughts.

What Happened To Him?

Before I tell what happened to him, know that Dr. Berardi was anything but fat and out of shape before he began his IF experiment. At the start of it, he was 10% body fat at 190 pounds. And yet, he got leaner — over the course of six months, he dropped twenty pounds of weight, from 190 pounds to 170 pounds, and reduced his body fat from 10% to 4% while maintaining most of his lean muscle mass.

Moreover, he found three IF strategies he could follow indefinitely with little effort; in fact, more easily and time-consuming than the “traditional” dieting about which he is a renowned expert.

Dr. Berardi’s Three Favorite IF Protocols

1. The Trial Fast

This is a fast whereby you simply go 24 hours without food.

The idea is to intentionally experience hunger, to get familiar with it, to learn that hunger won’t kill you.

Do this fast by choosing any 24-hour period during which you don’t eat. Dr. Berardi suggests this approach to make this experiment beneficial to you:

10 PM Saturday:

  • Eat your last meal of the day

    Choose your Intermittent Fasting protocol and get lean like Dr. Berardi

    Dr. John Berardi

  • Drink 500 mL (2 cups) of water

10 AM Sunday:

  • Drink 1 L (4 cups) of water + 1 serving greens powder
  • Drink 250 mL (1 cup) of green tea
  • Take 5 grams BCAA (branched chain amino acids) powder (or take 5 capsules)

3 PM Sunday:

  • Drink 1 L (4 cups) of water + 1 serving greens powder
  • Drink 250 mL (1 cup) green tea
  • Take 5 grams BCAA (branched chain amino acids) powder (or take 5 capsules)

10 PM Sunday:

  • Eat a small snack before bed
  • Drink 500 mL (2 cups) of water

Monday:

  • Eat normally

Tips and Strategies for the Trial Fast:

  • The tea, greens, and BCAAs aren’t essential to fasting, but they’ll probably make it easier.
  • Drinking water helps to mitigate feelings of hunger. I’ve found that mixing a teaspoon of organic apple cider vinegar with eight ounces of pure water makes drinking lots of water more palatable.
  • Be aware of your body cues. Feeling stressed out or “upset” during your fast? Relax. Take a few deep breaths, and pay close attention — this is what hunger can feel like. You don’t have to react to it by running to the fridge. The more familiar you get with the hunger sensation, the more manageable it will become.
  • Have healthy food (lean meats, veggies, etc.) in the house and ready to go when you “break” the fast on Sunday night with a small meal. Perhaps a tablespoon of almond butter and some celery is a good way to start eating again. Be mindful of eating slowly.

2. The Periodic Fast

As the name suggests, you fast periodically – eat sometimes, fast other times. The reason to do this is to practice hunger management and experience more of the potential health and fat loss benefits of intermittent fasting.

So while you should still eat well (high protein, lots of veggies, a balance of fats, and a moderate intake of minimally processed carbohydrates), you’d periodically take a full day to fast (just like the Trial Fast).

Do this once a week. More than that might be problematic for all but the committed, as Dr. Berardi explains here.

The Periodic Fast is flexible. Choose whichever 24 hours you want:

  • From breakfast to breakfast — Eat breakfast on Monday, and don’t eat again until breakfast on Tuesday.
  • Dinner to dinner — Eat dinner on Wednesday, and don’t eat again until dinner on Thursday.

To do it, follow the rules above from the “Trial Fast”.

Tips and Strategies:

Perhaps a good time to do the Periodic Fast is when traveling, a time when quality food may be scarce. Or if travel stresses you, don’t add to it by doing IF, but instead pick the least stressful day in your week or month.

3. The Daily Fast

The Daily Fast is an 8-hour feeding period followed by a 16-hour fast. It’s very effective at getting lean, lean, lean and is the one I regularly practice.

This Intermittent Fasting protocol is best for people who are already fit, have plenty of experience eating healthily and want to be leaner than the average bear.

Know this:

  • The Daily Fast will typically be harder to adhere to for men over 15% body fat and women over 22% body fat, which frankly is most of us.
  • Men generally respond best to the 16-hour fast, 8-hour eating split .
  • Women seem to need a longer eating window and shorter fast, so might try a 14-hour fast with an 10-hour eating window, or a more relaxed approach.
  • This is not for pregnant women, people who have or have had eating disorders, and people simply looking to be healthy and fit with no particular desire to be unusually lean.

The Daily Fast is outlined in more detail in here, but here’s the essence of this 8-hour feeding/16-hour fasting period:

  • High protein & vegetable intake: During the 8-hour eating window, eat a lot of protein (lean meat, poultry, fish) and vegetables (think green growing things). Err on the side of eating too much of these foods.
  • Fasted training: Do intense resistance training 3 times per week, right before you eat your first meal. In other words, you’ll be training on an empty stomach. (Check out this selection of exercise routines.)
  • Carb cycling: On training days, add carbs (quinoa, rice, whole grain bread, fruit, etc.) to your base diet of protein and veggies.
  • Nutrient timing: On training days, eat as much of your food as soon after training as possible. Your biggest meal should come right after your workout.

Most people who follow this protocol fast from 9 PM until 1PM the next day and exercise around noon while consuming 10 grams of BCAAs (branched chain amino acids) during training, says Dr. Berardi.

(In my case, I fast from 8 PM till 1 PM the next day, usually exercise later in the afternoon and after I’ve eaten my first meal at 1 PM, and I’m light on the BCAAs. Might this be why my six pack remains a steadfast fantasy?)

After exercising, eat two to three large meals before 9 PM, with your biggest meal coming right after exercise, as mentioned.

Of course, many people can’t exit work or other commitments in the middle of the day to work out. As mentioned, this typically includes me. If this is your situation, you won’t have the benefit of exercising in a fasted state, but as long as you follow the rest of the protocol (and in this case exercising later in the day), you’ll get lean.

Sample Single-Day Schedule:

8:00 AM – Wake up, drink 500 mL (2 cups) water

9:00 AM – Drink 1 L (4 cups) water with 1 serving greens+, 250 mL (1 cup) green tea

11:00 AM – 250 mL (1 cup) green tea

12:00 PM – Workout session with 10 g BCAA during session

1:30 PM – Eat first meal, largest of the day

4:30 PM – Eat second meal, moderate sized meal

8:30 PM – Eat third meal, moderate sized meal

Tips and Strategies:

  • Don’t fool yourself into thinking you can just skip breakfast and get shredded; what makes it work is combination of all the principles at play, including the food selection, fasted training and nutrient timing. This is an advanced strategy, not a magic bullet.
  • Even if you think you can do the Daily Fast, consider choosing the Trial or Periodic Fast first.
  • If you find eating this way is too strict, try a) extending the eating window from 8 hours to 9 or even 10 hours, or b) turning your hardest training day into an “eat what you want” day to relax things a little. Or try two “eat what you want” days. These aren’t rules, just guidelines; better to follow a more relaxed plan than abandon a stricter one.
Dr. Berardi’s “Big” Takeaways

He encourages anyone experimenting with IF to remember these four things:

  1. Trial fasting is a great way to practice managing hunger. This is an essential skill for anyone who wants to get in shape and stay healthy and fit.
  2. More regular fasting isn’t objectively better for losing body fat. While Dr. Berardi’s experiments worked quite well, the intermittent fasting approach (bigger meals, less frequently) didn’t produce better fat loss than a more conventional diet approach (smaller meals, more frequently) might have.
  3. More regular fasting did make it easier to maintain a lower body fat percentage. Intermittent fasting isn’t easy, but Dr, Berardi found this approach made it easier to maintain a low body weight and a very low body fat percentage versus. more conventional diets.
  4. Intermittent fasting can work but it’s not for everyone, nor does it need to be. In the end, IF is just one among may ways for improving health, performance, and body composition. To wit, check out my articles on diet and nutrition.

In case you’re wondering if IF really works to improve lean body composition, know that the title picture for this article is the “before and after” pics of Dr. Berardi’s clients, which I’ll copy again so you don’t have to bother scrolling up:

Choose an Intermittent Fasting protocol and get these results for yourself

Impressive, I say, so let’s stay with this IF thing for just a few beats more.

 

A Quick Review of Intermittent Fasting Protocols

Yes, grasshopper, there are more than the three Intermittent Fasting protocols profiled above that you may choose from.

Ayesha Muttucumaru from Get The Gloss wrote a good review of several fasting plans that reduce your feeding window; meaning, the time period in which you feed yourself.

In her article, From 5:2 to 16:8Which Fasting Plans Do What?, Ms. Muttucumaru segments various fasts into three categories:

  • Intermittent Fasts,
  • Time-restricted Feeding, and
  • Periodic Fasting

She points out something I’ve written quite a bit about in this site regarding the health benefits derived from fasting and other caloric-restriction protocols.

Fasting increases fat loss, specifically of visceral fat – the dangerous type that clings to our middles and that has been linked to increased risk of type 2 diabetes, heart disease, certain cancers and Alzheimer’s. Fasting has also been associated with improved blood pressure and insulin sensitivity, better gut health, lower cholesterol and increased cognitive function as well as supporting an important repair process in the body called autophagy, which only happens when in a fasted state. Think of autophagy as a ‘time-out’ or the ‘repair mode’ that allows the body the chance to rid itself of a buildup of cellular debris, too much of which can increase the risk of age-related diseases such as arthritis and type 2 diabetes.

Another point Ayesha Muttucumaru makes is that the benefits derived from fasting are related to its duration. For example, to benefit by cellular autophagy, you need to fast for a minimum of 12 to 14 hours; whereas it only takes five hours to improve your gut microbes and insulin sensitivity.

Without further adieu, check out these various fasting protocols to see which might resonate with you.

1. Intermittent Fasting

Fasting only on certain days of the week.

The plans:

The 5:2 diet: aka The Fast Diet, the best known of the fasting methods made famous by Dr Michael Mosley. (See his videos below.) It’s five days of regular eating and two ‘fast’ days of 800 calories,  and has been associated with improved DNA repair and brain function, plus an increase in fat loss as demonstrated in a 2011 Manchester University study. Dr Mosley lost 20lb in 12 weeks and saw his blood sugar and cholesterol levels returned to normal after being pre-diabetic and suffering from high cholesterol.

The 1:1 diet: aka Alternate Day Fasting. Published as The Every Other Day Diet by Dr Krista Varady and Bill Gottlieb, it involves eating 500 calories every other day. You’re able to eat what you like during the fast, provided calorie intake is limited on the fast days.

The 6:1 diet: Made famous by Coldplay’s Chris Martin, this diet involves completely fasting for one day and eating normally for the rest of the week. Sounds simple enough.  Drink lots of water on the fast day.

2. Time-restricted feeding

This is about reducing your “feeding widow” per 24 hour period. You can reduce your meal frequency from three per day to two, or just one — or eat within a “window” of time, often eight hours.  As mentioned above, my feeding widow is from 1 PM to 8 PM.

The plans:

The 2 Meal Day: Created by personal trainer and online health coach Max Lowry, this plan involves skipping one meal (either breakfast or dinner) and extending your night fast (that is, while you’re sleeping) to around 16 hours. Read more about the 2 Meal Day here.

The Warrior Diet: Published by Ori Hofmekler in 2001, this approach involves one meal per day in the evening, supposedly emulating warriors of olden times who only ate what they killed and did so at night (I guess). Its emphasis is placed on whole foods and whole grains.

How to Lose Weight Well: Published by Dr. Xand van Tulleken and Georgina Davies, this evening meal focused plan can be adapted to best suit your lifestyle and objectives. To help achieve faster weight loss and the benefits of intermittent fasting, it recommends one 800-calorie meal a day or if that’s too infrequent, two healthy meals a day of 1,200 calories or three meals of 1,500 calories.

Metabolic Balance: Founded by Dr. Wolf Funfack, this diet plan claims to aid weight loss and improve sleep, digestion and energy levels by advocating a five-hour fast in between meals over a three-month time period.

16:8: aka The 8-Hour Diet. Published by Men’s Health Editor David Zinczenko and Peter Moore, this plan comprises of 16 hours fasting and an eight-hour “feeding window”.

3. Periodic fasting

Fasting for a few days or weeks at a time.

The plans:

Fast Mimicking diet: Created by Professor of gerontology and biological sciences at USC, Valter Longo, it comprises of meal boxes designed to be used for 5 days every month. Using natural, gluten-free and plant-based ingredients, meals are low-protein, low-carb and high in good fat, with 770 to 1,100 calories aimed for per day.

The Bodhimaya Method: Founded by brothers Daniel and Cornelius O’Shaugnessy, the method combines the format of the 16:8 plan (outlined above) with a fast day food plan portion ratio of 1:7:2 (carbs to veg to protein). Find out more about The Bodhimaya Method here.

Buchinger Wilhelmi: A selection of medically supervised fasts starting from a minimum of four days (10, 14 and 21 day programs are also available). Fast days feature small amounts of food (of around 250 calories) and a carefully regulated exercise plan to prevent muscle loss.

8-weeks: aka The Blood Sugar Diet. Created by Dr Michael Mosley to prevent and reverse type 2 diabetes, this plan involves eating three small meals totaling 800 calories per day for eight weeks.

As cited above, Dr. Mosely is also the creator of the the 5:2 Diet described by his book, The Fast Diet. Watch this self-described former “skinnyfat” BBC science journalist, executive producer and medical doctor describe his motivation behind his work and how it transformed his life:

 

(Go here to learn about High Intensity Interval Training, which Dr. Mosely suggests be incorporated with his 5:2 diet.)

If intrigued by the video above, watch this to-the-point video by Kevin Partner, which he calls The Fast Guide to the Fast Diet – for people too lazy to read the book:

 

 

Soups and Smoothies

Perhaps you’ve just scrolled past every Intermittent Fasting protocol to get here, because there’s just no way in hell (cause it would be hell) to fast for longer than, say, from breakfast to lunch.

Certainly, you don’t have to fast to whittle away some body fat. What you do have to do is get into a caloric deficit, which basically means to consume fewer calories than you do now.

One way to cope with fewer calories than you’re accustomed to is to make them satiate you more than they otherwise would by employing some tricks. That’s where soups and smoothies enter the picture.

I’ll get right to the bottom line here:

  • Smoothies offer an opportunity to quickly create a very nutritious meal from ingredients you might not ordinarily eat (like kale and spinach), and be as satiating as the meal it replaces — if they’re drunk slowly.
  • Soup will satiate you more that the very same ingredients eaten whole on a plate, as opposed as blended and heated as soup.

Want to know why?

Watch nutrition expert Dr. Michael Greger take you through the experiments on this:

 

I wholeheartedly recommend that you consume more smoothies and soups.

Just make sure that your smoothies are not dominated by sweet stuff like sugary fruit — dates, bananas, papaya.  Rather, for the fruit ingredients use mainly berries with just a bit of the sugary fruits.  Then add green veggies like kale, watercress, broccoli, beets and spinach.  For protein use whey if the smoothies is to be consumed after a workout, given that whey is quickly absorbed into the bloodstream, or pea, hemp or sprout-derived protein powders.  Finally, use water, almond milk or keifer, or combinations of all three.

For soups, search the Interwebs for good soup blender recipes; meaning, get guidance for what combination of veggies ingredients, stock and herbs you can throw in a blender, heat up and slowly eat.  In my case, I often mix whatever vegetables are handy, along with some vegetable stock I get at the grocer and season to taste.  Fast, nutritious and satiating.

 

Your Takeaway

Yes, lots to digest here.

Suggest you do this:

  • Grab a friend and together look for an Intermittent Fasting protocol that does not seem overwhelming, one you feel you could do without feeling that you’ve sentenced yourself to torture, and then give it a whirl. You have a better chance getting through it with a friend, because misery loves company.
  • Start small and step up big if IF seems right for you.
  • If you’d rather poke yourself in the eye than feel hunger pangs, try adding soups and smoothies to your diet. Consume them mindfully, slowly.  And let yourself eat less for the next meal, rather than eating the usual amounts of food.

OK, then… get to it!

Taking a pill to combat aging is getting closer to reality everyday

Two fast ageing mice. The one on the left was treated with a FOXO4 peptide, which targets senescent cells and leads to hair regrowth in 10 days.

The day we pop up a pill or get a jab to stave off ageing is closer, thanks to two high profile papers just published today.

A Science paper from a team, led by David Sinclair from Harvard Medical School and the University of NSW, shows how popping a pill that raises the levels of a natural molecule called nicotinamide adenine dinucleotide (NAD+) staves off the DNA damage that leads to aging.

The other paper, published in Cell, led by Peter de Keizer’s group at Erasmus University in the Netherlands, shows how a short course of injections to kill off defunct “senescent cells” reversed kidney damage, hair loss and muscle weakness in aged mice.

Taken together, the two reports give a glimpse of how future medications might work together to forestall ageing when we are young, and delete damaged cells as we grow old. “This is what we in the field are planning”, says Sinclair.

Sinclair has been searching for factors that might slow the clock of ageing for decades. His group stumbled upon the remarkable effects of NAD+ in the course of studying powerful anti-ageing molecules known as sirtuins, a family of seven proteins that mastermind a suite of anti-ageing mechanisms, including protecting DNA and proteins.

Resveratrol, a compound found in red wine, stimulates their activity. But back in 2000, Sinclair’s then boss Lenny Guarente at MIT discovered a far more powerful activator of sirtuins – NAD+. It was a big surprise.

“It would have to be the most boring molecule in the world”, notes Sinclair.

It was regarded as so common and boring that no-one thought it could play a role in something as profound as tweaking the ageing clock. But Sinclair found that NAD+ levels decline with age.

“By the time you’re 50, the levels are halved,” he notes.

And in 2013, his group showed that raising NAD+ levels in old mice by giving them Nicotinamide Mononucleotide  restored the performance of their cellular power plants, mitochondria.

One of the key findings of the Science paper is identifying the mechanism by which NAD+ improves the ability to repair DNA. It acts like a basketball defence, staying on the back of a troublesome protein called DBC1 to keep it away from the key player PARP1– a protein that repairs DNA.

When NAD+ levels fall, DBC1 tackles PARP1. End result: DNA damage goes unrepaired and the cell ‘ages’.

“We ‘ve discovered the reason why DNA repair declines as we get older. After 100 years that’s exciting,” says Sinclair .

His group has helped developed a compound, nicotinamide mono nucleotide (NMN), that raises NAD+ levels. As reported in the Science paper, when injected into aged mice it restored the ability of their liver cells to repair DNA damage. In young mice that had been exposed to DNA-damaging radiation, it also boosted their ability to repair it. The effects were seen within a week of the injection.

These kinds of results have impressed NASA. The organisation is looking for methods to protect its astronauts from radiation damage during their one-year trip to Mars. Last December it hosted a competition for the best method of preventing that damage. Out of 300 entries, Sinclair’s group won.

As well as astronauts, children who have undergone radiation therapy for cancer might also benefit from this treatment. According to Sinclair, clinical trials for NMN should begin in six months. While many claims have been made for NAD+ to date, and compounds are being sold to raise its levels, this will be the first clinical trial, says Sinclair.

By boosting rates of DNA repair, Sinclair’s drug holds the hope of slowing down the ageing process itself. The work from de Keizer’s lab, however, offers the hope of reversing age-related damage.

His approach stems from exploring the role of senescent cells. Until 2001, these cells were not really on the radar of researchers who study ageing. They were considered part of a protective mechanism that mothballs damaged cells, preventing them from ever multiplying into cancer cells.

The classic example of senescent cells is a mole. These pigmented skin cells have incurred DNA damage, usually triggering dangerous cancer-causing genes. To keep them out of action, the cells are shut down.

If humans lived only the 50-year lifespan they were designed for, there’d be no problem. But because we exceed our use-by date, senescent cells end up doing harm.

As Judith Campisi at the Buck Institute, California, showed in 2001, they secrete inflammatory factors that appear to age the tissues around them.

But cells have another option. They can self-destruct in a process dubbed apoptosis. It’s quick and clean, and there are no nasty compounds to deal with.

So what relegates some cells to one fate over another? That’s the question Peter de Keizer set out to solve when he did a post-doc in Campisi’s lab back in 2009.

Finding the answer didn’t take all that long. A crucial protein called p53 was known to give the order for the coup de grace. But sometimes it showed clemency, relegating the cell to senesce instead.

De Keizer used sensitive new techniques to identify that in senescent cells, it was a protein called FOXO4 that tackled p53, preventing it from giving the execution order.

The solution was to interfere with this liaison. But it’s not easy to wedge proteins apart; not something that small diffusible molecules – the kind that make great drugs – can do.

De Keizer, who admits to “being stubborn” was undaunted. He began developing a protein fragment that might act as a wedge. It resembled part of the normal FOXO4 protein, but instead of being built from normal L- amino acids it was built from D-amino acids. It proved to be a very powerful wedge.

Meanwhile other researchers were beginning to show that executing senescent cells was indeed a powerful anti-ageing strategy. For instance, a group from the Mayo Clinic last year showed that mice genetically engineered to destroy 50-70% of their senescent cells in response to a drug experienced a greater “health span”.

Compared to their peers they were more lively and showed less damage to their kidney and heart muscle. Their average lifespan was also boosted by 20%.

But humans are not likely to undergo mass genetic engineering. To achieve similar benefits requires a drug that works on its own. Now de Keizer’s peptide looks like it could be the answer.

As the paper in Cell shows, in aged mice, three injections of the peptide per week had dramatic effects. After three weeks, the aged balding mice regrew hair and showed improvements to kidney function. And while untreated aged mice could be left to flop onto the lab bench while the technician went for coffee, treated mice would scurry away.

“It’s remarkable. it’s the best result I’ve seen in age reversal,” says Sinclair of his erstwhile competitor’s paper.

Dollops of scepticism are healthy when it comes to claims of a fountain of youth – even de Keizer admits his work “sounds too good to be true”. Nevertheless some wary experts are impressed.

“It raises my optimism that in our lifetime we will see treatments that can ameliorate multiple age-related diseases”, says Campisi.

The Ketone body β-Hydroxybutyrate a key signaling metabolite in disease and aging

However, in its oxidized form (NAD+), NAD is also a cofactor for sirtuin enzymes and poly-ADP-ribose polymerase (PARP), both of which consume NAD in the course of removing acyl groups from and adding poly-ADP to proteins, respectively. Sirtuins and PARP thereby regulate cellular functions ranging from gene expression and DNA damage repair to fatty acid metabolism (133). During times of fasting, or relative scarcity of cellular energy, more NAD is in the oxidized state, and sirtuins and PARP can be more active.

NAD+, a simple energy carrier, thereby acts as a fulcrum around which many cellular processes can be regulated in response to changes in the external environment. Such signaling metabolites include acetyl-CoA (coenzyme A), another carrier of high-energy bonds that is also substrate for a widely prevalent protein posttranslational modification (lysine acetylation), and S-adenosylmethionine, which similarly is substrate for a common posttranslational modification of histones and other proteins (methylation) (43).

Independent manipulation of these signaling molecules can recapitulate, or abrogate, some of the broader biological effects of environmental changes such as fasting or dietary restriction. For example, long-term dietary restriction can prevent the onset of common age-related hearing loss in C57BL/6 mice. However, dietary restriction in mice that carry a genetic knockout of the NAD-dependent sirtuin gene SIRT3 has no such beneficial effect (121).

Inhibition of the TOR (target of rapamycin) signaling complex by rapamycin (46), activation of AMPK by metformin (81), or provision of NAD+ precursors (159) recapitulates some of the beneficial effects of dietary restriction on diseases of aging and longevity. Understanding the specific molecular actions of these signaling pathways and signaling metabolites that link changes in the environment to broad regulation of cellular functions will permit researchers to more precisely capture the therapeutic potential of metabolic or dietary changes to treat disease. It might also help explain the heterogeneous responses of individuals to such environmental changes, depending on their genetic or epigenetic capacity to generate and respond to these signaling metabolites.

Here, we review the signaling activities of the endogenous metabolite β-hydroxybutyrate (BHB). BHB is the most abundant ketone body in mammals. Ketone bodies are small molecules synthesized primarily in the liver from fats that circulate through the bloodstream during fasting, prolonged exercise, and when carbohydrates are restricted.

They are taken up by tissues in need of energy, converted first to acetyl-CoA and then to ATP. Emerging evidence, however, shows that BHB not only is a passive carrier of energy but also has a variety of signaling functions both at the cell surface and intracellularly that can affect, for example, gene expression, lipid metabolism, neuronal function, and metabolic rate. Some of these effects are direct actions of BHB itself. Some are indirect effects governed by downstream metabolites into which BHB is converted, such as acetyl-CoA. We focus this review on BHB itself, referring to ketogenic diets only when necessary for translational context.

Although ketogenic diets have been widely used both for research into the effects of ketone bodies and as therapeutics for conditions ranging from epilepsy to obesity, a ketogenic diet is a complex physiological state with many possible active components of which BHB is only one. Still, the signaling effects of BHB we summarize are likely relevant to the molecular mechanisms of interventions such as fasting, dietary restriction, and ketogenic diets. Altogether, these observations present a picture of a powerful molecule that offers both opportunities and cautions in its therapeutic application to common human diseases.

BHB: STRUCTURE AND METABOLISM 

Ketone bodies are small, lipid-derived molecules that provide energy to tissues when glucose is scarce, such as during fasting or prolonged exercise. Over 80% of the human body’s stored energy resides in the fatty acids contained in adipose tissue (7). During fasting, after muscle and liver stores of glycogen are depleted, fatty acids are mobilized from adipocytes and transported to the liver for conversion to ketone bodies. Ketone bodies are then distributed via blood circulation to metabolically active tissues, such as muscle or brain, where they are metabolized into acetyl-CoA and eventually ATP (7).

In humans, serum levels of BHB are usually in the low micromolar range but begin to rise to a few hundred micromolar after 12–16 h of fasting, reaching 1–2 mM after 2 days of fasting (13, 108) and 6–8 mM with prolonged starvation (12). Similarly, serum levels of BHB can reach 1–2 mM after 90 min of intense exercise (64). Consistent levels above 2 mM are also reached with a ketogenic diet that is almost devoid of carbohydrates (60). The term ketone bodies usually includes three molecules that are generated during ketogenesis: BHB, acetoacetate, and acetone. Most of the dynamic range in ketone body levels is in the form of BHB.

When ketogenesis is activated, such as during fasting, blood levels of BHB rise much faster than either acetoacetate or acetone (74).

Regulation of Ketone Body Metabolism 

The biochemistry of ketone body production and utilization is well understood and has been recently summarized both in the literature and in textbooks (e.g., 7, 66, 92) (Figure 1). Two points are particularly relevant to understanding the signaling activities of BHB. First, the same enzyme, β-hydroxybutyrate dehydrogenase (BDH1; EC 1.1.1.30), interconverts BHB and acetoacetate in both the final step of ketogenesis and the first step of BHB utilization.

BDH1 imparts chirality to BHB, as described below. Second, regulation of BHB synthesis is controlled via two principal mechanisms: substrate availability in the form of fatty acids and expression and activity of the enzyme HMG-CoA synthase (HMGCS2; EC 2.3.3.10). Ketogenesis occurs mostly in the liver (7), although expression of HMGCS2 may be sufficient to produce ketogenesis in other tissues (127, 158). Insulin and glucagon regulate ketogenesis primarily by modulating the availability of fatty acid substrates at the levels of mobilization from adipose tissue and importation into hepatic mitochondria (71).

HMGCS2 gene expression is regulated by insulin/glucagon via acetylation and deacetylation of the FOXA2 transcription factor (143, 144, 135). FOXA2 deacetylation is controlled in part by the NAD-responsive enzyme SIRT1 (135). HMGCS2 gene expression is also regulated indirectly by the target of rapamycin complex mTORC1; mTORC1 inhibition is required for the activation of peroxisome proliferator-activated receptor alpha (PPARα) and fibroblast growth factor 21 (FGF21), both of which are required to induce ketogenesis (3, 4, 49, 116).

The activity of HMGCS2 is regulated posttranslationally by succinylation and acetylation, regulated by the mitochondrial desuccinylase SIRT5 (104) and deacetylase SIRT3 (117), respectively. Altogether, this network of regulation centered on HMGCS2, involving substrate availability, transcriptional control, and posttranslational modification, lends tight temporal and spatial precision to BHB synthesis.

BHB Transport 

BHB transport is relatively less well understood than its synthesis and utilization. As a small, polar molecule, BHB is readily soluble in water and blood (7). Several monocarboxylic acid transporters, including MCT1 and MCT2, carry BHB across the blood-brain barrier (99), and their expression can regulate brain BHB uptake (5). The monocarboxylate transporter SLC16A6 may be the key transporter for exporting BHB from the liver (52), but the putative transporters that facilitate the uptake of BHB into target tissues or its intracellular movement remain to be identified.

BHB Chirality 

BHB is a chiral molecule at the 3′ hydroxyl group, an important feature in consideration of its signaling activities and possible therapeutic applications. There are two enantiomers, R/D and S/L. R-BHB is the normal product of human and mouse metabolism. This chiral specificity is introduced by BDH1, which catalyzes the final step in BHB synthesis by reducing the nonchiral 3′ carbonyl group of acetoacetate to the chiral 3′ hydroxyl group of BHB.

BDH1 is also required for the utilization of BHB, by catalyzing the same reaction in reverse. As a result of the chiral specificity of BDH, only R-BHB is produced by normal metabolism and only R-BHB can be readily catabolized into acetyl-CoA and ATP. Fasting, exercise, caloric restriction, ketogenic diet, and any other state that results in endogenous production of BHB will produce only R-BHB.

S-BHB itself is not a normal product of human metabolism. However, S-BHB-CoA is a transient intermediate in the final round of β-oxidation of fatty acids. Under normal circumstances, it should not persist long enough to leave the mitochondrion or circulate in the blood. Experiments involving infusions of labeled R-BHB, S-BHB, or mixtures thereof into rats or pigs found that S-BHB is converted mostly to R-BHB (74); the molecular pathway for this is not known, but it may occur through conversion of S-BHB to acetyl-CoA and then production of R-BHB from acetyl-CoA.

At least some of the S-BHB is eventually converted to CO2, presumably also after being metabolized to acetyl-CoA. S-BHB is metabolized much more slowly than R-BHB is (138), so that infusion of the same amount of S-BHB may result in higher and more sustained blood levels of S-BHB compared with a similar infusion of R-BHB (19). We discuss the chiral specificity of BHB signaling activities below.

DIRECT SIGNALING ACTIONS OF BHB 

Several direct signaling actions of BHB have been described, including binding to cell-surface receptors, competitive inhibition of enzymes, as a substrate for protein posttranslational modification, and modulation of ion channel activity (Figure 2).

Schematic of direct and indirect signaling functions of the ketone body BHB. Indirect signaling functions require catabolism to other molecules, whereas direct signaling functions are actions of BHB itself. The major downstream effects of signaling functions are noted. Abbreviations: BHB, β-hydroxybutyrate; CoA, coenzyme A; FFAR3, free fatty acid receptor 3; GABA, γ-amino-butyric acid; HDAC, histone deacetylase; HCAR2, hydroxycarboxylic acid receptor 2; NAD, nicotinamide adenine dinucleotide; VGLUT, vesicular glutamate transporter.

BHB Inhibits Class I Histone Deacetylases 

BHB inhibits class I histone deacetylases (HDACs) (41), a family of proteins that have important roles in regulating gene expression by deacetylating lysine residues on histone and nonhistone proteins (reviewed in References 85, 90, and 150). Class I HDACs (e.g., HDAC1, HDAC2, HDAC3, and HDAC8) are small, mostly nuclear proteins that consist primarily of a deacetylase domain, and are usually found in large regulatory multiprotein complexes. Histone hyperacetylation is generally associated with activation of gene expression; so as a broad generality, class I HDAC activity suppresses gene expression. Many nonhistone proteins, including NF-κB, TP53, MYC, and MYOD1, among others (34), are also subject to HDAC-mediated deacetylation and regulation.

BHB inhibits HDAC1, HDAC3, and HDAC4 (classes I and IIa) in vitro with an IC50 of 2– 5 mM. BHB treatment of certain cultured cells induces dose-dependent histone hyperacetylation, particularly at histone H3 lysines 9 and 14 (118). Fasting, which increases plasma BHB levels, is associated with increases in histone acetylation in a number of mouse tissues by Western blot analysis (118), as well as in the liver by quantitative mass spectrometry (147). BHB can also increase histone H3 acetylation in vitro in macrophages (153) and neurons (120).

Treating mice with BHB via an osmotic pump increases histone hyperacetylation, particularly in the kidney, and causes specific changes in gene expression, including induction of forkhead box O3 (Foxo3a), the mammalian ortholog of the stress-responsive transcriptional factor DAF16 that regulates life span in C. elegans (59). Induction of Foxo3a appears to be a direct effect of HDAC inhibition, as HDAC1 and HDAC2 are found on its promoter, knockdown of both relieves HDAC-mediated Foxo3a repression, and BHB causes hyperacetylation of histones at the Foxo3a promoter that results in increased Foxo3a expression (118).

BHB regulates Bdnf (brain derived neurotrophic factor) expression in the mouse brain by a similar mechanism after exercise. Exercise increases BHB levels and Bdnf expression in the hippocampus, and Bdnf expression is increased by treating hippocampal slices with BHB or by infusing BHB intraventricularly. Treating primary neurons with BHB increases histone H3 acetylation, reduces Bdnf promoter occupancy by HDAC2 and HDAC3, and increases Bdnf expression (120).

Inhibition of class I HDACs appears to be a direct effect of BHB. Enzymatic inhibition in vitro is observed using immunopurified FLAG-tagged HDAC proteins with a synthetic peptide substrate, which should provide no opportunity for BHB metabolism or secondary effects (118). Competitive inhibition of the catalytic site is the likely mechanism.

Crystal structures of the human class I HDAC8 bound to several hydroxamic acid inhibitors (122, 130), as well as modeling of other inhibitors, show that a carbonic or hydroxamic acid group of an inhibitor is commonly bound to the catalytic zinc at the bottom of the hydrophobic active site channel of the HDAC (137). BHB is structurally similar to the canonical HDAC inhibitor butyrate.

Butyrate demonstrates the kinetics of a competitive inhibitor (115), suggesting that its carboxylic acid group might chelate the catalytic zinc in a manner similar to that of other acidic moieties on HDAC inhibitors. The structures of butyrate, BHB, and acetoacetate differ only in the oxidation state of the 3′ carbon. Increasing oxidation may be a barrier to binding within the hydrophobic channel of the HDAC active site, and as expected, the IC50 of the three compounds for HDAC1 increases with the oxidation state (115, 118).

β-Hydroxybutyrylation of Proteins 

In addition to inhibiting enzymes involved in the regulation of protein posttranslational modifications such as HDACs, BHB can itself modify proteins at the posttranslational level. Lysine β-hydroxybutyrylation [K(BHB)] was detected via mass spectrometry as a histone modification in yeast, fly, mouse, and human cells (147). Western blot analysis detected that histone K(BHB) increases in human cells in proportion to treatment with exogenous BHB, and increases in mouse liver in proportion to increases in plasma BHB levels with either fasting of normal mice or induction of diabetic ketoacidosis with streptozotocin. At least 40 BHB-modified histone lysine sites were detected in human cells or mouse liver by mass spectrometry, including sites critical for transcriptional regulation such as H3K9. Fasting increased the relative abundance of K(BHB) at these sites by up to 40-fold (147).

Chromatin immunoprecipitation (ChIP) with specific antibodies also revealed that K(BHB) of H3K9 is preferentially associated with the promoters of actively transcribed genes (147). A comparison of ChIP data and RNAseq expression data from fasted mouse liver found a strong correlation between genes with the greatest increase in expression and genes with the greatest increase in K(BHB) at the promoter.

H3K9 K(BHB) is correlated with other activation markers, such as acetylated H3K9 and trimethylated H3K4, but has an association with gene activation independent of these other two markers, suggesting an independent function (147). What that function is remains to be determined. The scope of β-hydroxybutyrylation as a posttranslational modification is not clear: It is not known whether nonhistone proteins are modified, or whether K(BHB) exists in organs other than the liver.

It is also not known whether any enzymes catalyze the addition or removal of K(BHB), providing opportunities for specific targeting and regulation. The wide diversity of lysine acylations removed by the various mammalian sirtuins (1) hints that hydroxybutyrylation might be removed by a specific sirtuin. In all, histone K(BHB) may be the nexus of an important new network of gene regulatory activity associated with fasting and other conditions linked to increase BHB production.

Cell Surface Receptors: HCAR2 and FFAR3 

BHB binds to at least two cell surface G-protein-coupled receptors (GPCRs), HCAR2 (hydroxycarboxylic acid receptor 2) and FFAR3 (free fatty acid receptor 3). These are among several GPCRs with fatty acid ligands that have important roles in metabolism and metabolic disease (9, 70). HCAR2 (also known as HCA2, PUMA-G, and Gpr109) is a Gi/o-coupled GPCR that was first identified as a nicotinic acid receptor (129). It was later shown to bind and be activated by BHB, with an EC50 of 0.7 mM (124).

HCAR2 activation reduces lipolysis in adipocytes (95, 124), which might perhaps represent a feedback mechanism to regulate the availability of the fatty acid precursors of ketone body metabolism. However, elevated levels of free fatty acids in plasma from dysregulated adipocytes are also thought to contribute to insulin resistance through a variety of mechanisms, including proinflammatory cytokines, oxidative stress, and endoplasmic reticulum stress (10).

Pharmacological agonists of HCAR2 reduce both plasma free fatty acids and plasma glucose levels in humans with type 2 diabetes (21). Infusion of BHB has long been observed to reduce the concentrations of nonesterified fatty acids in plasma, even when insulin levels (which also regulate fatty acid release from adipocytes) are held constant (108). In retrospect, this reduction of free fatty acids in plasma may be due to HCAR2 activation.

HCAR2 is also expressed in a variety of other cell types, including immune cells, microglia, and colonic epithelial cells, in which its activation induces anti-inflammatory effects (38). In the central nervous system, this is associated with neuroprotection mediated in part by the activation of IP3dependent intracellular calcium release, alterations in prostaglandin production, and downstream inhibition of NF-κB activation (reviewed in Reference 96).

More specifically, HCAR activates a neuroprotective subset of macrophages via the production of PGD2 by COX1 (103). The neuroprotective effect of ketogenic diet in a mouse stroke model is abrogated in Hcar2 knockout mice, and it appears that activation of HCAR2 on brain-infiltrating macrophages/monocytes is crucial to this neuroprotection (103). Finally, HCAR2 activation in neurons can potentiate glutaminergic signaling, which in one particular region of the brain helps regulate blood pressure and heart rate (106).

Activation of HCAR2 in the gut epithelium by short-chain fatty acids produced by bacterial fermentation of dietary fiber activates the NLRP3 inflammasome and maintains gut membrane integrity (79). The mechanism for inflammasome activation appears to be potassium efflux stimulated by intracellular calcium release. Inflammasome activation is beneficial in mouse models of colitis, and appears to explain the benefit of a high-fiber diet in these conditions, but stands in interesting contrast to the role of BHB in suppressing NLRP3 inflammasome activation described below.

BHB is also a ligand for FFAR3 (also known as GPR41). FFAR3 is another Gi/o-proteincoupled receptor that is highly expressed in sympathetic ganglions (62) throughout the body of mice (94). Ffar3 knockout mice have reduced basal oxygen consumption and body temperature but are then insensitive to the usual further sympathetic depression seen during prolonged fasting (62).

Antagonism of FFAR3 by BHB suppresses sympathetic tone and heart rate and may be responsible for the sympathetic depression commonly seen during fasting (62). However, an electrophysiological study in rats later reported that BHB in fact acts as an agonist of FFAR3 (145), which regulates voltage-dependent calcium channels. In fact, other endogenous short-chain fatty acids, including acetate, butyrate, and propionate, have been reported as agonists of FFAR3 (11). Further work is needed to confirm the activity of BHB on FFAR3, but a substantial literature is emerging on other biological functions of FFAR3 relevant to human health.

One such function is glucose homeostasis. Deletion of Ffar3 (together with Ffar2) in mouse pancreatic β cells improves insulin secretion and glycemic control on a high-fat diet (125). Genetic gainand loss-of-function neurotransmitter models of Ffar3 alone similarly show that lower FFAR3 signaling increases insulin secretion from
pancreatic β islet cells (132). An alternative route by which FFAR3 affects glucose metabolism
is via activation by gut-derived propionate in the periportal afferent neural system. This feeds

into a brain-gut signaling circuit that induces intestinal gluconeogenesis, with beneficial effects on glucose and energy homeostasis (17).

FFAR3 also regulates inflammation. Activation of FFAR3 by gut-derived propionate helps rescue allergic airway inflammation in mice by reducing the capacity of lung-resident dendritic cells to promote TH2 -mediated inflammation (128). Similarly, activation of FFAR2 and FFAR3 by acetate suppresses the expression of inflammatory cytokines in human monocytes, which suggests FFAR2/3 agonists may help ameliorate inflammatory bowel diseases (2). As these examples illustrate, whether activation or inhibition of FFAR3 is beneficial to health may be highly dependent on the specific tissue and disease contexts.

Membrane Channel and Transporter Regulation 

Two threads of indirect evidence imply a role for BHB in the modulation of potassium flux across the plasma membrane. Inhibition of potassium efflux is the suggested mechanism by which BHB inhibits activation of the NLRP3 inflammasome (153). An extensive series of careful in vitro experiments excluded other known direct and indirect signaling functions of BHB, including HDACs, HCAR2, and metabolism to acetyl-CoA. The event most upstream of inflammasome activation that is affected by BHB treatment is prevention of the decline in intracellular potassium in response to inflammasome-activating signals (153). This effect is the reverse of HCAR2 activation stimulating potassium efflux.

Application of acetoacetate or R-BHB to brain slices reduces the rate of firing from γ-aminobutyric acid (GABA)ergic neurons, and pharmacological inhibition of ATP-sensitive K (KATP) channels or knockout of the Kir6.2 subunit abrogates the effect (78). Although this might suggest that BHB could increase K channel opening, several lines of evidence indicate that the change in KATP activity is more likely an indirect effect of the absence of glucose on local intracellular ATP concentrations.

The nonmetabolized enantiomer S-BHB did not have a similar effect on neuron firing (78); a later study showed that the change in KATP channel opening is due to reduced glycolysis in the presence of BHB (76) and that providing sufficient BHB and oxygen to maintain normal cellular ATP production can prevent the change in KATP activity (77).

BHB appears to have a direct regulatory effect on the neuronal vesicular glutamate transporter VGLUT2 (56). Cl− is an allosteric activator of glutamate uptake in an in vitro system consisting of proteoliposomes containing purified VGLUT2. Acetoacetate, BHB, and pyruvate inhibit this Cl−-dependent glutamate uptake, with kinetics indicating competition for the Cl− binding site. All these effects require the anions to be exposed to the extravesicular side of the membrane transporter.

Acetoacetate is >10-fold more potent than BHB at inhibiting VGLUT2, but the IC50 of 3.75 mM for BHB still suggests that biologically relevant effects on glutamate uptake might occur at physiological low-millimolar BHB concentrations. Cl−-dependent activation of other VGLUT transporters were similarly inhibited by acetoacetate, but the vesicular GABA transporter VGAT was not.

Consistent with these biochemical findings, acetoacetate inhibits glutamate release from neurons in a manner suggesting a reduced vesicular quantity of glutamate (56). In other contexts, however, BHB enhances glutaminergic transmission by increasing neurotransmitter release (120). Nevertheless, VGLUT inhibition may be a mechanism by which BHB can reduce excitatory glutamate neurotransmission without affecting inhibitory GABA neurotransmission.

Enantiomeric Specificity of Direct Signaling Activities 

As noted above, BHB is a chiral molecule, and R-BHB is the enantiomer generated and readily consumed in normal mammalian metabolism. Signaling functions or other effects that depend on the rapid catabolism of BHB therefore are relevant only to the R-enantiomer. Signaling functions that are direct actions of BHB, however, might be recapitulated in part or in full by S-BHB depending on the stereoselectivity of the proteins involved. Indeed, several of the direct signaling functions described here have been reported to be nonstereoselective in the literature.

S-BHB can bind the GPCR HCAR2, albeit with somewhat lower affinity than R-BHB. An in vitro assay with modified Chinese hamster ovary cells expressing human HCAR2, using calcium flux as the readout, found that both R-BHB and S-BHB showed robust, similar receptor activation at concentrations of 15 mM. A quantitative binding assay using radiolabeled GTP to measure nucleotide exchange found that the EC50 was 0.7 mM for R-BHB and 1.6 mM for S-BHB with human HCAR2, and 0.3 mM and 0.7 mM, respectively, with mouse HCAR2. Acetoacetate was inactive (124). The chirality of BHB used to test activation of FFAR was not reported (62).

S-BHB can also block inflammasome activation (153). The use of caspase-1 activation in lipopolysaccharide-treated bone marrow–derived macrophage cells as an in vitro assay of NLRP3 inflammasome activation showed that S-BHB effectively blocks inflammasome activation, albeit perhaps with lower efficacy than R-BHB.

The stereoselectivity of HDAC inhibition by BHB remains to be explored, but if, as described above, the relevant biochemical action is chelation of a catalytic zinc at the base of a hydrophobic channel, then the chirality of the trailing 3′ hydroxyl group may not be a critical determinant of activity. There is at least one suggestion that both R-BHB and S-BHB can increase histone acetylation in vitro (154).

The chirality of histone K(BHB) may be important to its biological function. The method used to detect K(BHB) could not distinguish modification with R-BHB from modification with S-BHB (147), but it is likely that both K(S-BHB) and K(R-BHB) are present. First, K(BHB) was detected in yeast and flies, and although generation of S-BHB-CoA as an intermediate of lipid β-oxidation is a conserved pathway in these metazoans, mitochondrial ketogenesis of R-BHB is not. Nor is Saccharomyces cerevisiae known to use polymers of R-BHB as an energy store, as is common in prokaryotes (18).

Second, although fasting increases synthesis of R-BHB in mouse liver, it also increases flux of S-BHB-CoA as an intermediary of fatty acid oxidation. A number of factors probably influence whether K(R-BHB) or K(S-BHB) predominates. By analogy with other protein acylations, K(BHB) is likely formed from CoA-activated BHB. β-Oxidation produces SBHB-CoA from an acyl-CoA precursor.

Free R-BHB (as well as free S-BHB) must undergo enzymatic activation by a CoA synthase, which has long been observed to occur (108), although the precise CoA synthase involved and cellular compartment in which the activation occurs are unknown. The balance of K(R-BHB) versus K(S-BHB) in the liver might therefore depend on the rate and site of activation of R-BHB and on the efficiency of extramitochondrial transport of both activated forms.

The balance in extrahepatic tissue might also depend on the relative utilization of fatty acids versus BHB for energy. Neurons, for example, which do not utilize fatty acids (7), would likely favor K(R-BHB) under ketogenic conditions. Whether the chirality of K(BHB) matters depends on its biological function, which is not yet understood. If the function is simply to occupy the lysine site and prevent alternative modifications, the chirality may be irrelevant. If the function is to serve as a binding site for other proteins, the 3′ hydroxyl group of BHB should remain both chiral and accessible to influence the binding of any putative K(BHB) recognition proteins.

INDIRECT SIGNALING ACTIONS VIA BHB CATABOLISM 

In addition to its direct signaling activities, BHB might exert additional signaling effects in the course of its catabolism to acetyl-CoA and ATP. These reflect the signaling activities of other intermediate metabolites, including acetyl-CoA, succinyl-CoA, and NAD. Finally, catabolism of BHB can alter the steady state of downstream metabolic pathways, such as those that regulate neurotransmitter synthesis. When considering the possible medical applications of BHB precursors, note that R-BHB should be much more potent at eliciting these indirect signaling actions than S-BHB is, as S-BHB is catabolized much more slowly and through a different route.

Production of Acetyl-CoA, Substrate for Protein Acetylation 

Catabolism of BHB into acetyl-CoA should raise intracellular acetyl-CoA levels, favoring both enzymatic and nonenzymatic protein acetylation. This effect complements HDAC inhibition by BHB but may have broader effects in multiple cellular compartments. Protein acetylation in mitochondria appears to be particularly sensitive to acetyl-CoA flux, as a variety of states associated with increased lipid utilization—including dietary restriction, fasting, and high-fat diets—increase mitochondrial protein acetylation. This effect on mitochondrial acetylation occurs despite the fact that neither acetyltransferases nor the HDACs that are inhibited by BHB enter mitochondria (48). Acetylation—and deacetylation by SIRT3—is widespread in mitochondria (105) and regulates the function of several mitochondrial enzymes, including HMGCS2 (117) and the long-chain acylCoA dehydrogenase (51).

Increased acetyl-CoA pools also affect nuclear protein acetylation. Mitochondrial acetylcarnitine is a source of acetyl-CoA for histone acetylation (80). Export of acetyl-CoA from the mitochondria is accomplished via a citrate shuttle mediated by citrate synthase inside mitochondria and ATP citrate lyase inside the cytoplasm (140).

ATP citrate lyase is a key enzyme in fatty acid biosynthesis, but its role in facilitating acetyl-CoA export from mitochondria is also required for the increase in histone acetylation that occurs with growth factor stimulation (140). An alternative pathway for acetyl-CoA export from mitochondria is via the enzymes carnitine acetyltransferase and carnitine/acylcarnitine translocase (89). Indeed, a muscle-specific knockout of carnitine acetyltransferase in mice compromises glucose tolerance and decreases metabolic flexibility (89), demonstrating the importance of intracellular acetyl-CoA transport to overall metabolic health.

Consumption of Succinyl-CoA, Substrate for Protein Succinylation 

Utilization of BHB in peripheral tissues uses succinyl-CoA to donate CoA to acetoacetate. This consumption of succinyl CoA may affect the balance of lysine succinylation, which, like acetylation, is widespread in mitochondria (104) and present across diverse organisms (139). A substantial fraction of these succinylation sites are regulated by the mitochondrial desuccinylase, the sirtuin SIRT5 (104). HMGCS2 has long been known to be succinylated, a modification that reduces its activity (102); HMGCS2 enzymatic activity in the liver is suppressed by succinylation and restored by desuccinylation mediated by SIRT5 (104). The mechanism of lysine succinylation is not clearly understood; succinyltransferase is not known to exist in mammalian cells, and because both liver succinyl-CoA abundance and succinylation of HMGCS2 are reduced in rats after treatment with glucagon (101, 102), it is possible that succinylation is primarily a nonenzymatic process dependent on local concentrations of succinyl-CoA. Although HMGCS2 itself is not expressed in the peripheral tissues that utilize BHB, enzymes in many other key mitochondrial pathways, including fatty acid oxidation, branched-chain amino acid catabolism, and the tricarboxylic acid (TCA) cycle, are heavily succinylated and regulated by SIRT5 (104). By analogy with acetylation (and the effect of succinylation on HMGCS2), these pathways may be activated by a reduction in succinylation. Consumption of succinyl-CoA during BHB utilization and consequent reduction in mitochondrial protein succinylation may therefore regulate many of these crucial mitochondrial pathways in peripheral tissues, perhaps favoring the switch to lipid-dependent energy usage.

Cytoplasmic and Mitochondrial NAD:NADH Equilibrium 

Cellular NAD balance is emerging as a crucial factor in metabolic disease and aging (123). NAD utilization during BHB metabolism differs from that during glucose metabolism in two important respects. Fewer NAD+ molecules are consumed per acetyl-CoA produced when BHB is used than when glucose is used, and the cellular compartment in which NAD+ is consumed is different. Metabolism of one molecule of glucose to two molecules of acetyl-CoA involves conversion of four molecules of NAD+ into NADH. Two of these molecules are converted in the cytosol during glycolysis; the other two are converted in the mitochondrion by pyruvate decarboxylase. The cytosolic NADH are shuttled into mitochondria, potentially depleting the cytoplasmic NAD+ pool with high glucose utilization.

By contrast, metabolism of one BHB molecule to the same two molecules of acetyl-CoA involves conversion of only two molecules of NAD+ into NADH, both in the mitochondrion by BDH1, thereby preserving the cytoplasmic NAD+ pool (7). The cytoplasmic and mitochondrial NAD pools are relatively distinct, so the preservation of cytoplasmic NAD+ by BHB may have important cellular effects. NAD+ is a cofactor for sirtuin deacylases (such as nuclear/cytoplasmic SIRT1) as well as poly-ADP-ribose polymerase (PARP) (133).

Consumption of NAD+ by PARP or overproduction of NADH may promote age-related diseases by decreasing the activity of sirtuins (53). Conversely, repletion of NAD+ by exogenous feeding with nicotinamide mononucleotide improves glucose tolerance in both high-fat-diet-fed and aged mice (152). The relative sparing of NAD+ by utilizing BHB vis a` vis glucose may therefore have important consequences for metabolic diseases and diabetes.

In the mitochondrion, BHB utilization is both determined by and changes the NAD:NADH equilibrium, with implications for signaling. The mitochondrial BHB:AcAc equilibrium is so closely linked to the NAD:NADH equilibrium that early metabolic studies of the liver used the former as a proxy for the latter (65). This tight relationship suggests that any influence that pushes the mitochondrial NAD:NADH equilibrium toward NADH (such as consumption of NAD by sirtuins or reduced activity of NADH dehydrogenase/complex I) will reduce BHB consumption. This reduction could increase the local concentration of BHB available for direct signaling functions within and around the mitochondrion, but also potentially reduce the flux of BHB transiting the cytoplasm and nucleus toward mitochondria.

However, BHB utilization also affects the mitochondrial redox state. Increased utilization of BHB is associated with pushing the NAD:NADH equilibrium toward NADH, as well as increasing the oxidation state of coenzyme Q (114). Owing to the increased heat of combustion of BHB compared with that of pyruvate, BHB also increases the efficiency of ATP production from the mitochondrial proton gradient and reduces the production of free radicals (131). Changes in free radical production might alter the activity of signaling networks that sense and respond to mitochondrial free radicals, such as p66Shc (33).

Neurotransmitter Synthesis 

The potential mechanisms of action of ketogenic diets in treating epilepsy remain complex and controversial and have been the subject of several thorough reviews (47, 83, 154). One mechanism consistently proposed, however, involves how the downstream effects of BHB catabolism on the abundance or flux of other intermediate metabolites might alter the biosynthesis of the inhibitory neurotransmitter GABA.

The biosynthesis of GABA in inhibitory GABAergic neurons begins with the synthesis of glutamine in astrocytes. Glutamine is exported from astrocytes to neurons, where it undergoes conversion to glutamate and then decarboxylation to GABA. An alternative fate for glutamate in neurons is donation of its amino moiety to oxaloacetate, producing aspartate and α-ketoglutarate. Studies of isotopically labeled BHB show that it is used as a substrate for the synthesis of glutamine and other amino acids (156). Data from clinical studies of children on ketogenic diet for epilepsy show that cerebrospinal fluid GABA levels are higher on ketogenic diet, and the highest levels correlate with best seizure control (16).

BHB may affect GABA production via increased synthesis and/or pushing the fate of glutamate toward GABA and away from aspartate. Studies in synaptosomes show that BHB increases the content of glutamate and decreases that of aspartate (25). Studies of ketogenic diet in rodents similarly show that less glutamate is converted to aspartate (156). In cultured astrocytes, the presence of acetoacetate reduces the conversion of labeled glutamate to aspartate (155). Infusion of labeled BHB into rats fed a normal diet rapidly increases the levels of all components of this pathway (glutamine, glutamate, GABA, and aspartate) (112).

Even when ketotic states are not associated with an increase in overall GABA levels, the proportion of glutamate shunted to GABA production is increased (84). The reason for this shunt may be the effect of BHB catabolism on TCA cycle intermediates. The relatively greater efficiency of BHB at generating acetyl-CoA compared with that of glucose, described above, increases the flux of acetyl-CoA through the TCA cycle. This increases the proportion of oxaloacetate required to condense with acetyl-CoA to permit its entry into the TCA cycle, reducing the availability of free oxaloacetate to participate in glutamate deamination to aspartate. By indirectly tying up oxaloacetate, BHB pushes the fate of glutamate toward GABA (154). Altogether, one effect of BHB catabolism, alone or as part of a ketogenic diet, appears to increase the capacity of GABAergic neurons to rapidly generate GABA from glutamate (154).

Although BHB is structurally reminiscent of GABA itself, evidence of a direct effect of BHB on activating GABA receptors is lacking. Neither BHB nor acetoacetate alters GABA currents in cultured rodent cortical neurons (22) or in rat hippocampal neurons (126). BHB did enhance the function of GABAA receptors expressed in Xenopus oocytes, but only modestly and at concentrations of 10 mM or higher (149), leaving the physiological significance of this effect unclear.

However, GABOB (γ-amino-β-hydroxybutyric acid) is an endogenous agonist of GABA receptors that differs structurally from BHB only in the presence of the γ-amino moiety. It is biochemically plausible that BHB might be a direct substrate for GABOB synthesis, but no such aminotransferase is known to exist. Nor has any pathway for conversion of GABA to GABOB yet been identified in mammals. Of interest in consideration of BHB precursors as therapeutics, the enantiomer of GABOB that would be derived from S-BHB has the more potent antiepileptic affect and is a stronger GABAB receptor agonist (148).

BHB SIGNALING IN REGULATION OF METABOLISM 

The integration of the various direct and indirect signaling functions of BHB appears to broadly help the organism adapt to a fasting state. The transition to a fasting state is already under way when ketogenesis is activated in the liver. BHB production might further promote that transition in extrahepatic tissues while also fine-tuning the control of lipid and glucose metabolism.

The combinatorial effects of BHB on gene expression, described below, might be expected to generally facilitate the activation of new transcriptional programs. The enrichment of histone K(BHB) at genes activated by fasting suggests that this might be particularly important for activating fasting-related gene networks, although this could also reflect a nonspecific association with activated transcription.

Inhibition of class I HDACs by BHB could play a major role in metabolic reprogramming, according to studies of HDAC knockout mice and of HDAC inhibitors. HDAC3 regulates expression of gluconeogenic genes (86), and HDAC3 knockout mice have reduced fasting glucose and insulin levels (8, 26, 63). In fact, chronic treatment with the HDAC inhibitor butyrate essentially keeps mice metabolically normal on a high-fat diet, with lower glucose and insulin levels, better glucose tolerance, reduced weight gain, and improved respiratory efficiency (32). Butyrate also provides some of these benefits even to mice already obese from being fed a high-fat diet (32).

Similarly, inhibition of class I HDACs, but not class II HDACs, increases mitochondrial biogenesis, improves insulin sensitivity, and increases metabolic rate and oxidative metabolism in a mouse diabetes model (31). The mechanism for these metabolic benefits of class I HDAC inhibition may be upregulation of PGC1α (Ppargc1a) in in a variety of tissues by relief of HDAC3-mediated transcriptional repression (31, 32). Transcription of Fgf21 is similarly upregulated via inhibition of HDAC3 by butyrate, activating ketogenesis in obese mice (72). Several single nucleotide polymorphisms in HDAC3 have been associated with an elevated risk of type 2 diabetes in a Chinese population (157).

Activation of HCAR2 reduces lipolysis in adipocytes; because the availability of fatty acids in the liver is a critical determinant of ketogenesis (and is strongly regulated by insulin), this may provide a self-feedback mechanism to limit the production of BHB. Why this mechanism is insufficient to prevent dysregulated BHB production in insulin-deficient states such as diabetic ketoacidosis, and whether it could be potentiated to treat such states, such as through HCAR2 agonists, is unclear.

HCAR2 was originally identified as a niacin receptor, spurring efforts to develop more specific agonists to capture the therapeutic benefits of niacin on cardiovascular risk or glycemic control that were thought to be due to HCAR2’s effects on the levels of free fatty acid in blood. An HCAR2 agonist, GSK256073, transiently reduces levels of free fatty acids in blood but has only a modest effect on glycemic control in type 2 diabetes mellitus (20). Two other HCAR2 agonists similarly lowered free fatty acids but without otherwise altering the lipid profile in humans, while niacin was found to produce beneficial changes to the lipid profile in Hcar2 knockout mice (69).

Thus, the model that niacin (and by extension BHB) exerts beneficial effects on cardiovascular risk through activation of HCAR2 in adipose tissue is probably too simplistic. It may even be the case that other cell types such as macrophages might mediate the therapeutic effects of HCAR2 agonists (30).

Interpreting the metabolic effects of BHB mediated by FFAR3 depends on whether BHB acts as an agonist or antagonist, and in which contexts. Strong evidence suggests that BHB antagonizes FFAR3 to reduce sympathetic activity, resulting in reduced heart rate, body temperature, and metabolic rate. If BHB also antagonizes FFAR3 in other contexts, it could improve insulin secretion from pancreatic β islet cells and impair intestinal gluconeogenesis. Altogether, these findings suggest that BHB would improve glycemic control, though a decrease in metabolic rate could be obesogenic.

The important role of the NLRP3 inflammasome in regulating obesity-associated inflammation and metabolic dysfunction has been extensively reviewed (15, 45). Briefly, the NLRP3 inflammasome appears to mediate an inflammatory response to nutrient excess and mitochondrial dysfunction. Mice deficient in NLRP3 are grossly normal when fed chow but are protected from obesity and insulin resistance when fed a high-fat diet. One proposed mechanism is through a reduction in inflammasome-induced IL-1β, which otherwise inhibits insulin signaling in adipocytes and hepatocytes while inducing pancreatic β-cell dysfunction.

While NLRP3 may have an important homeostatic role in the response to day-to-day nutrient fluctuations, its chronic activation by nutrient excess may contribute to the development of metabolic disease—and inhibition of the NLRP3 inflammasome by BHB might ameliorate these maladaptations.

BHB SIGNALING IN REGULATION OF GENE EXPRESSION 

Regulation of gene expression is the most common theme that emerges from the direct and indirect signaling functions of BHB. Histones are at the nexus of this theme, with their posttranslational modifications, including acetylation, succinylation, and β-hydroxybutyrylation. Histone acetylation is a well-understood mechanism for both broad and specific regulation of gene expression, and BHB can alter histone acetylation by directly inhibiting HDACs and by indirectly promoting acetyltransferase activity via acetyl-CoA flux.

The biology of histone β-hydroxybutyrylation largely remains to be elucidated but is an area that should receive strong interest for its potential relevance to gene expression reprogramming in response to metabolic stimuli. Lysine succinylation is another histone posttranslational modification (146) and is regulated by the sirtuin SIRT7 in the context of the DNA damage response (73). Finally, alterations in cytoplasmic and nuclear NAD+ levels can affect the activity of sirtuins, which deacylate a number of histone tail residues (54).

The net integration of all these effects might be expected to facilitate gene transactivation, particularly of quiescent genes that are activated in response to stimuli. Two well-characterized examples of how HDAC inhibition (and acetyltransferase activation) can activate gene expression include reactivation of HIV latency and activation of lineage-specific genes during muscle differentiation. The HIV provirus sits in a transcriptionally inactive state in resting T cells, providing a reservoir of potential virus production that is impossible for current antiretroviral therapy to eradicate (44).

The class I HDACs HDAC1, HDAC2, and HDAC3 help maintain this transcriptionally silenced state, as components of several transcriptional repressor complexes, by deacetylating histone tails. Ordinarily, a key step in the reactivation of HIV transcription is the recruitment of complexes containing the acetyltransferase p300 to acetylate histone tails. Inhibition of HDACs with vorinostat or panobinostat also promotes histone acetylation, resulting in the loss of latency and reactivation of HIV transcription (44). In vivo, such HDAC inhibitors broadly reactivate transcription from a diverse pool of latent proviruses (6).

The differentiation of a satellite cell (i.e., muscle stem cell) into the muscle lineage involves the transcriptional activation of a sequence of differentiation-promoting transcription factors (see Reference 119 for a review). One of these factors, MYOD1, further activates a wide range of muscle-specific genes. HDACs, including HDAC1 and HDAC2, reside at the promoters of many of these MYOD1 targets, maintaining histones in a deacetylated state.

Activation of the genes requires dissociation of the HDAC from the promoter, and often recruitment of a p300 complex to promote histone acetylation. HDAC inhibitors potentiate this process, much as in HIV latency, and both increase acetylation at MYOD1 target promoters and increase myogenic differentiation. One contrast with HIV latency is that many gene promoters in satellites cells are maintained in a poised or bivalent state, possessing both activating and repressing histone modifications (119).

Thus, whereas HIV latency is an example of HDAC inhibition waking a gene from deep silencing, muscle differentiation is an example of potentiating or lowering the threshold of activation for a gene already poised to do so. A similar example of activating poised genes may be relevant to cognition and dementia (see below).

How histone K(BHB) participates in epigenetic regulation largely remains to be determined. K(BHB) was particularly enriched after fasting at genes that were upregulated by fasting (147). Other stimuli or contexts expected to change gene expression were not examined, nor were cells or animals treated with BHB in the context of such stimuli.

Thus, we do not yet know whether K(BHB) is specifically associated with a gene network that is responsive to fasting, or whether it is generally associated with newly transactivated promoters. We also have yet to understand the biological meaning of K(BHB)—whether it is an active signal that stimulates transcription through regulatory or binding interactions with the protein machinery of chromatin remodeling and transactivation, or whether it is a bystander modification emplaced at fasting-activated promoters owing to the confluence of increased BHB-CoA levels and newly accessible histone tails.

An additional layer of regulation can occur on nonhistone proteins involved in gene expression, as these posttranslational modifications are not restricted to histones. Acetylation and succinylation occur throughout the proteome and can affect protein function. It is possible that β-hydroxybutyrylation will be found to as well. Acetylation of nonhistone proteins is a critical step in both HIV latency and muscle differentiation, where acetylation activates the transcription factors Tat (44) and MYOD1 (119), respectively. The multilayered effects of BHB on gene expression can be illustrated with HMGCS2 itself, the rate-limiting enzyme in BHB synthesis. As described above, the transcription factor FOXA2 helps control Hmgcs2 transcription.

FOXA2 is itself acetylated by EP300 in a reaction using acetyl-CoA as the acetyl group donor (increased by BHB). FOXA2 is deacetylated by a class I HDAC (inhibited by BHB) and/or by the sirtuin SIRT1, which requires NAD+ as a cofactor (increased by BHB). Initiation of Hmgcs2 transcription by activated FOXA2 might involve displacing or deactivating HDACs (inhibited by BHB) to permit emplacement of activating histone marks such as H3K9 acetylation by acetyltransferases (via acetyl-CoA increased by BHB). As this example illustrates, the overall impact of BHB might generally favor initiation or upregulation of transcription, but the effects on any specific loci could vary depending on the posttranslational regulation of the proteins involved at that site.

BHB IN THE BRAIN: EPILEPSY, DEMENTIA, AND COGNITION 

The ketogenic diet has been clinically used for decades to treat epilepsy and currently has a wide range of therapeutic applications, mostly in childhood epilepsies (142). Despite this extensive clinical history, the mechanism of action of the ketogenic diet remains controversial (107). In fact, whether BHB itself is necessary or even active in the therapeutic effect of ketogenic diets is controversial, and the evidence varies between animal models (107). The various possible mechanisms of the antiepileptic effect of ketogenic diets have been reviewed (83, 107).

Several of the signaling activities described above may be relevant, particularly modulation of potassium channels, FFAR3 activation, and promotion of GABA synthesis. Epigenetic modifications may also contribute to neuronal hyperexcitability and the long-term effects of epilepsy on the brain through persistent changes in gene expression (111). REST (RE1-silencing transcription factor) is a transcriptional repressor that recruits HDACs, among other chromatin-modifying enzymes, to help silence target genes.

REST expression is increased in neurons after seizures and promotes aberrant neurogenesis. However, whether REST activity is helpful or harmful for seizure control differs in different seizure models (111). The contribution of epigenetic modifiers, including those that are modulated by BHB, to epilepsies and their long-term effects requires much further study.

Ironically, given the decades of study on the role of ketogenic diets in epilepsy, more molecular detail is known about the potential mechanisms of BHB in ameliorating dementia. Two major threads link BHB signaling with dementia: epigenetic modifications and neuronal hyperexcitability. There is a growing literature on the importance of epigenetic regulation in learning and memory, specifically in mouse models of dementia. Age-related impairments in learning and memory in wild-type mice are associated with alterations in histone acetylation (98), and treatment with HDAC inhibitors improves memory performance in both young and aged mice (42, 98).

HDAC inhibitors also improve cognition in the CK-p25 dementia mouse model (28). HDAC2 appears to be the crucial mediator of these effects, as overexpression of HDAC2, but not HDAC1, impairs learning and memory in wild-type mice (42). Conversely, Hdac2 knockout mice show improved memory formation, which is not further improved by HDAC inhibitors (42). HDAC2 expression is increased in the brains of two mouse dementia models as well as the brains of humans with Alzheimer’s disease (39). One model of how HDAC inhibitors regulate cognition is via epigenetic priming, reminiscent of the poised transcriptional state of genes involved in muscle differentiation (40). The broader role of epigenetics in cognition and neurodegenerative disease has been reviewed (67, 68, 100).

The worlds of epilepsy and dementia have been linked through the finding that mouse models of Alzheimer’s disease show neuronal hyperexcitability and epileptiform spikes from dysfunctional inhibitory interneurons (97, 134). Epilepsy, an extreme manifestation of this hyperexcitability, is associated with more rapid cognitive decline in patients with Alzheimer’s disease (136). Promising treatments that reduce epileptiform spikes, including at least one commonly used antiepileptic drug, improve cognition in these models (113, 134).

The various signaling activities by which BHB acts in epilepsy may thus be relevant to ameliorating cognitive decline in Alzheimer’s disease. In small studies, provision of BHB precursor molecules improves cognition in an Alzheimer’s mouse model (58) and in a patient with Alzheimer’s disease (93). Further exploration of the links between BHB signaling, epilepsy, and dementia may prove fruitful in generating new translational therapies.

Inhibition of the NLRP3 inflammasome could also prevent cognitive decline and dementia. β-amyloid protein, which aggregates into the amyloid plaques characteristic of Alzheimer’s disease, activates the NLRP3 inflammasome in microglia, the resident macrophage population in the brain, releasing inflammatory cytokines including IL-1β (reviewed in References 29 and 35).

This activation is evident in the brain of humans with both mild cognitive impairment and Alzheimer’s disease, and Alzheimer’s mouse models that carry deficiencies in NLRP3 inflammasome components are protected from β-amyloid deposition and cognitive decline (50). Microglia, as critical mediators of brain inflammation, may be the site of integration of various BHB-related signals, including HCAR2 activation.

BHB INTERACTIONS WITH AGING PATHWAYS 

The hypothesis that BHB may play a broad role in regulating longevity and the effects of aging comes in part from the observation that many of the interventions that most consistently extend longevity across a wide range of organisms, such as dietary restriction and fasting, intrinsically involve ketogenesis and the production of BHB in mammals (92).

The effects of such regimens on invertebrate, rodent, and human health have been reviewed and can include extended longevity, cognitive protections, reductions in cancer, and immune rejuvenation (75, 82). More specific interventions that promote ketogenesis, such as transgenic overexpression of FGF21, also extend life span in rodents (161). BHB itself extends longevity in C. elegans (24), and whether it would do so in rodents remains to be investigated.

Several of the signaling functions of BHB described above broadly regulate longevity and diseases of aging pathways, most prominently HDAC inhibition and inflammasome inhibition. The data from invertebrate organisms showing that reduction in class I HDAC activity extends life span, and generally acts through similar pathways as dietary restriction, have been reviewed (92). Briefly, deletion of Rpd3, the yeast and fly homolog of mammalian class I HDACs, extends replicative life span by 40–50% in S. cerevisiae (61).

Rpd3 deletion enhances ribosomal DNA silencing (61), the same mechanism by which overexpression of the sirtuin Sir2 enhances replicative longevity in S. cerevisiae (57). Drosophilids heterozygous for a null or hypomorphic Rpd3 allele show a 30–40% extension of life span, with no further increase with caloric restriction (110). Both caloric restriction and reduced Rpd3 activity increase expression of Sir2 (110). Conversely, mutations in Sir2 block life span extension by either caloric restriction or Rpd3 mutations (109). In both organisms, then, modest reductions in HDAC activity (stronger reductions are lethal) extend life span via the same mechanisms as in dietary restriction and Sir2 expression.

Other possible longevity mechanisms downstream of Rpd3 in invertebrates include autophagy, which is regulated by histone acetylation of specific genes (151), and enhanced proteostasis through increased chaperone expression (162).

No life span data yet exist for reduced HDAC function in rodents. However, Hdac2 knockout mice display impaired IGF-1 signaling and are 25% smaller than normal (163), a potential longevity phenotype (87). Hdac2 knockout is also protective in models of tumorigenesis (163). Conditional knockouts in mouse embryonic fibroblasts and embryonic stem cells demonstrated roles for HDAC1 and HDAC2 in hematopoiesis (141) and stem cell differentiation (23). By analogy to the modest reductions in class I HDACs that enhance longevity in invertebrates, it may be of interest to determine whether heterozygous HDAC1/2 knockout mice, or mice treated with low-dose pharmacological HDAC inhibitors, have enhanced longevity.

An inducible compound heterozygote knockout of HDAC1 and HDAC2 does suppress one translatable age-related phenotype, cardiac hypertrophy, as do HDAC inhibitors (88). HDAC inhibitors ameliorate cardiac dysfunction in mouse diabetes models (14) and prevent maladaptive cardiac remodeling (160). The mechanism for the effect on cardiac hypertrophy appears to be inhibition of HDACs that suppress the activity of a mechanistic mTOR complex (88). This is one of several examples of intersections between BHB, its signaling effects, and mTOR/rapamycin, a canonical longevity-regulating pathway (55). As described above, mTOR is also a checkpoint in the activation of ketogenesis; inhibition of mTORC1 is required to activate the transcription factors and hormones that control ketogenesis (4, 116).

Inhibition of NLRP3 inflammasome activation might also have broad effects on aging and longevity, as reviewed in References 27 and 37. The NLRP3 inflammasome in particular has a wide range of activating stimuli, many of which accumulate with age such as urate, amyloid, cholesterol crystals, and excess glucose. The age-related phenotypes that may be ameliorated by its inhibition are similarly diverse: insulin resistance, bone loss, cognitive decline, and frailty.

In two such examples, BHB inhibited NLRP3 inflammasome activation in urate crystal–activated macrophages, and ketogenic diet ameliorated flares of gout arthritis in rats (36). Whether genetic or pharmacological inhibition of the NLRP3 inflammasome would extend mammalian life span remains unknown, but the potential certainly exists for translational application to human diseases of aging.

APPLICATION AND FUTURE DIRECTIONS 

The ketone body BHB expresses a variety of molecular signaling functions, in addition to its role as a glucose-sparing energy carrier, that may influence a broad range of human diseases. There is sufficient evidence for several significant human diseases, including type 2 diabetes mellitus and Alzheimer’s dementia, in model organisms to justify human studies of BHB or a BHB-mimetic intervention. The diversity of age-associated diseases and pathways affected by BHB signaling suggests that therapies derived from BHB may hold promise for broadly enhancing health span and resilience in humans (91).

The translation of these effects into therapies that improve human health span requires the pursuit of two converging strategies: deeper mechanistic understanding of the downstream effects of BHB signals and improved systems for the targeted delivery of BHB for both experimental and therapeutic goals. Deeper mechanistic understanding would solidify some of the transitive connections described above. For example, BHB inhibits HDACs, and HDAC inhibition protects against cognitive decline in rodents; but does BHB protect against cognitive decline? Via HDAC inhibition? Which gene promoters are targeted? Establishing such links would permit rational design of human studies to test specific effects of BHB, with plausible biomarkers and intermediate outcomes. Improved delivery systems would facilitate both animal and human studies.

BHB-mimetic drugs, or ketomimetics, would recapitulate the desired activity of BHB. The key obstacles to exogenous delivery of BHB are its nature as an organic acid and the rapid catabolism of R-BHB. The quantity of exogenous BHB required to sustain blood levels over a long period would likely be harmful because of either excessive salt load or acidosis. Alternatively, approaches to ketomimetics include (a) the use of agents that activate endogenous ketogenesis in an otherwise normal dietary context, (b) the delivery of BHB prodrugs or precursors that avoid the acid/salt problem, and (c) the use of agents that phenocopy specific downstream signaling events.

The last approach, such as using HCAR2 agonists or HDAC inhibitors, is tempting, but a perhaps crucial advantage of adapting BHB itself is utilizing the existing endogenous transporters and metabolite gradients to bring BHB to its sites of action. Esters of BHB are a promising approach to delivering BHB as a prodrug, but the expense of synthesis is challenging. Confirming whether such synthetic compounds need be enantiomerically pure, or indeed whether S-BHB has better pharmacokinetics for the desired signaling function, might help reduce cost.

The ketone body BHB, a fasting fuel and fasting signal, is emerging as a poster child of the endogenous metabolite that transmits signals from the environment to affect cellular function and human health. Researchers have made important strides in understanding the signaling functions of BHB, many of which have crucial implications for the management of human diseases. A deeper knowledge of the endogenous actions of BHB, and improved tools for delivering BHB or replicating its effects, offers promise for the improvement of human health span and longevity.

Atkins Diet: Does it work for weight loss?

The atkins diet is widely known to be a weight loss program that is high in protein and low in carbohydrates. There’s a vegerarian alternative, which was developed called the Eco-Atkins Diet. This article will focus not only on vegetarianism but also on veganism, which means that dairy products and eggs are not included in the diet. In Atkins diet alternative, protein sources would not come from animal meat and animal-based products, but from other protein sources such as soy and gluten, among other things.

This means that instead of bacon ans steak originally found in the first recipes of the Atkins diet, people who want to lose weight would have to eat food that consists of healthy fats and non-anominal protein alternatives. This is then called a low-carbohydrate, plant-based diet.

The low carbohydrate and high protein Atkins diet coupled with a Vegan lifestyle disease by lower weight and prevent hear disease by around 10% through reducing bad cholesterol LDL.

HOW DOES ATKINS DIET WORK?

The idea behin the Atkins diet is simple, your body can either use sugar for fuel or fat. It is easier for the body to burn sugar than fat, so if sugar is available, this is what the body will use. When you eat carbohydrates, the body converts them into sugar to use for fuel. If you restrict your carb intake, your body will have to find anathor fuel, which is when it turns to utilizing your fat stores to burn for energy.

A typical diet asks for the dieter to reduce calories taken is, but generally, dieters still consume a high level of carbohydrates. So, when the body converts them to sugar, you get an energy spike shortly after eating, but then an energy low once the sugars have been burned. You’ve heard people talk about sugar highs and sugar lows, and this is exactly what happens. Your body goes on a sugar high after you eat because your body has sugar to burn, but then your energy decreases and you crash. When you crash, you become hungrier and develop cravings, usually for sugars and carbs, and you want to eat. This makes it very hard to lose weight and stick to a diet long term.

The Atkins diet is a different, because your body does not have sugars to burn, it turns to burning the fat stores in your body. And because it has a constant source of fuel, rather than relying solely on what you eat for energy, it is able to burn fat at a regular pace, meaning there are no highs and lows in your energy cycle. Plus, because your body has a steady source of fuel that does not reply on eating, you won’t fell as hungry, your cravings will decrease, and you will lose weight very quickly. Although it may take a few days to a few weeks for your body to really adjust to this new way of eating, once you do, you will no longer feel hungry all the time and you will have a constant energy store to use to get you throught the day.

To sum it all up, on the Atkins diet, the body will learn to efficiently burn fat stored in your body, which will lead to weight loss. Without sugars to use as fuel, your body will adapt and convert the fat stores to fuel, and you’ll lose weight, feel less hungery, and have more energy throughout the day.

BENEFITS OF ATKINS DIET

Most people start the Atkins diet because they are overweight and want to gain control of their weight loss. This is one area where Atkins excels. If you follow the diet, you will lose weight. And when you lose weight, you will feel better both physically and emotionally, have more energy, and be able to do more in life. Studies have shown that cutting out carbs will help reduce the hunger you feel while dieting, making it easier to stick to. Plus, much of the weight losy is around the abdomen, which is oftentimes the hardest weight to lose! The beauty of the Atkins diet is that it also has health benifits far beyond just losing weight. Here are some of the many benifits that have been verified that the Atkins diet has had.

SEIZURE DISORDERS

A modified version of the Atkins diet has been given to both and adults suffering from epilepsy and other seizure disorders. People who have not had any success with seizures being controlled on medications saw a great reduction in seizures by following the Atkins diet. More than 30 studies conducted over a ten year period have verified these results.

ACID REFLUX

It is possible that people following the Atkins diet have been seen a reduction in acid reflux symptoms. More research is needed in this area, but preliminary findings look good.

HEADACHES

Some people have been a reduction of migraine headaches after following the Atkins diet. Again, more research necessary, but anecdotal reports have backed up this claim.

HEART DISEASE

The Atkins diet have been shown through numerous studies can reduce or prevent the risk of heart disease. Frst, weiht loss can help relieve pressure on the heart. Also, a low-carb diet can help to lower cholesterol and decrease inflammation in the body. And inflammation and high cholesterol have been shown to increase the risk of heart disease. Following the Atkins diet has also been shown to raise the HDL, or good cholesterol, in the body. It’s also been shown that being on the Atkins diet helped to lower people’s blood pressure.

DIABETES

because you are cutting out carbs, which are converted to sugar in the body, the Atkins diet reduces blood sugar levels and insulin levels, which improves the health of people with the 2 Diabetes. If you have diabetes, talk to your doctor about starting the Atkins diet, as your medications may need to be adjusted when you eat fewer carbs.

CANCER

Because some cancers are affected by obesity, it makes sense that if people lose weigt, they will naturally reduce their risk of the cancers. A low carbohydrate diet was shown to reduce the risk of breast cancer recurrence in women who had already suffered from this cancer. Also, it was shown that a high carbohydrate, high glycemic index diet increased the recurrence and mortality rates of people suffering from stafe 3 colon cancer. So, it makes sense that a low carbohydrate, low glycemic index diet will help someone suffering from colon cancer.

DEMENTIA

A high calorie diet and high carbohydrate diet has been demonstrated to increase the risk of suffering from these debilitating diseases.

As you can see, the Atkins diet has many benifits for the people who follow them. Along with losing weight, following the Atkins diet can help you deal with many different health issues that you may suffer from. This makes the Atkins diet a great way to get healthy.

How to Optimize Thyroid Function?

The reasons women are so prone to this condition are complex, though one important factor is simply the delicate nature of a woman’s hormonal system. The thyroid gland belongs to a group of glands in the HPAT axis. This stands for “hypothalamus, thyroid axis, pituitary, adrenal.” The HPAT axis is the locus of all hormonal direction and instruction in the body. All of the glands in it work in synergy. If the body detects a state of stress or starvation, the hypothalamus tells the pituitary and the thyroid gland to slow down. The thyroid gland is yoked to the success and health of other glands in a woman’s body, so it’s no wonder that it is so sensitive to damage.

There are several different ways that the thyroid gland can malfunction. The most prominent way is due to the autoimmune disease Hashimoto’s thyroiditis, which accounts for approximately 90 percent of cases of clinical hypothyroidism in the US.

An autoimmune disease is one in which the body’s immune system has gone into overdrive and accidentally started attacking its own cells as a result of poor gut barrier health. In Hashimoto’s thyroiditis, the thyroid gland is the victim.

You can find out for certain if you have Hashimoto’s (as opposed to other kinds of thyroid malfunction) only through getting blood work done. A quick explanation of thyroid function is helpful for understanding this blood work

First, your thyroid gland works only after it receives a “green light” signal for production by the pituitary gland, which comes in the form of Thyroid Stimulating Hormone (TSH). When TSH gets to the thyroid gland, the thyroid gland makes a molecule called T4. That’s not the end of it, though. T4 is not used by your body’s cells. T3 is. T4 is converted to T3 by the liver. T3 then goes on to be active in the body. It is responsible for delivering energy to all of your cells.

In Hashimoto’s thyroiditis, the body receives a TSH signal from the pituitary gland, but the thyroid gland struggles to produce T4. As a result, low T4 is the primary marker most doctors look for on a blood exam to signal Hashimoto’s thyroiditis. High TSH is also a potential indicator of Hashimoto’s, as TSH levels increase when the body tries to convince the weakened thyroid to make more T4. The final and most definitive test for Hashimoto’s thyroiditis is a test for the actual thyroid antibodies (TPO) themselves. When present in high quantities in the bloodstream, you know that your thyroid gland is being attacked.

The way to overcome Hashimoto’s thyroiditis is to heal the gut as well as possible. Do so using the recommendations made earlier: avoiding gut irritants such as grains, dairy, and even legumes, focusing on vitamin-rich foods like vegetables, organ meats, and egg yolks, consuming fermented foods or probiotic supplements on a regular basis.

Unfortunately, with Hashimoto’s, some or much of the thyroid gland is irreparably destroyed. If that is the case, you will likely need to go on some form of thyroid hormone supplementation to achieve optimal health.

While Hashimoto’s may be the most common form of hypothyroidism, it is not the only one. The other primary form of hypothyroidism that affects women is simple thyroid sluggishness. Many women struggle from this regardless of whether their blood thyroid hormone levels are clinically “low” or not. It is entirely possible to suffer from this problem and not test “officially low,” but close to it.

Regardless of whether you test “super low,” “low,” or simply “moderate,” nearly all women can benefit from optimizing thyroid function.

Thyroid production slows down in response to stress. This is what I have called thyroid “sluggishness” (and no, this is definitely not a medical term). This includes both physical and psychological kinds of stress. Physical stressors include undereating, a low-carbohydrate diet, excessive weight loss, over-exercise, or an inflammatory diet. Psychological stressors are all the usual pressures that come from adult life. In response to both types of stress, thyroid production shuts down in two primary ways. First, signals from the HPAT axis say, “Stop!” This “stop!” signal shows up on blood tests as lowered TSH production. With low TSH comes a lower T4 level, and often a lower T3 level as well.

The second way that stress impairs thyroid function is to throw a wrench in the link between T4 and T3 production. Stress causes the body to produce something called Reverse T3, which actually blocks T3 from working in your body. Therefore, a blood test that indicates this kind of hypothyroidism will show lower T3, elevated RT3, and possibly T4 and TSH on the low end as well.

The way to overcome “sluggishness” is to reduce stress, sleep more, eat when you are hungry and stop when you are full, and perhaps, most importantly, make sure you eat plenty of carbohydrates. The liver needs carbohydrate in order to convert T4 to T3. Be sure to eat at least 100 grams of dense carbohydrate every day (approximately four servings of fruit or starch) on a low-fat diet, and at least 25-50 grams (1-2 servings of fruit or starch) on a low-carb diet.

You can also bolster thyroid health by making sure you have some iodine and selenium in your diet, as these nutrients are necessary for thyroid function. Include iodized salt in your diet. If you do not consume iodized salt (note that most sea salt does not have iodine in it), consume seaweed once a week if you can. For selenium, you can take a supplement or simply eat Brazil nuts, which are an excellent source of selenium. Seafood also contains selenium. If you have Hashimoto’s, be certain to keep iodine and selenium in good balance (or avoid supplementing altogether), as excess iodine for Hashimoto’s patients can cause a brief period of intense hyperthyroid activity called a “thyroid storm” and damage to the thyroid gland.

Alternate-Day Fasting Increases Fullness After Meals

Alternate-day fasting is a version of intermittent fasting, which is currently one of the world’s most popular weight loss trends.

Recently, a group of scientists examined the effects of 8-week alternate-day fasting on appetite ratings, appetite hormones and body weight.

Here is a detailed summary of their results.

Alternate-Day Fasting

BACKGROUND

Alternate-day fasting (ADF) is a weight loss technique that has recently become popular.

One popular version of ADF restricts calories by 75% every second day, while allowing unrestricted eating in between.

Human trials have shown that this method may lead to 4–8% weight loss in just 2–3 months. Here is a summary of study results from over the years:

  • 2005: 16 non-obese men and women fasted every other day for 22 days and lost 2.5% of their initial body weight.
  • 2007: 9 overweight asthma patients consumed 20% of their calorie needs every second day for 8 weeks and lost 8% of their initial body weight.
  • 2009: 16 obese people consumed 25% of their calorie needs every second day for 8 weeks and lost 12.4 lbs (5.6 kg).
  • 2013: 32 obese people fasted every other day for 8 weeks and lost 4.8% of their body weight on a high-fat diet (45% fat), but 4.2% on a low-fat diet (25% fat).
  • 2013: 32 obese people fasted every other day for 12 weeks and lost 6.6 lbs (3 kg). When fasting and doing endurance exercise, they lost 13.2 lbs (6 kg).
  • 2013: 15 overweight or obese women fasted every other day for 6 weeks and lost 7% of their initial body weight.

Additionally, giving in to hunger and cravings is the main reason why people fail to adhere to a diet.

This seems to be less common during ADF, though the reason is not clear.

ARTICLE REVIEWED

This trial examined how ADF affects appetite ratings, appetite hormones and weight.

Changes in hunger and fullness in relation to gut peptides before and after 8 weeks of alternate day fasting.

STUDY DESIGN

This trial examined the effects of 8-week ADF on subjective ratings of appetite, appetite hormones and body weight.

It should be noted that results from this study have been published before.

A total of 59 middle-aged, obese adults completed the trial, or 80% of those who initially started. 84% of the participants were women.

The study was divided into 3 periods:

  • Control period 1: For 2 weeks, the participants followed their habitual diets. Initial measurements took place during this period.
  • Alternate-day fasting: For 8 weeks, the participants fasted every second day.
  • Control period 2: Immediately after the ADF, participants followed their habitual diet for 2–3 days before final appetite measurements were taken.

Bottom Line: This trial examined how ADF affects appetite and body weight. The study included 59 people, and was divided into three periods.

ALTERNATE-DAY FASTING

For 8 weeks, the participants fasted every second day, with 75% calorie restriction. Conversely, on “feed days” they were allowed to eat whatever they wanted.

To improve compliance, all participants were provided with the food they were allowed to eat on fast days.

This food contained 60% of calories from carbs, 24% from fat and 16% from protein. Participants were allowed to consume unlimited amounts of calorie-free drinks.

Every week, the researchers measured body weight. Fat mass, lean mass and intra-abdominal fat were also measured using DXA.

Bottom Line: The participants consumed 25% of their calorie needs every other day for 8 weeks.

APPETITE ASSESSMENT

Subjective ratings of appetite were assessed after a 12-hour fast, before and after a standardized meal.

The standardized meal consisted of a liquid meal, providing 440 calories. It was designed to have a similar macronutrient profile as a typical breakfast, or 60% of calories from carbs, 24% from fat and 16% from protein.

Fasting blood samples were taken before the meal. Blood was also drawn immediately after the meal, and at 30, 90 and 120 minutes afterwards.

The blood was analyzed for total ghrelin, peptide YY (PYY) and several other hormones. Immediately before each of the blood draws, the participants rated their appetite using a visual analog scale (VAS).

Bottom Line: Appetite hormones and subjective ratings of appetite were assessed before and after the 8 weeks of ADF.

FINDING 1: BODY WEIGHT DECREASED

During eight weeks of ADF, the participants lost 8.6 lbs (3.9 kg).

This weight loss was largely due to loss of fat — 4.9 lbs (2.2 kg) — but also lean mass (water and muscle) — 3.1 lbs (1.4 kg).

The chart below shows the changes in fat mass and lean mass.

Bottom Line: Fasting every other day for 8 weeks led to 8.6 lbs (3.9 kg) weight loss.

FINDING 2: FULLNESS AFTER MEALS INCREASED

Subjective ratings of fullness after the test meal were significantly higher after 8 weeks of ADF, as shown below.

This increase in fullness was associated with higher levels of peptide YY, which is a hormone that reduces appetite after meals.

Similar to fullness, PYY levels after meals increased after 8 weeks of ADF. The reason why ADF increased PYY levels and fullness is unclear.

Bottom Line: Post-meal fullness was greater after 8 weeks of ADF, compared to before.

FINDING 3: RATINGS OF HUNGER REMAINED UNCHANGED

Eight weeks of ADF did not change hunger ratings.

This is consistent with previous studies suggesting that hunger remains unchanged after 3–12 weeks of ADF.

Conversely, studies on hunger after continuous calorie restriction indicate that compensatory increases in hunger are common.

Taken together, these findings indicate that intermittent calorie restriction is easier to stick to than continuous dieting or fasting.

However, levels of the hunger hormone ghrelin were significantly higher after the test meal at the end of the trial, compared to its levels before the trial.

The reason for these findings is unknown.

Bottom Line: Despite the loss of weight, subjective ratings of hunger didn’t change. This indicates that ADF is easier to adhere to than dieting.

LIMITATIONS

This study had a few limitations.

First, meals were not standardized the day before the appetite measurements took place. Even though the tests were preceded by a 12-hour fast, the previous evening’s meal might have affected the findings.

SUMMARY AND REAL-LIFE APPLICATION

ADF is an effective weight loss strategy, causing significant weight loss after 8 weeks. Yet despite the weight loss, hunger ratings after a standardized meal remained unchanged.

Additionally, when the ADF was over and the participants went back on their regular diets, subjective ratings of fullness were significantly higher after the standardized meal, compared to a similar meal before the fast.

These findings suggest that ADF is relatively easy to stick to. However, further studies need to examine its long-term effects.