Fasting for Weight Loss and Longevity: Total energy expenditure (TEE) and the intriguing new science of energy envelopes and fasting

I. The Age-Dependent Energy Envelope

It is widely believed that excess fat on our bodies reflects an imbalance between the amount of energy (measured in calories or kcal) that we consume vs. the amount we burn, and that diet is the driver of energy consumption while activity and lifestyle are the chief drivers of energy expenditure.
According to this line of thinking, if a sedentary person eats the same number of calories as an exerciser, we would expect that the sedentary person would burn fewer calories and store more fat compared to the exerciser.
But new research is showing that, while diet does determine energy intake, activity might not be a critical driver of total energy expenditure (TEE). For one thing, regardless of lifestyle or activity, it has now been established that how many calories we burn each day is highly age-dependent.
TEE ramps up during infancy when our brains and immune systems are developing, then starts to drop until we reach our mid-20s. At that point, it stabilizes throughout early and middle adulthood, dropping again with each decade of life after about age 60.
This lowering of metabolism helps explain the difficulty many of us have trying to lose weight as we age. And this is true regardless of whether we are manual laborers or accountants; exercise addicts or couch potatoes.
It turns out most of our TEE is linked to automatic ‘basal activities’ like digesting food, pumping blood, mediating inflammatory processes in areas of the body under stress, and to other relatively low-exertion activities such as thinking (in humans, brain activity accounts for about 20% of TEE), moving from one room to another, or fidgeting while we work, rather than to occasional larger exertions like taking a run or mowing the lawn.
We now understand that the body regulates energy expenditure according to an internally calculated daily allotment or ‘energy envelope’ which is based on age, and it is hard to burn more or fewer calories than the age-dependent, pre-allotted amount.  If we use a lot of energy during a workout, our bodies try to make up for it by spending fewer calories on other things (like generating an inflammatory response) in order to stay within the daily TEE allotment.
Our bodies also adapt physiologically to regular exercise, becoming more efficient over time, burning fewer and fewer calories during exertion. For example, in one study, sedentary women who trained to run a half marathon increased their TEE at first but after a few weeks, gradually dropped back to about the same TEE as before they had started to train. This is hormesis at work. The body is getting stronger and more efficient by repeatedly stressing it in a consistent way over time.
Of course, it is possible to push through the limitations of our energy envelope with more extreme amounts of exertion. People who routinely exercise for many hours per day such as ultramarathon runners, Olympic swimmers, and Ironman triathletes can push their TEE beyond the envelope to induce weight loss. But even during extreme endurance activities, we quickly reach an upper limit to how many calories we can burn–about 2.5 times the basal metabolic rate (BMR) which is the amount we burn at rest.
This has repercussions for health–especially with regard to weight loss. After 35 years in clinical practice, it is abundantly clear to me that while exercise is a critical hormetic practice that strengthens the heart, lungs, and muscles, promoting longer lifespan and healthspan, it is not a good strategy as a monotherapy for weight loss. If, short of dedicating several hours a day to working out, we can’t exercise our way to an ideal body weight, then weight loss must be driven mainly by our diet.

II. Why Diets Fail

The strategy of most weight loss programs like Weight Watchers, Jenny Craig, and even Optavia (the program we use at the office) is to tilt the balance between calories consumed and calories burned. Taking in fewer calories while keeping activity levels constant can, in the short term, induce weight loss.
But calorie restriction diets only work for a while. After about 3-4 months, the weight loss hits a plateau. At this point, even if someone is consuming less than half their normal amount of calories, they will struggle to lose any more weight.
That’s because, over time, our bodies adapt to lower food intake by adjusting down our metabolism. A 30-year-old who spends too much time on a calorie restriction diet can lower her metabolic rate to a level comparable to a 70-year-old, and that’s bad. To make matters worse, when this happens it becomes very difficult to raise metabolism again–sadly, it doesn’t automatically adjust back upward when we resume eating more calories.
When weight loss stops due to slowed metabolism, we lose the feeling of reward that came with the initial good results. This leads most people to (understandably) drop the diet. And when they return to the eating habits developed over a lifetime–only now, in the context of a slower metabolism–they gain weight quickly.
Research shows that roughly 80% of people who lose significant weight on calorie-restriction diets, with or without exercise, will begin to regain their weight within the first year of coming off their diet and will regain, on average, more than half of what they lost within two years.

III. A Better Strategy: The Modern Human Diet

At our clinic, we promote a high-fiber, low-glycemic diet which I have called the Modern Human Diet (MHD) to induce and maintain healthy body weight.  The MHD resembles what is commonly referred to as the Mediterranean diet but it adds some science-based twists designed to promote better gut health and avoid sharp rises in blood sugar. 
When patients transition from the standard American diet (SAD) or from a calorie restriction diet to the MHD, they report better mental acuity, sleep quality, and overall feeling of wellbeing. Why?  The MHD diet keeps blood sugar stable. Most calorie restriction diets drive blood sugar too low and that doesn’t feel good (more about this below).
The MHD also improves the gut microbiome–the trillions of microorganisms that live inside our digestive systems and inform our health in myriad ways ranging from immunity to mood.  You can read more about the gut microbiome here.  But for the purpose of this post, it is sufficient to understand that diets like the SAD which are low in naturally occurring plant fiber are a key driver of obesity, diabetes, cardiovascular disease, and other forms of chronic illness because they deprive the gut microbiome of their food source: fiber. Without fiber, the healthy bacteria in our gut die-off leaving our health weakened.
Establishing comfort on the MHD diet is the prelude to the second phase of weight loss and makes up half of the blueprint for the style of eating that patients are encouraged to maintain long-term after they’ve reached the weight at which they feel and look their best. 

IV.  Fasting
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In recent years, intermittent fasting or time-restricted eating (also known as ‘the 16/8 method’) has become a popular weight loss technique. There are many versions of fasting being promoted in books and on the internet. Some make sense scientifically, many do not.
For the purpose of this discussion, fasting refers to taking in no calories for 24 or more continuous hours. This is something I have employed both personally and in my practice for many years. But there is a lot of misinformation regarding how it works and how to do it correctly.
It may seem strange but our bodies respond very differently to calorie restriction than to fasting. Unless we are on a highly carbohydrate-restricted diet (like keto), blood sugar can dip low enough during calorie-restricted diets to cause fatigue, headache, lightheadedness, extreme hunger, and impaired concentration. 

When you eat, your pancreas releases insulin to put the body into a state of energy storage. Insulin signals cells in the muscles and liver to take in glucose (sugar) absorbed from food and convert it into glycogen, the stored form of glucose that acts as a ready energy reserve. It also signals fat cells to convert glucose into triglycerides and store those as adipose or body fat. And insulin also directs liver, muscle, and fat cells to shut down the release of stored energy for use by the body. In short, when you eat high glycemic foods that cause blood sugar to shoot up (like baked goods, chips, and sweets) your body makes insulin and insulin is a hormone that promotes calorie storage while blocking calorie-burning.  If someone eating a high glycemic SAD with toast and jam or instant oatmeal for breakfast; a burger and fries or a sandwich and chips for lunch, and pizza for dinner, while sipping sweet soft drinks at work to keep their energy levels up, they are constantly over-secreting insulin which hangs around after meals.  If they skip a meal, their blood sugar will continue to drop as residual insulin drives it down lower and lower, making them feel ravenously hungry, tired, nauseated, light-headed, even sick.  
Let’s imagine that your body’s TEE envelope is 2,000 kcal/day when you begin a calorie restriction diet such as time restricted eating or Weight Watchers.  Prior to dieting, you had been consuming 2,500 kcal/day, on average, and had been gaining about 5 lbs. each year. If the new diet involves eating several times each day, that keeps insulin levels relatively high since you release insulin each time that you eat, and the effect of insulin on cells continues for 1-2 hours after a meal. So, even though you are restricting your intake to just 1,000 kcal/day, you don’t have access to the stored calories in glycogen (liver and muscles) or triglycerides (fat) because the regular secretion of insulin which blocks the release of stored energy won’t allow it! The result is a 1,000 kcal deficit that results in extreme hunger, fatigue, and other unpleasant symptoms until, eventually, metabolism slows down to meet the chronically reduced caloric availability of the diet.
Summing up to this point: calorie restriction in the context of a SAD means high insulin levels which block access to stored energy and low blood sugar which feels terrible.  And having access to just the 1,000 kcal that you are eating causes metabolism to adjust downward, setting you up for weight gain once you come off the diet and go back to consuming a more normal amount of calories.
So, if eating fewer calories than we burn is how we get rid of fat, how can we lose weight feeling miserable and slowing our metabolism?  At our practice, the weight loss journey begins by transitioning from a SAD to the MHD.  There are no blood sugar spikes on the MHD and once you are used to it (about a month), calorie restriction becomes easy.  Without all that extra insulin hanging around from blood sugar spikes, we feel tolerably hungry when we eat less without feeling tired or irritable.  But prolonged calorie reduction diets, including time-restricted eating, can lead to slowing of our metabolism so once we find we are able do with less, we introduce the second piece of the puzzle: fasting.  

It is counterintuitive that fasting does not slow our metabolic rate–in fact it slightly boosts it!  In addition, fasting causes the body to halt the release of insulin. Dropping insulin levels during fasting signals cells in the liver and muscles to start breaking down glycogen into glucose and releasing it into the blood for energy.  It also signals fat cells to do the same with regard to their stored triglycerides, breaking them down into glycerol and free fatty acids which are carried to the liver and converted into ketone bodies which serve as an alternative energy source to sugar.
Lowering insulin through fasting enables us to maintain our normal TEE, keeping metabolism high while burning fat, losing weight, and feeling well on a steady supply of energy supplied from mobilized glycogen and triglycerides (glucose and ketone bodies).
Summing up further: when you fast, you lower insulin and your body starts to eat its own stored energy, keeping metabolism high and inducing weight loss.

More Benefits To Fasting: Hormesis
In a recent briefing, I discussed the concept of hormesis, the physiological process whereby we grow stronger in response to repeated exposure to a particular stressor. I discussed how regular exercise and other practices such as sauna bathing have been shown to improve both lifespan and healthspan. Fasting is another hormetic practice. How does it work?
The cells of our body contain several distinct membrane-bound structures called organelles, each of which acts like a miniature organ doing its own special work inside the cell that ensures proper functioning. For example, the mitochondrion is an organelle that has the function of producing energy; the lysosome has the function of breaking large molecules down into smaller ones; and phagosomes are organelles that capture and eliminate foreign or toxic material such as viral proteins.
As we age, organelles like mitochondria and lysosomes start to lose energy and become less efficient. We also make fewer phagosomes as we age which lowers our self-protection. These organelles can collect toxins and defective old proteins that are unusable, mucking up their ability to perform their specialized jobs. Cells containing significantly dysfunctional organelles are referred to as senescent cells.

After about 24 hours without taking in any calories, we enter the hormetic fasting state which induces the production of a special kind of phagosome called an autophagosome.
Autophagosomes help repair or digest dysfunctional organelles within senescent cells as a way of extracting needed energy from them during fasting. They swallow up waste, attach themselves to lysosomes whose job is to break big molecules down into smaller ones, and then feed the cell by degrading these senescent organelles to release energy–a process known as autophagy.

Autophagy can be thought of as the body’s way of keeping energy levels high during cellular starvation and also as a way of getting healthier and stronger by clearing out toxic and dead materials to improve the quality and function of organelles within our cells. This is why people who fast regularly often look much younger than their age.
Fasting dramatically increases the number of autophagosomes within cells, driving autophagy. The longer we fast, the more autophagosomes we make, and the healthier and ‘younger’ our cells become. Of course, there are limits to fasting as there are to all hormetic practices. I personally fast for 26 - 28 hours 2 times per week and for 48-72 hours about once every 2-3 months. Many studies have demonstrated that fasting extends lifespan.

Studies vary in terms of how long a fast is required to increase the production of autophagosomes to induce autophagy. Some studies indicate autophagy may begin as soon as 16-20 hours without any calories. Most studies suggest it takes closer to 24 hours of fasting to induce autophagy. And it looks like the rate of autophagy continues to increase during prolonged periods of fasting, reaching peak levels at about 2 - 3 days. It also seems that fasting during the night may promote more autophagy than daytime fasting so, for example, fasting from breakfast to breakfast may induce more autophagy than from lunch to lunch or dinner to dinner.

Fasting is part of our evolution

Humans evolved over a period of about 6 million years, during which time we lived by a rhythm of feasting and fasting that was necessitated by our natural environment. During cold seasons, floods, droughts, or other environmentally hostile periods when little plant food was available for consumption, humans would often go days or longer before they were able to kill an animal and feast for a day or two, surviving in the interim on just water and whatever calories they had been able to store in their bodies.  Animal migration and hibernation added to the food scarcity issue, especially during wintertime.  
Because of this feasting-and-fasting pattern of eating, our bodies evolved to become excellent at storing fat. That served us well throughout most of our evolutionary history when calories were often scarce. But now, amidst unprecedented abundance, both in terms of the density of calories in today’s extremely carbohydrate-rich processed foods and the ever present availability of things to eat in advanced societies like ours, this evolutionary advantage today is working against us.  For nearly all of our history as a species, getting enough to eat was our greatest day-to-day challenge. Now, one of our greatest challenges is learning how to eat less!

Autophagy is an evolutionary adaptation. A way of promoting health and self-preservation by utilizing the reserve energy of intracellular toxins, senscent proteins and other debris to feed starving cells while cleaning them and bringing them back to optimal functioning.
When modern societies conceived of the ‘three square meals a day’ pattern of eating, this represented an attempt to ensure that all citizens were afforded adequate nutrition. We didn’t know it then, but this rhythm of feeding, designed to put an end to malnutrition, closed us off from the hormetic practice of fasting which had been part of human societies for millions of years.

And today, with food not only exceedingly available but also manufactured to be hyper-delicious (to the point of driving ‘soft addictions’), most people eat more than three times per day, supplementing their meals with snacks–some of which are taken strictly for pleasure. And many of us now habitually eat throughout the day to soothe anxiety, loneliness, boredom, or stress. Snack food manufacturers have succeeded in promoting this as part of a lifestyle and have even invented the concept of ‘healthy snacking’ as though supplementing meals with better quality food could make snacking a health practice. But we now know that the opposite is true. Snacking drives up insulin and insulin blocks fat burning. Snacking is making us fat.

Fasting is more than a tool for weight loss, it’s a health practice
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When we lose weight through fasting, we maintain our metabolic rate, burn fat, and enjoy good energy and mental clarity. Fasting turns on autophagy, reversing our biological age, and induces the production of hormones called sirtuins that have been shown to protect against cancers and extend lifespan. Weight loss achieved through fasting is less likely to result in rebound weight gain, feelings of misery during the weight loss period, or the development of stretch marks once the fat goes away.
Fasting, it can be said, is a tool for health and happiness. It stresses the body hormetically, making it stronger and healthier when done consistently over time. It has been a traditional practice among many cultures and a spiritual practice among many different religions. It promotes a kind of physiological cleansing at the cellular level, the benefits of which can be felt almost immediately among those who commit to doing it.

C19 Weekly Briefing Supplement on the importance of maintaining high circulating levels of neutralizing antibodies through vaccine boosters.  

Booster Shots

The new wave of the pandemic is being driven by Delta which bypasses prior immunity at a higher rate than any previous variant.  How is Delta managing to do this?  It appears likely that some combination of mutations allow it to escape key neutralizing antibodies while affording it the ability to generate more viral copies (viral titers among people infected with Delta are 1,000 times higher than those of people infected with the original strain of the virus), combined with timing.  People have the highest level of neutralizing antibodies shortly after getting vaccinated or infected and then those levels wane gradually over months until they are low enough to allow for breakthrough infections.  It is likely that those who were vaccinated or infected several months ago have less immune protection against getting infected than those who were vaccinated or got infected more recently.  

The process of getting C19 starts with exposure–a person inhales viral aerosols that stick to mucous membranes in the nose, nasopharynx, or lungs.  This is called colonization.  If someone has high levels of circulating neutralizing antibodies in the immune system of the mucous membranes (called the "MALT"), they can kill off the virus before it penetrates into the body's interior to cause an infection.  This is what happens in most people who were recently vaccinated.  However, as circulating neutralizing antibody titers wane over time, the MALT has fewer soldiers to keep colonization contained and this allows breakthrough infections to occur.

There are now sufficiently ample data showing that an additional shot of vaccine boosts circulating neutralizing antibodies to levels much higher than those seen after completion of the initial vaccination regimen.  This should provide those who get booster shots with much stronger protection against getting infected (lots of neutralizing antibodies circulating in the MALT).  And there have been no reports of adverse events from receiving a third shot of mRNA vaccine or a second shot of Janssen vaccine.  So what's the delay and why are so many experts still not recommending booster shots across the board?  Three reasons have been given: 

1. It isn't fair that some people get a third shot when others have not received even one shot.  This is the argument the WHO is making against boosters in rich countries.  And on a global level, they have a good point.  But this is not a scientific argument and domestically, we have more vaccine here than people who want it.  In fact, we are throwing out thousands of doses every day.  Why not make use of them instead of throwing them away? 
2. Breakthrough infections rarely lead to severe disease because B and T cells are durable and once the infection takes hold in someone who has been vaccinated, it is very unlikely to land them in the hospital and extremely unlikely to kill them.  Therefore, since breakthrough infections are less severe, boosters are not needed.  True, but C19 is a disease with at least two and possibly three phases.  The first is the acute viral phase when some people get very sick and die.  The current standard vaccination regimen, as stated, is sufficient to protect against this.  The second is the post-viral phase when about 30% of people struggle with ongoing physical and mental symptoms (long-covid).  And a potential third phase to the disease has yet to be seen: what happens down the road to patients whose hearts, brains, blood vessels, lungs, etc., have been damaged by the primary infection?  Will they develop higher rates of cardiovascular or Altzheimer's disease?   These latter two phases of C19 can happen to people who have mild or even asymptomatic viral periods and there is no indication that this will not happen or will happen less often among vaccinated persons who experience breakthrough infections.  
3. We don't yet know if boosters will help, harm, or do nothing because large scale Phase III clinical trials have not been conducted.  That's also true, but there are significant preliminary data showing boosters to be both safe and likely highly effective at helping prevent infections and no data to suggest otherwise.    

The focus of most public health and infectious disease experts has been on the acute viral period of C19.  That's largely because, while some other infections can cause long-term health consequences, most do not, and most doctors by training are concerned about preventing severe illness and death.  But C19 has shown itself to be different from other common RTIs in so many ways (it's airborne, it's more contagious, it's more deadly, it shape-shifts more quickly than expected, etc.) and the fact that it causes such a high degree of chronic and potentially chronic illness is just one more distinguishing feature of this novel virus.  It is not unreasonable to be concerned that in the end, the second and third phases of C19 will wind up taking a larger toll on society than the (sometimes deadly) first phase.  If boosters were available today, I'd take one immediately.  

943. Iceland recommends booster shots for all citizens who got Janssen at 8 weeks post-vaccination.  
https://www.landlaeknir.is/um-embaettid/frettir/frett/item47133/maelt-med-orvunarbolusetningu-fyrir-einstaklinga-sem-fengu-covid-19-boluefni-janssen

944.  Moderna seeks authorization of the first variant-specific booster shot; but it's tuned to Beta, not Delta.  
https://www.healio.com/news/primary-care/20210225/moderna-sends-variantspecific-vaccine-to-nih-for-clinical-study

945.  Pfizer submits data from Phase I clinical trials on booster doses which they now recommend for the general population.  Boosters triggered the production of significantly higher levels of circulating neutralizing antibodies against Delta.  
https://www.cnbc.com/2021/08/16/covid-vaccine-booster-shot-pfizer-submits-data-to-fda-for-approval.html

946.  Dr. Fauci: "Everyone will need a booster shot."  
https://www.cnbc.com/2021/08/12/covid-booster-shot-fauci-says-it-is-likely-everybody-will-eventually-need-a-third-vaccine.html

947.  Israel is now doing booster shots for all persons 50 and over and for all healthcare workers. 
https://www.voanews.com/middle-east/israel-rolls-out-covid-booster-shots-anyone-over-50

948.  Biden Administration to approve booster shots for most Americans at 8 months post-vax, beginning with healthcare workers. 
https://www.nytimes.com/2021/08/16/us/politics/booster-shots.html