The Science of Intermittent Fasting

by Cory Smith

Aging, metabolism and caloric restriction

"To lengthen thy life, lessen thy meals." ~Benjamin Franklin

A major public health concern of our 21st century society is overeating and inactivity which has led to ~42.4% of the US population being classified as obese(1) defined as having a body mass index of greater than 30. Obesity is a risk factor for many severe diseases including cardiovascular disease, type 2 diabetes, stroke, and kidney problems. Despite awareness of these risks the incidence of obesity is increasing with no clear resolution in sight. There is a long history of experiments demonstrating that reducing the amount of food eaten increases healthy lifespan. First shown in a 1935 study by C. M. McCay that rats receiving less food attained extreme ages with less frequency of disease(2). It should be noted that to achieve these beneficial results to health and longevity the diet must be well balanced and lack any nutritional deficiencies. Simply starving yourself won’t cut it, obviously. This has been replicated in other animals including primates (rhesus monkey) and is a continued area of study nearly a century later(3).

During the early history of humanity, we did not have the regular three meals per diem and would often go several days without eating. Our bodies evolved under these conditions and are prepared for periods of intermittent fasting. It may even benefit our health in many ways. In this post I will review the science of caloric restriction, its cellular and molecular mechanisms, its role in maintaining proper circadian rhythm, a strong immune system and proper glucose-insulin signaling. An organism’s ability to maintain a relatively stable equilibrium of internal, physical and chemical conditions ideal to its survival is known as homeostasis. The systems that maintain homeostasis are linked to ancient survival circuits ubiquitous amongst living organisms. You may think that optimum health is achieved by keeping strict homeostasis of all our vital living conditions but as it turns out, getting a little bit outside your comfort zone may build resilience and strength. This concept is known as hormesis which suggests that there may be bioprotective advantages to low level exposure to several environmental stimuli including temperature, DNA repair, antioxidant function, apoptosis and immune response.

"He who buries his head deep into a nosebag full of food cannot hope to see the invisible world." ~Al-Ghazali

Most of us grew up with the phrase “breakfast is the most important meal of the day,” but as it turns out this may have been more to do with marketing than public health. Even talking to most nutritionists today they will emphasize breakfast and eating consistent snacks throughout the day. As new research comes out on the effects of caloric restriction and intermittent fasting in healthy humans it may be time to rethink many of our eating habits and culture around food.

Health benefits of caloric restriction

One of the few experimentally validated ways to extend lifespan in mammals is to reduce the total amount of food consumed, also known as caloric restriction. While the average lifespan has been steadily increasing primarily due to decreased infant mortality rate and increased recovery and resistance to infectious disease, the maximum lifespan hasn’t improved much for humans(4). There is an inverse relationship between the total caloric intake in mammals and their average as well as maximum lifespan(5). This extension of life was observed even when caloric restriction was initiated in middle aged mice, although the greatest extension was seen in mice with a restricted diet their entire lives. While these changes may takes years of commitment to observe changes in lifespan other beneficial effects such as reduced blood glucose and insulin levels have been reported after only a few days to a few months but return to normal after the modified diet has been ended(6). There is evidence that caloric restriction achieves an anti-inflammatory response by increasing cellular oxidative stress, decreasing reactive oxygen species (ROS), increasing bioavailability of NO leading to a suppression of vascular disease progression and aging effects(7).

"Fasting today makes the food good tomorrow." ~German Proverb

Sirtuins are a set of evolutionarily conserved genes that regulated metabolic activity and DNA repair that aid in signaling the body (or cell) to slow down reproduction and focus on rejuvenation. Dr. David Sinclair, a professor researching aging at Harvard, has hypothesized that this ancient survival circuit was one of the first genes evolved by our primordial single cell ancestors that enabled them to ‘hunker down’ in times of stress allowing for enhanced DNA repair at the cost of cellular division or reproduction. Bypassing the primal evolutionary urge to reproduce at all costs, this sensor circuit is still linked to metabolic fitness and longevity today and is the foundations of the company Elysium (https://www.elysiumhealth.com/en-us/science-101/why-sirtuins-are-important-for-aging). SIRT1, one of the seven sirtuins in humans, is induced by caloric restriction, and by fasting(7). Boosting expression of sirtuins has been shown to extend lifespan in worms(8), flies(9), fish(10), and mice(11). Sirtuins are Nicotinamide adenine dinucleotide (NAD) dependent enzymes which is a major hub in metabolism that you may remember from high school biology for its role in glycolysis and oxidative phosphorylation. SIRT3 is found in high levels in brown adipose tissue and increases expression in response to exercise and cold exposure(12).

When I was young, I observed a couple from Germany sitting in the snow, calm and collected and asked my dad, why are they doing that? We tried it out ourselves and enjoyed the cold shock and adaptation that occurred by trying to tough it out and the tingles that occurred when we jumped back into the lukewarm swimming pool in the Colorado mountains. I just did it to be adventurous and try new things, but I may have been setting up my brown fat and sirtuins for success! Dr. David Sinclair suggests this in his book Lifespan: Why We Age—and Why We Don’t Have To (https://www.amazon.com/gp/product/1501191977/ref=as_li_tl?ie=UTF8&camp=1789&creative=9325&creativeASIN=1501191977&linkCode=as2&tag=yogasciencear-20&linkId=9a4df30ff2122b52b192929c76fc7b72) that all the hallmarks of aging may have a single cause related to mis-regulated sirtuins and NAD availability:

  1. Genomic instability and DNA damage
  2. Degradation of telomeres
  3. Epigenetic dysregulation
  4. Disruption of proteostasis, normal protein regulation
  5. Deregulation of nutrient sensing and metabolism
  6. Mitochondrial dysfunction
  7. Cellular senescence
  8. Stem cell depletion
  9. Buildup of extracellular debris
  10. Disrupted intracellular communication
  11. Increased production of inflammatory molecules

Caloric restriction has been studied in primates since the early 1990’s and found to be safe (13), and have beneficial effects in terms of body weight, and body fat compared to control rhesus monkeys (14). A longer term study of rhesus monkeys started caloric restriction later in life (18.5 to 21.5 years old) and found that after 9 years the animals on the caloric restriction diet had improved survival, body weight, fasting glucose levels, and age-related morbidity (15). While there have been some contradictory results indicating no beneficial effect, this is likely due to methodological explanations such as not providing enough water for the animals on caloric restriction(16).

Intermittent Fasting

“There is evidence to suggest that the circadian rhythm fasting approach, where meals are restricted to an eight to 10-hour period of the daytime, is effective” – Dr. Deborah J. Wexler

An alternative to simply reducing the amount of food eaten is to restrict the period of eating also known as intermittent fasting. Humans, and most animals, evolved under conditions of intermittent fasting leading our biochemistry and genetics to be tuned to handle days without eating. In our modern culture endorsing three square meals a day in addition to treats, brunch, and midnight snacks, the idea of fasting may sound like blasphemy but in many ways is returning to our ancestral diet. Here are the most common eating schedules to implement intermittent fasting:

  1. Time Restricted Eating also known as 16:8
  2. Eat-Stop-Eat also known as 5:2
  3. Alternate day fasting
  4. OMAD – One Meal A Day

Time restricted eating is a type of intermittent fasting that involves limiting the time of day that eating occurs, typically a 16 hour fast each day with an 8-hour eating window. This can be achieved by skipping breakfast and late-night snacks. This is one of the few methods that has shown promising results when tested in humans(17). Although this study investigated people with metabolic syndrome (a precursor to diabetes) the results showed improvements in weight loss, reduced waist size, lower blood pressure, and reduced lipids and cholesterol levels. It is as yet unverified to have beneficial effects in healthy people but based on other mammalian and primate studies its very promising. Another regimen for intermittent fasting is known as 5:2. This schedule of eating involves eating normally for five days of the week but only eating about ¼ of your normal calories for two nonconsecutive days. Alternate day fasting is pretty self-explanatory as it involves a complete day of fasting followed by an unrestricted diet the next day. One meal a day or OMAD involves eating one meal each day typically around the same time resulting in ~24 hour daily fast. This diet has recently been endorsed by Twitter CEO, Jack Dorsey (https://www.businessinsider.com/fabulous-life-of-billionaire-jack-dorsey-taking-square-public), and is the preferred diet of Dr. George Church.

Fasting produces a few other notable effects such as inducing autophagy, increased human growth hormone, reduced fasting glucose levels, reduced insulin resistance and weight loss. Autophagy (self-eating), a process by which old or misfolded proteins and components of the cell are broken down and recycled resulting in reduced inflammation. This process occurs by tagging the old proteins for delivery to the lysosome, a membrane bound organelle in Eukaryotes with an acidic environment and digestive enzymes responsible for breaking down and recycling old organelles, proteins, food, and even engulfed bacteria or viruses. Mice that are deficient in autophagy suffer from reduced lifespan, and early induction of p53 leading to premature neuron death(18). As expected, intermittent fasting is beneficial to achieving weight loss and of the 27 trials available in humans results in a 0.8% to 13.0% reduction in baseline weight without serious adverse effects(19). The studies which compared intermittent fasting to general caloric restriction found similar results. Intermittent fasting may be beneficial to patients with metabolic syndrome also known as prediabetes by improving glucometabolism. While it remains controversial whether these benefits all derive from the weight loss associated with fasting, recent human studies have shown benefits independent of weight loss including increased insulin sensitivity, and  cell responsiveness along with decreased blood pressure, oxidative stress and appetite(20). Many of these benefits are attributed to the lysosome-autophagy pathway mentioned earlier along with increases in neurogenin3, which promotes endocrine progenitors such as the beta cells in the pancreas(21).

“Whether the condition is diagnosed as a severe cold, as influenza, or as pneumonia, the first thing that should be done is to stop eating. Absolutely no food, but water, should be allowed to pass the patient’s lips until the acute symptoms have subsided. No drugs of any kind should be resorted to. Go to bed and rest. Keep warm. Rest, fasting, warmth, — these are the needs. Have plenty of fresh air in your room. Under these conditions you may lie in bed and get well in a short time with no complications and no sequels…. You don’t need treatment. The fever, inflammation, coughing, etc., constitute the healing process. Just get out of their way and permit them to complete their work. Don’t try to ‘aid nature.’ She doesn’t need your puny aid — she only asks that you cease interfering.” ~Herbert M. Shelton

Immune system deficits or over-reactivity are associated with aging and a variety of related diseases. Many promising therapies of the future involve immune modulation such as the Chimeric Antigen Receptor T-Cells (CAR-T) which reprograms the immune cells to detect a specific antigen, CD19, along with a T-cell activating protein within a single receptor. The word chimera derives from Greek mythology of a monster with a goat’s body, the tail of a serpent, and the head of a lion. Modern science has aptly used this term to describe in this case a receptor that has two dual functions. More commonly this refers to an animal that is composed of multiple different types of genetically distinct cells.

How does diet, caloric restriction and fasting relate to the immune system? This question has been studied by many researchers with promising results revealing a potential mechanism for how periods extending fasting alter the body. Unlike general caloric restriction and intermittent fasting which we have discussed so far, the next two experiments on immune function use a diet of prolonged fasting (48-120 hours). The physiological changes that occur during other types of fasting are further pronounced during prolonged fasting, but after 24-48 hours the body fully switches from the stored glycogen reserves as they are depleted and begins fat and ketone body catabolism. The body reduces pro-growth signaling and gains enhanced resistance to toxins, such as chemotherapy(22). Additionally, as the body seeks new sources of energy it increases a process known as autophagy, or self-eating, which breaks down damaged or undesirable molecules within cells and repackages them into building blocks to be recycled. This may seem stressful or damaging to cells but is in line with previous observations of hormesis, pushing the body outside its normal living conditions actually strengthens the systems of homeostasis and promotes health and longevity. Natural autophagy decreases with age which leaves room for damaged or toxic cells to accumulate and wreak havoc on normal metabolic processes.

“In a fast, the body tears down its defective parts and then builds anew when eating is resumed.” ~Herbert M. Shelton

Prolonged fasting represents a powerful mean to modulate key regulators of cellular protection and tissue regeneration but also provide a potential therapy to reverse or alleviate the immunosuppression or immunosenescence caused by chemotherapy treatment and aging, respectively. There may also be reported benefits affecting hematopoiesis, immune function, and other systems and organs (23). Prolonged fasting was also shown to benefit lymphocyte protection and alterations to hematopoietic stem cells that promote stress resistance, self-renewal and lineage balanced regeneration(23). These changes collectively boost immune function, and regeneration capacity towards a more youthful phenotype. A more recent study in mice observed a similar boost to the immune system, along with many other benefits including regulation of key proteins consoling glucose and lipid metabolism, circadian clock, DNA repair, cytoskeleton remodeling, immune system and cognitive function (24). This study used a dawn to dusk fasting regime and suggests that it can be a preventative therapy in cancer, metabolic syndrome, and several neuropsychiatric diseases. There is now evidence that caloric restriction promotes a healthy sleep-wake cycle, also known as circadian rhythm(25) by modulating the daily changes in leptin levels. Leptin is a hormone that regulates energy storage by inhabiting hunger and is produced primarily by adipose tissue and acts on the hypothalamus and skeletal muscles by decreasing thyroid and increasing mitochondrial efficiency respectively.

My Experience with Intermittent Fasting

When I first learned about the health and longevity benefits of caloric restriction, I considered implementing it in my own life, but I loved eating too much to make that sacrifice. It didn’t seem worth it to live in hunger without enjoying the full culinary experience. The stories of those who chose to embrace this lifestyle of reduced food intake seemed to be a bad trade in my opinion and reading their stories reaffirmed that this was similar to accepting lifelong torture and hunger for a few extra years. I wanted something that would not only extend the lifespan but extend the healthspan, the length of healthy, happy and vibrant years to your life. After years of reading about the benefits of fasting the tipping point for me was my renewed interest in resistance training and the proper diet that goes along with it. Many of my favorite personal fitness twitter personalities were endorsing the diet with apparent success and touting the psychological benefit of controlling your urges for hunger to gain mastery over the mind in other areas of your life as well. This particularly interested me due to similarities to Patanjali’s Yoga Sutra’s and its ‘science’ of the mastery of the mind. Then when one of my new co-workers in the Church lab, Raphael, told me that he was following the diet and sent along a recent review(26) I was committed and decided to try this out myself.

I jumped right into an 8-hour time restricted diet and found the transition difficult at first. My stomach would rumble, and I experienced discomfort and extreme hunger as I counted down the hours until my mid-day meal. I didn’t expect this as I would often skip breakfast but would usually have at least a snack before noon. My body was conditioned to its morning meal and tried to convert me back to my old ways. This subsided after about a week and I know now that having a glass of sparkling water limits these sensations releasing the uneasy stomach with a burp and satisfaction without any caloric intake. Even when I would skip breakfast before starting intermittent fasting, I would frequently drink a glass of chai tea latte with some milk. I found this habit the hardest to break but now I limit my milk tea drinking to the afternoon eating interval. Others have recommended black coffee in the morning to limit appetite while fasting, this may work for you, but I have always hated the taste of coffee. Others have suggested tea without sugar or milk, but this upsets my stomach when taken before food.

After a tough week of adaptation, I really began to enjoy the benefits of intermittent fasting. The first change I noticed was a ravenous appetite and increased satisfaction of eating when I would break my fast at mid-day. I started timing my weightlifting at the gym to occur right before my first meal and would consume all my protein first within the meal to stimulate the anabolic growth process right after resistance training. This totally changed my perspective on hunger and food making the protein in my meal smell and taste so delicious I would just devour it. My HDL cholesterol or good cholesterol increased ~50% after six months of intermittent fasting without increasing LDL. As I continue and adapt to this diet, I will share updates and new science as it comes along. Live long and prosper!

Other resources

https://www.hsph.harvard.edu/nutritionsource/healthy-weight/diet-reviews/intermittent-fasting/

https://www.medicalnewstoday.com/articles/327398#diabetes

https://www.forbes.com/sites/stevensalzberg/2020/01/06/can-intermittent-fasting-reset-your-immune-system/#2eb0bf8327ac

https://www.healthline.com/nutrition/intermittent-fasting-guide#benefits

P. D. Mangan (@Mangan150)

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