Nature’s Anti-Aging Resilience Diet: Flipping the Metabolic Switch

No topic in the health sciences is more fundamental or more poorly understood than nutrition. How and what we eat now causes more disease and death than any other health risk factor. About half of all American adults have one or more preventable, diet-related chronic diseases.

Our norm of three meals a day with snacks between is antithetical to our biology. Recent research suggests a new paradigm with remarkable effects on aging, disease and weight control.

It’s about time.

Caloric restriction (CR), a dramatic reduction in caloric intake without malnutrition, has been shown to not only reduce weight but prolong healthy lifespan in a variety of species from worms to nonhuman primates. Risk for cardiovascular disease, diabetes and cancer, the leading causes of death and disability, are markedly diminished by CR regimens. However, few people can tolerate the deprivation. It is also associated with undesirable side effects such as fatigue, loss of libido, impaired cold tolerance and muscle wasting.

These obstacles drove a quest for a more user-friendly variation of CR. Valter Longo, at the Longevity Institute USC, was a pioneer in so-called fasting-mimicking diets. He demonstrated that 5 days of CR per month for three months caused beneficial changes in risk factors of age-related diseases in humans. 5 days of CR is still a tough ask.

A big breakthrough came in 2012. Satchidananda Panda at the Salk Institute for Biological Studies found that mice fed a high-fat diet eight hours per day were healthier and leaner than mice allowed to eat the same diet whenever they wanted, even though both groups consumed the same number of calories. The key variable appeared to be defining a daily time frame for feeding and fasting, hence the name — Time Restricted Feeding (TRF).

Panda then investigated this effect under a variety of conditions that mimic the real world.

The team studied TRF with preexisting obesity and diverse diets (high fat, high sugar, high fat and sugar). TRF appeared to prevent elevated cholesterol, insulin resistance and inflammation despite the consumption of these obesity-causing diets. In other words, it seemed to block the pathological consequences of the eating habits of many Americans. The benefits were proportional to the fasting duration.

This signaled the beginning of the Intermittent Fasting (IF) movement. IF diets are defined by the duration and frequency of the fast. Daily IF requires 12–16 or more hours without eating. In alternate-day fasting (ADF), one alternates between zero calorie consumption one day and unrestricted feeding the next. A middle ground IF, alternate-day modified fasting (ADMF), entails alternating between a day of consuming few calories (<25% of energy needs) and eating without restriction the next.

These IF regimens have been shown to trigger many of the same biological pathways as caloric restriction.

How could this scheduled eating regimen have such profound effects?

Two components are at play.

Flipping the Metabolic Switch

The body can use either glucose or fatty acids for fuel. After eating, glucose provides energy and unused glucose is stored as glycogen, an easily mobilized form of glucose. In the absence of long or intense physical activity, glycogen is not depleted and unused glucose is converted to triglycerides and stored in fat tissue.

Sufficient fasting first empties the glycogen stores and then taps fat tissue. Triglycerides are broken down to produce fatty acids. The liver converts these fatty acids to ketone bodies that can be used as fuel. Ketone levels begin to rise after 8 to 12 hours without food. The time needed to flip the metabolic switch depends on the starting liver glycogen content and on energy expenditure during the fast.

This metabolic switch from glucose to ketone utilization activates evolutionarily conserved cellular responses that improve glucose regulation, increase stress resistance and suppress inflammation. In the fasted state damaged molecules are repaired or removed. This has been shown to improve or prevent a wide range of disorders including obesity, diabetes, cardiovascular disease, cancers and neurodegenerative brain diseases.

It is striking that both physical and mental function is improved with IF. Endurance, coordination and balance are increased and muscle mass is maintained despite the regular period of fasting. Ketones allow greater energy production and appear to increase the generation of mitochondria. Ketones also boost levels of brain-derived neurotrophic factor, a protein which is essential for maintaining healthy neurons and creating new ones. Spatial memory, associative memory and working memory are all enhanced by IF.

The fact that a period of food deprivation flips a metabolic switch that enables superior functioning makes sense from an evolutionary perspective. As hunter-gatherers we did not have breakfast before going out in search of food. Our most important activities for survival were carried out on an empty stomach. Persistence hunting consisted of long periods of moderate effort punctuated by short bouts of maximal sprints. Gathering required precise memory for identification of nourishing and poisonous plants.

The contemporary cultural norm of three meals per day with snacks eliminates the possibility of this higher level of function. Humans have lived as hunter-gatherers for 99% of our existence. Our physiology is the result of millions of years of adaptation to periods of food scarcity during which superior cognitive and physical performance conferred survival. We now know that our feeding habits not only impair our fitness but fuel an epidemic of chronic diseases.

Time of Day

The second component is when you eat and when you fast.

Recent discoveries have shown that a meal consumed at 8 a.m. is not processed the same way as an identical meal consumed at 8 p.m.. All mammals possess this metabolic circadian rhythm (changes that follow a 24 hour-cycle driven by environmental light and darkness) for good reason.

Energy requirements are defined by activity level. The human day (until recently in our history) consisted of an active daylight phase and a resting night phase. This resulted in the evolution of a metabolic day shift, so to speak, bearing little resemblance to the night shift. Daytime metabolism excelled at eating, energy harvesting and storage while nighttime metabolism was designed for fasting and accessing stored energy. Melatonin, the body’s expression of darkness, orchestrates these changes.

Traditionally, melatonin was considered primarily as a sleep cue. It is now recognized as the most powerful messenger to switch from active to resting metabolic function, a chemical signal of day’s end. Darkness triggers the secretion of this ancient hormone. Light, whether natural or artificial, blocks melatonin secretion.

The widespread adoption of electric lighting ended sunlight-entrained human circadian rhythms. Illuminated night blocks the natural transition to a fasting state. Energy (calorie) acquisition and storage continue. Even dim light at night has been shown to significantly decrease melatonin secretion in humans. This disconnection from nature’s clock is now considered an important cause of our struggle with weight gain.

Melatonin exerts its effect on weight by modulating the action of several key metabolic hormones such as insulin, ghrelin and leptin. These hormones orchestrate appetite, satiety, calorie uptake and fat storage. It also appears to increase activity level and core body temperature thereby increasing energy expenditure. Investigators believe this increased calorie usage is due to activation of brown fat. Unlike white fat (most body fat) that stores energy, brown fat burns up lots of extra calories by producing heat.

Animals who have had the pineal gland (location of melatonin production) removed become overweight. Timed administration of melatonin reverses the weight gain. In addition, middle-aged fat animals given melatonin and studied to old age showed decreased weight and visceral fat. These changes were eliminated if melatonin was withheld.

Getting Started

For most people any departure from 3 meals a day with snacks between is a shock to the system. Switching to an IF regimen often causes intense hunger, irritability and impaired concentration. .Side-effects usually subside within a month. Elimination of all snacks is a good starting point. Then gradually lengthen the time interval between dinner and the first meal of the next day. The goal is to fast for 16 to 18 hours per day.

It is important to note that IF can be dangerous for diabetics. The risk of hypoglycemia is a concern. These regimens should be discussed with a physician.

Thinking about the fact that as cavemen and women didn’t have breakfast, ready foods or fridges. They must have not only been very hungry, but they must have been very healthy & brainy too. Hence the evolution of societies and industries. Imagine knowing nothing but that there T-Rex wants to kill me and I need that food else I’ll starve. How resourceful must they have been and were to become? What an enticing thought that is.

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