When rodents are kept in captivity they are usually given their food in one go which they eat in one or two hours and then they fast for 22 hours. Most carnivores in nature eat one meal a day or maybe even every other day, depending on if they can find food to eat. Even the lordly lion goes hungry sometimes. Why did humans develop the three meals a day plus snacks habit and is this the best regime? In a 1997 article in the New England Journal, Weindruch and Sohal showed that reducing food availability over a lifetime (caloric restriction) has remarkable effects on aging and the life span in animals. May be it is good news that in a world which has managed to overpopulate itself, mismanaged both food production, equity of food availability, and climate change a bit of hunger is good for the human race. Hundreds of studies in animals and scores of clinical studies of controlled intermittent fasting regimens have been conducted in which metabolic switching from liver-derived glucose to adipose cell–derived ketones occurs daily or several days each week.
This image given below also taken from NEJM shows that the nucleus has to deal with stress which it tries to reduce, proteostasis and autophagy (remember that the proteins in our bodies are not only metabolically active molecules but also serve the function of growth, repair and endocrine signalling and also need to be removed when no longer needed but may also serve as sources of food and energy), regulate glucose and fat metabolism, mitochondrial biogenesis and cell survival. Hence health and stress resistance are closely linked to each other.
Many of the health benefits of intermittent fasting are not simply the result of reduced free-radical production or weight loss. Intermittent fasting is an evolutionarily conserved, adaptive cellular response that is integrated between and within organs in a manner that improves glucose regulation, increases stress resistance, and suppresses inflammation. Remember well stocked shelves in grocery stores have only recently become a feature of our lives. We need our hunter-gatherer reponses to stay healthy and stress free. During fasting, cells activate pathways that enhance intrinsic defenses against oxidative and metabolic stress and those that remove or repair damaged molecules. During the feeding period, cells engage in tissue-specific processes of growth and plasticity. However, most people consume three meals a day plus snacks, so intermittent fasting does not occur.
Preclinical studies consistently show the robust disease-modifying efficacy of intermittent fasting in animal models on a wide range of chronic disorders, including obesity, diabetes, cardiovascular disease, cancers, and neurodegenerative brain diseases. Periodic flipping of the metabolic switch not only provides the ketones that are necessary to fuel cells during the fasting period but also elicits highly orchestrated systemic and cellular responses that carry over into the fed state to bolster mental and physical performance, as well as disease resistance.
Studies in animals and humans have shown how intermittent fasting affects general health indicators and slows or reverses aging and disease processes. During periods of fasting, triglycerides are broken down to fatty acids and glycerol, which are used for energy. The liver converts fatty acids to ketone bodies, which provide a major source of energy for many tissues, especially the brain, during fasting. In the fed state, blood levels of ketone bodies are low, and in humans, they rise within 8 to 12 hours after the onset of fasting, reaching levels of 0.2 to 0.5 mM, which are maintained through 24 hours, with a subsequent increase to 1 to 2 mM by 48 hours. In rodents, an elevation of plasma ketone levels occurs within 4 to 8 hours after the onset of fasting, reaching millimolar levels within 24 hours. Intermittent fasting in humans should be recommended for 12-18 hours. The three most widely studied intermittent-fasting regimens are alternate-day fasting, 5:2 intermittent fasting (fasting 2 days each week), and daily time-restricted feeding as recommended above.
Why do we need to switch to a ketone based metabolism? Ketone bodies are not just fuel used during periods of fasting; they are potent signaling molecules with major effects on cell and organ functions. Ketone bodies regulate the expression and activity of many proteins and molecules that are known to influence health and aging. These include peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α), fibroblast growth factor nicotinamide adenine dinucleotide (NAD+), sirtuins, poly(adenosine diphosphate [ADP]–ribose) polymerase 1 (PARP1), and ADP ribosyl cyclase (CD38). By influencing these major cellular pathways, ketone bodies produced during fasting have profound effects on systemic metabolism. Moreover, ketone bodies stimulate expression of the gene for brain-derived neurotrophic factor, with implications for brain health and psychiatric and neurodegenerative disorders.
Some improvements are caused by weight loss: such as improvements in glucose regulation, blood pressure, and heart rate; the efficacy of endurance training; and abdominal fat loss. Intermittent fasting stimulates autophagy and mitophagy while inhibiting the mTOR (mammalian target of rapamycin) protein-synthesis pathway. These responses enable cells to remove oxidatively damaged proteins and mitochondria and recycle undamaged molecular constituents while temporarily reducing global protein synthesis to conserve energy and molecular resources. These pathways are untapped or suppressed in persons who overeat and are sedentary.
Does intermittent fasting affect aging and longevity? Goodrick and colleagues reported that the average life-span of rats is increased by up to 80% when they are maintained on a regimen of alternate-day feeding, started when they are young adults. However, the magnitude of the effects of caloric restriction on the health span and life span varies and can be influenced by sex, diet, age, and genetic factors. In two. trials, overweight women (approximately 100 women in each trial) were assigned to either a 5:2 intermittent-fasting regimen or a 25% reduction in daily caloric intake. The women in the two groups lost the same amount of weight during the 6-month period, but those in the group assigned to 5:2 intermittent fasting had a greater increase in insulin sensitivity and a larger reduction in waist circumference. Young men who fast daily for 16 hours lose fat while maintaining muscle mass during 2 months of resistance training.
In a clinical trial, older adults on a short-term regimen of caloric restriction had improved verbal memory. There is certainly a need to undertake further studies of intermittent fasting and cognition in older people, particularly given the absence of any pharmacologic therapies that influence brain aging and progression of neurodegenerative diseases.
How can we use intermittent fasting in clinical practice?
Weight loss: in a 12-month study comparing alternate-day fasting, daily caloric restriction, and a control diet, participants in both intervention groups lost weight but did not have any improvements in insulin sensitivity, lipid levels, or blood pressure, as compared with participants in the control group.
Cardiovascular health: Intermittent fasting improves multiple indicators of cardiovascular health in animals and humans, including blood pressure; resting heart rate; levels of high-density and low-density lipoprotein (HDL and LDL) cholesterol, triglycerides, glucose, and insulin; and insulin resistance. In addition, intermittent fasting reduces markers of systemic inflammation and oxidative stress that are associated with atherosclerosis. The CALERIE (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy) study showed that a 12% reduction in daily calorie intake for a period of 2 years improves many cardiovascular risk factors in nonobese persons.
Cancer: Specific intermittent-fasting regimens vary among studies, but all involve imposition of intermittent fasting during chemotherapy. Clinical trials of intermittent fasting in patients with cancer have been completed or are in progress. Most of the initial trials have focused on compliance, side effects, and characterization of biomarkers. For example, a trial of daily caloric restriction in men with prostate cancer showed excellent adherence (95%) and no adverse events. No studies have yet determined whether intermittent fasting affects cancer recurrence in humans.
Epidemiologic data suggest that excessive energy intake, particularly in midlife, increases the risks of stroke, Alzheimer’s disease, and Parkinson’s disease. There is strong preclinical evidence that alternate-day fasting can delay the onset and progression of the disease processes in animal models of Alzheimer’s disease and Parkinson’s disease.
ASTHMA, MULTIPLE SCLEROSIS, AND ARTHRITIS
Weight loss reduces the symptoms of asthma in obese patients. In one study, patients who adhered to the alternate-day fasting regimen had an elevated serum level of ketone bodies on energy-restriction days and lost weight over a 2-month period, during which asthma symptoms and airway resistance were mitigated. A reduction in symptoms was associated with significant reductions in serum levels of markers. Multiple sclerosis is an autoimmune disorder characterized by axon demyelination and neuronal degeneration in the central nervous system. Alternate-day fasting and periodic cycles of 3 consecutive days of energy restriction reduce autoimmune demyelination and improve the functional outcome in a mouse model of multiple sclerosis (experimentally induced autoimmune encephalomyelitis). Two recent pilot studies showed that patients with multiple sclerosis who adhere to intermittent-fasting regimens have reduced symptoms in as short a period as 2 months. Because it reduces inflammation,17 intermittent fasting would also be expected to be beneficial in rheumatoid arthritis, and indeed, there is evidence supporting its use in patients with arthritis.
Preclinical studies and clinical trials have shown that intermittent fasting has broad-spectrum benefits for many health conditions, such as obesity, diabetes mellitus, cardiovascular disease, cancers, and neurologic disorders. Animal models show that intermittent fasting improves health throughout the life span, whereas clinical studies have mainly involved relatively short-term interventions, over a period of months. Young adults are probably better subjects for intermittent fasting which may not be sustainable in older people in whom the effect may not be so well observed.