Long Term Cognition and Longevity via Intermittent Fasting

Intermittent fasting (IF) is supported by evolutionary principles.

Dr. Mike Hansen explains the benefits of intermittent fasting here.

From this illuminating video: Our bodies are designed to be in the fasted state 12-14 hours per day. Fasting does not begin for 5 hours after eating. Eating good food at the wrong time is akin to eating junk food. Gut lining repair takes place in the fasted state. Injuries heal faster. Mice have demonstrated a remarkable increase in energy as from intermittent fasting. Human athletes have also benefitted. The motivation to continue intermittent fasting will happen due to feeling better: better gut health, increased energy, better sleep. The problem with one meal per day is that some necessary nutrients may be lacking.

Ketone bodies and beta-hydroxybutyrate are produced after 8-10 hours of fasting. When we eat, we are consuming glucose which drives metobolic processes, but we also generate reactive oxygen species. The damage due to this is only healed during the period of fasting. During this period of fasting, our energy does not come from glucose, but from either fat oxidation, or gluconeogenesis, or, more likely, ketone bodies.

Fasting while experiencing fever

It is common for people to lose their appetite when they are sick. This could be the body’s natural response to the illness. Prolonged caloric restriction or fasting reduces inflammation as immune system adapts to low glucose supply and energy metabolism switches towards mitochondrial fatty acid oxidation, ketogenesis and ketolysis^2–6.

The pro-regenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting, to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal and regeneration.

Betahydroxybutyrate (BHB) is naturally produced during fasting. Attenuated production of BHB is correlated with impaired CD4⁺ T cell function in patients with severe COVID-19, and BHB supplementation through a ketogenic diet or oral administration of ketone esters enhances survival of CD4⁺ T cells and their capacity to produce interferon-γ (IFNγ), thereby boosting the antiviral immune response

Fasting during a bacterial infection may be especially useful. This study in mice showed that fasting dramatically interrupted infection and subsequent gastroenteritis by suppressing Salmonella’s SPI-1 virulence program, preventing invasion of the gut epithelium. Despite Salmonella’s restored virulence within the intestines of mice, fasting down-regulated pro-inflammatory signaling, greatly reducing intestinal pathology.

This study of mice showed that most of the benefits of TRF are age-independent but are sex-dependent. TRF protects both sexes against fatty liver and glucose intolerance while body weight benefits are observed only in males. We also find that TRF imparts performance benefits and increases survival to sepsis in both sexes.

This study (here is the reference) might be cause for concern, but closer examination reveals the real problem: “skipping meals usually means ingesting a larger energy load at one time, which can aggravate the burden of glucose metabolism regulation and lead to subsequent metabolic deterioration.” The solution is “don’t be a pig” – minimize concentrated calories.

Mice who were restricted to eating for 8-9 hours showed an increase in endurance, but the mice who ate for 12 hours did not display that endurance benefit. Increased mitochondrial volume in the liver and in the endoplasmic reticulum also happened with the shorter feeding period. There is also less damaged mitochondria in the liver. Increased mitochondria volume was found in brown adipose tissue.

This video with Dr. Brad Stanfield and Prof. Matt Kaeberlein provided that observation that dogs fed once per day had a lower risk for all 9 of the age-related conditions that were looked at, they tended to have better cognitive function and a reduced risk of cognitive decline .

Intermittent fasting promoted repair of rotator cuff injury in the early postoperative period by regulating the gut microbiota, in which Parabacteroides distasonis played an important role.

From the Mayo Clinic:

Some research suggests that intermittent fasting may be more beneficial than other diets for reducing inflammation and improving conditions associated with inflammation, such as:

• Alzheimer’s disease
• Arthritis
• Asthma
• Multiple sclerosis
• Stroke

From Hopkins Medicine.org:

Here are some intermittent fasting benefits research has revealed so far:

• Thinking and memory. Studies discovered that intermittent fasting boosts working memory in animals and verbal memory in adult humans.
• Heart health. Intermittent fasting improved blood pressure and resting heart rates as well as other heart-related measurements.
• Physical performance. Young men who fasted for 16 hours showed fat loss while maintaining muscle mass. Mice who were fed on alternate days showed better endurance in running.
• Type 2 diabetes and obesity. In animal studies, intermittent fasting prevented obesity. And, in six brief studies, obese adult humans lost weight through intermittent fasting. People with type 2 diabetes may benefit: Most of the available research shows that intermittent fasting can help people lose body weight and lower their levels of fasting glucose, fasting insulin and leptin while reducing insulin resistance, decreasing levels of leptin and increasing levels of adiponectin. Certain studies found that some patients practicing intermittent fasting with supervision by their doctors were able to reverse their need for insulin therapy.
• Tissue health. In animals, intermittent fasting reduced tissue damage in surgery and improved results.
• The shock of fasting leads the brain to create new cells. As neurons are coaxed to grow, the brain becomes more resistant to the effects of protein plaques that underlie cases of Alzheimer’s, or the damage inflicted by Parkinson’s.
• Ketone bodies are good for the brain. If increases neurotrophic factors. It takes 10-12 hours to switch to ketone metabolism.

Ketogenesis, or the increase of ketones in the bloodstream, initiates activity in a variety of cellular signaling pathways known to influence health and aging. This activity enhances the body’s defenses against oxidative and metabolic stress and initiates the removal or repair of damaged molecules. The impact of ketogenesis carries over into the non-fasting period and can improve glucose regulation, increase stress resistance and suppress inflammation.

The following is from a video (with lots of references) by Dr. Dan Maggs

Eating all the time is not normal. Humans did not evolve to eat continuously.  The #1 benefit is weight loss. Fasting lowers insulin levels. Eating sugar and carbohydrates causes our blood glucose level to go up. Our pancreas responds by producing insulin. Insulin drives glucose out of our blood and into storage. Prolonged periods without food enables our insulin level to drop. High levels of insulin keep us in fat storage mode, low insulin levels means that we can use our storage fat for energy, which is key for helping us to lose weight.

Extended periods of eating disrupts our appetite signalling. Leptin is released by our fat cells and should function as the off switch for eating when we are full. With too much leptin over time, we can become leptin resistant where the brain doesn’t receive the off signal properly, and so keeps stimulating us to eat. It also leads to decreased energy expenditure. Intermittent fasting can help reset these hormones so that we naturally want to eat less.

Frequent eating negatively affects our gut microbiome. Prolonged eating periods don’t suit the natural rhythms of gastric emptying. Our digestive systems need rest. The absorption of food and of glucose is much slower towards the end of the day, so you end up with raised glucose and insulin levels for a longer period of time which can lead to weight gain.

Intermittent fasting may reduce the risk of cardiovascular disease. Cardiovascular disease is mainly caused by chronic inflammation in our blood vessels. This causes damage to the inner cell layer of the blood vessels, the endothelium, and the development of plaques, which can lead to blockages in the blood vessels within the heart muscle. Angina, heart attacks, and, within the brain, strokes. Elevated insulin levels can cause this chronic inflammation. Fat cells also cause inflammation as they release proteins called cytokines. Leptin can also cause inflammation. Intermittent fasting enable all of this inflammation sources to be reduced.

Intermittent fasting may reduce the risk of Alzheimer’s Disease. Insulin resistance wreak havoc in the brain. The blood-brain barrier can become insulin-resistant, resulting in insufficient blood glucose passing from the blood into the brain. Alzhiemer’s is sometimes referred to as type 3 diabetes by many scientists as the underlying mechanisms are so similar. This glucose shortfall can be present for years before memory problems are apparent.

There is strong evidence that the brain is able to use ketones for fuel. Ketones are produced from the breakdown of fat and do not need insulin to cross the blood-brain barrier, so can bypass problems with insulin resistance. Ketones are produced when we fast, as well as with a ketogenic diet, so intermittent fasting may prevent brain deterioration, and may possibly improve symptoms of dementia.

Improved sleep is another feature of intermittent fasting. Prolonged periods of eating distorts the natural circadian rhythm of digestion. There is an association between poor quality sleep and poor metabolism, leading to obesity, diabetes, and cardiovascular disease. Poor sleep leads to feeling grumpy and inappropriately hungry. And research has shown the people make poor decisions when they are tired. Thus continues the vicious cycle of distorted hormones, poor sleep, and poor health. Refraining from late night meals can stop this.

There is a system-wide, molecular impact of time-restricted eating in mice. Time-restricted eating influences gene expression across more than 22 regions of the body and brain. Time-restricted eating aligned the circadian rhythms of multiple organs of the body.

Increased human growth hormone is another feature of fasting. Human growth hormone helps to repair bodily tissues including in the brain. Boosted metabolism and fat burning is another benefit. Eating too frequently will diminish growth hormone. Diminished growth hormone can lead to sarcopenia and falls in older people.

Autophagy is turned on by fasting, and turned off by eating. Autophagy is linked to mTor, another master regulator of nutrient signalling and involving other hormones in the metabolism of our food. mTor is linked to cellular growth. It is suppressed by glucagon – insulin’s opposite number. Glucagon is raised when insulin is low. Glucagon enables autophagy. If insulin level is raised, mTor is over-active, and autophagy cannot happen.

Fasting may prevent some cancers. Many cancers occur when the normal cellular processes that regulate their growth become damaged. Intermittent fasting may be beneficial alongside cancer treatments.

Chronically elevated insulin can cause clogged arteries. In some ill patients it can take days of fasting for insulin level to decline to baseline. The majority of the available research demonstrates that intermittent fasting is effective at reducing body weight, decreasing fasting glucose, decreasing fasting insulin, reducing insulin resistance, decreasing levels of leptin, and increasing levels of adiponectin.

Dr. Mike Hansen on increasing one’s energy

When you are eating three meals per day + snacks, you are not allowing  the AMP-kinase (AMPK)  to turn on for a long enough period of time. This is especially true if you a taking in too much glucose, or, taken to a whole ‘nuther level,  too much fructose. Same thing if you are not exercising, you are not allowing your AMPK to rev up for a long enough period of time. Mamalian target of rapamycin (mTor) is what determines a cell’s fate: if it is to die (apoptosis) to make way for a new cell, or grow, or remain. The status of mTOR is highly dependent on the status of AMPK. MTOR can only be turned on when AMPK is turned off. When you are not eating, or when you are exercising, AMPK is turned on due to using ketones for energy. Most people hit hat metabolic switch about 12 hours from the last meal.

Glycogen stores depend on four main factors:

• The time since your last meal
• The amount of carbs that you ingested
• The amount of exercise that you engaged in
• The intensity of that exercise

Without much exercise, fasting for 16-18 hours per day depletes the glycogen and flips the metabolic switch. Once that metabolic switch and you’re now burning ketones, amazing things start to happen: 

• The ketones enter that krebs cycle to generate maximal ATP
• Cells activate “stress resistant” genes
• Cells reduce their uptake of amino acids and stop growing
• Autophagy and DNA repair are stimulated to prevent mutations and cancer
• Production of antioxidant enzymes is increased

Upon re-feeding, insulin sensitivity and uptake of glucose and amino acids is increased. The mTOR pathway is activated upon consumption of foods high in amino acids (protein). MTOR’s response is to rapidly synthesize new membranes (with lipids) – this includes mitochondria. This growth is aided by human growth hormone, secreted in the second half of the night.

In the cell, in a process called glycolysis, glucose is broken up into a bit of ATP and pyruvic acid. Pyruvate can enter the krebs cycle where a lot more ATP is created along with carbon dioxide which is exhaled. Sometimes the mitochondria are not up to the task due to damage or ageing. This is why we need autophagy/mitophagy. This happens in the ketosis/metabolic switch zone where insulin levels are low. It has been proven that intermittent fasting stimulates mitochondrial biogenesis and autophagy in the cells of the brain, heart muscle, and skeletal muscle.

One specific way the intermittent fasting promotes mitophagy is by stimulating production of the mitochondrial enzyme SIRT-3. SIRT-3 improves mitochondrial ATP production, the removal of free radicals, and it stabilizes mitochondrial membranes.

More from Dr. Mike Hansen: Intermittent fasting increases heart rate variability by increasing parasympathetic activity. Intermittent fasting increases BDNF in the brain due to ketones that are generated, specifically beta hydroxy butyrate. 

One interesting variation of intermittent fasting is the fast mimicking diet. Here is a study that shows a reduction in neuroinflammation.

From Pubmed: (slightly less definitive than Harvard or Hopkins Medicine)

If you don’t eat for 10–16 hours, your body will go to its fat stores for energy, and fatty acids called ketones will be released into the bloodstream. This has been shown to protect memory and learning functionality, as well as slow disease processes in the brain.

IF may protect neurons against adverse effects of Abeta and tau pathologies on synaptic function. We conclude that CR and IF dietary regimens can ameliorate age-related deficits in cognitive function by mechanisms that may or may not be related to Abeta and tau pathologies.

Intermittent fasting resulted in beneficial effects in mice that met or exceeded those of caloric restriction including reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress. Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake.

Chronic intermittent fasting improves cognitive functions and brain structures in mice.

A study in mice shows that time-restricted feeding influences the activity of genes in 22 diverse tissues all over the body, including the brain, heart, lungs, liver, and gut. The study also adds to evidence that time-restricted feeding may promote longevity and have cancer-fighting effects.

Intermittent fasting protects the blood-brain barrier

Chronic cerebral hypoperfusion (CCH) is an important pathophysiological mechanism of vascular cognitive impairment (VCI). 16 hours per day IF in mice alleviated CCH-induced neurovascular pathologies by reducing the number of leaky microvessels, blood-brain barrier breakdown and loss of tight junctional proteins. In addition, IF mitigated the severity of white matter lesions, and maintained myelin basic protein levels, while concurrently reducing hippocampal neuronal cell death.

Metabolic benefits of intermittent fasting

8-hour time-restricted feeding (TRF) without intentional calorie limitation produces mild caloric restriction and weight loss in obese adults⁵⁸. A number of trials testing IF in humans show positive effects on metabolic markers. Varady and colleagues showed that ADF in overweight or obese adults with insulin resistance produces a greater reduction in insulin levels and insulin resistance than CR does, despite achieving a similar decrease in body weight⁵⁹.  Panda and colleagues, who had shown the beneficial effects of TRF for preventing and treating obesity and metabolic disorders in mice^32–34, showed similar cardiometabolic benefits in people with metabolic syndrome who consumed food for only 10 hours daily^61,62.

In one trial, 16 healthy participants (aged between 23 and 53 years with a BMI between 20 and 30) assigned to a regimen of ADF for 22 days lost 2.5% of their initial weight and 4% of their fat mass, with a 57% decrease in fasting insulin levels⁶⁴.

In two other trials, overweight women (approximately 100 women in each trial) were assigned to either a 5:2 IF 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 the 5:2 IF had a greater increase in insulin sensitivity and a larger reduction in waist circumference^30,65.

In humans and rodents, IF results in decreased levels of circulating insulin and leptin, elevated ketone levels, and reduced levels of pro-inflammatory cytokines and markers of oxidative stress. Liver cells respond to fasting by generating ketones and by increasing insulin sensitivity and decreasing lipid accumulation. Markers of inflammation in the intestines are reduced by IF. The insulin sensitivity of muscle cells is enhanced and inflammation reduced in muscle cells in response to the metabolic switch triggered by fasting and exercise.

Exercise and intermittent fasting is synergistic

Many of the benefits of intermittent fasting resemble those from exercise. Doing both of those has a synergistic effect that enhances such benefits. Maximum oxygen uptake is significantly enhanced with time-restricted feeding protocols. A 2020 study randomly assigned 16 otherwise healthy males to follow early-TRE for 2 weeks or just regular calorie restriction. It found the TRE group saw an improved ability for their muscle to use glucose and branched-chain amino acids.

Maintenance of lean mass and muscle strength: A 2020 study found that 4 weeks of TRE and a 25% reduction in calories kept lean mass to the same level as a regular calorie restriction in 26 active young males. Both groups saw an equal loss in body fat without adverse effects to their lean mass or muscle strength.

A 2021 study randomly assigned 21 middle-aged adults who were overweight or had obesity to complete 8 weeks of TRE or regular eating for 8 weeks. Both groups had a small increase in lean mass, muscle strength, and muscle endurance.

A 2016 study asked 20 young males to stick with their TRE or regular eating pattern for 10 extra months. According to the 2021 study that published the results, both groups increased their bench press and leg press performance despite losing fat-free mass. The TRE group maintained a 10% energy decrease while keeping protein intake around 1.9 grams per kilogram of body weight.

During fasting, fat tissue provides energy to the rest of the body by releasing fatty acid molecules. However, the researchers found visceral fat became resistant to this release of fatty acids during fasting. This suggests the visceral fat can adapt to repeated fasting bouts and protect its energy store. Exercise to the rescue. Exercise is compatible with intermittent fasting. Dr. Mike Hansen demonstrates exercise in the fasted state.

Prevent weight gain

TRF prevents excessive body-weight gain, improves sleep, attenuates age- and diet-induced deterioration in cardiac performance and improves blood pressure and accumulation of atherogenic lipids⁶².

Intermittent fasting does not help one lose weight more than, for instance, continuous energy restriction, but it may be psychologically easier.

Keep your marbles as you age

Age is a risk for dampening the endogenous circadian clock. With increased human longevity, age-related dampening of the circadian clock is becoming a risk for chronic circadian disruption.

Fasting may help prevent some neurodegenerative disorders. Eating too frequently may be involved with abnormal buildup of proteins that damage our brain.  When autophagy is unable to occur due to the over stimulation of mTor through the lack of fasting, it leads to neurodegenerative conditions. “Autophagy dysfunction is strongly implicated in the pathogenesis of neurodegenerative disorders”.

In Alzheimer’s disease, there’s a problem with nerve cell networks in the brain controlling their excitability so that certain circuits become uncontrollably excited, hyper-excited, and in fact patients with Alzheimer’s disease, they have a greatly increased incidence of epileptic seizures compared to age-match control subjects. And that’s because we think there’s impairment in GABA, the inhibitory neurotransmitter, signaling or even death of the neurons – they use GABAs and neurotransmitters. So intermittent fasting will constrain excitability within normal limits and protect neurons against what we call excitotoxicity.

IF works via foxO transcription factors, sirtuins and peroxisome proliferator-activated receptor.

IF works via neuronal autophagy. Upregulation of autophagy may be neuroprotective and will promote mitochondrial efficiency.

IF healed nerve damage in mice. This happened due to gut bacteria.

“extending the time between meals” stimulates adult hippocampal neurogenesis

Intermittent fasting causes ketogenesis, but a ketogenic diet would be high fat (BAD: see below).

IF affects energy and oxygen radical metabolism, and cellular stress response systems, in ways that protect neurons against genetic and environmental factors to which they would otherwise succumb during aging. Human and non-human animal studies have shown that IER increases synaptic plasticity (a biological marker of learning and memory), enhances performance on memory tests in the elderly, leads to the growth of new neurons, promotes recovery after stroke or traumatic brain injury, decreases risk for neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, and may improve quality of life and cognitive function for those already diagnosed with these diseases.

A calorie restricted diet via every other day fasting was an effective means of promoting Klotho gene expression in mice. Klotho, which is often referred to as the “longevity gene” has now been shown in this study to play a central role in the production of hippocampal adult-born new neurons or neurogenesis.

The fast-mimicking diet promotes hippocampal neurogenesis and improves cognitive performance in mice. Short cycles of the fast-mimicking diet has been shown to lessen Alzheimer’s symptoms in mice genetically engineered to develop the disease

IF promotes brain-derived neurotrophic factor (BDNF)

Rodents maintained on an IF regimen exhibit increased resistance of heart and brain cells to ischemic injury in experimental models of myocardial infarction and stroke. When the body goes without nutrition for 10 to 14 hours, it stops living off energy stored in the liver and turns to fat stores as a replacement. For the body to use fat stores, it must first convert them to ketones. Ketones act directly on nerve cells, causing them to produce brain-derived neurotrophic factor (BDNF). Some of the beneficial effects of IF on both the cardiovascular system and the brain are mediated by BDNF signaling in the brain. Interestingly, cellular and molecular effects of IF and CR on the cardiovascular system and the brain are similar to those of regular physical exercise, suggesting shared mechanisms.

IF (and exercise) activates SIRT3 via ketones which then creates BDNF.

The beneficial effects of intermittent fasting, appear to be the result of a cellular stress response that stimulates the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors such as BDNF, protein chaperones such as heat-shock proteins, and mitochondrial uncoupling proteins.

Eat breakfast, then lunch, then quit.

Eating only early in the day may be the best intermittent fasting strategy. This will support a strong circadian oscillation. Mice that fasted every day all day (similar to overnight fasting in humans) for 11 months exhibited a superior cognitive ability in the Barnes maze test of spatial memory. This blog post circadian functioning explains why.

Early time-restricted feeding improves insulin sensitivity, blood pressure, and oxidative stress even without weight loss in men with prediabetes.

Skipping breakfast, which is perhaps the most common method adopted to reach a daily 14- to 18-hour daily fasting period, is associated with an increased risk of mortality from cardiovascular and all-cause mortality in the US population⁶⁷. Dr. Valter Longo: Multiple meta-analyses point to breakfast being important to, not just mortality, but avoiding diabetes and cardiovascular disease. If you are going to skip a meal, do not make that breakfast.

Relative to the control schedule, early time-restricted feeding (eTRF) decreased mean 24-hour glucose levelsand glycemic excursions. In the morning before breakfast, eTRF increased ketones, cholesterol, and the expression of the stress response and aging gene SIRT1 and the autophagy gene LC3A ), while in the evening, it tended to increase brain-derived neurotropic facto and also increased the expression of MTOR, a major nutrient-sensing protein that regulates cell growth. eTRF also altered the diurnal patterns in cortisol and the expression of several circadian clock genes. eTRF improves 24-hour glucose levels, alters lipid metabolism and circadian clock gene expression, and may also increase autophagy and have anti-aging effects in humans.

For those who exercise (resistance training during a fast is essential) and practice intermittent fasting, consuming protein powder outside of one’s normal eating window may be beneficial. Pre-sleep casein protein intake (30–40 g) provides increases in overnight muscle protein synthesis and metabolic rate without influencing lipolysis (the breakdown of fats). Protein powder does not trigger an insulin response, so it is unlikely to mess up a good fast.

A cautionary note

The risk of gallstone disease nearly doubles between women who fast for 8 hours per day and those who fast for over 14 hours per day⁶⁶. Being obese is a gallstone risk factor. Medical News Today has a good guide on avoiding gall stones.

If you’re already marginal as far as body weight goes, you might lose too much weight while fasting, which can affect your bones, overall immune system, and energy level.

Intermittent fasting may be harmful if you have diabetes and need food at certain times or take medication that affects your blood sugar.

According to a study which analyzed data from over 2,700 adolescents and young adults in Canada, intermittent fasting was found to be linked to disordered eating behaviors in women, including binge eating and compensatory behaviors such as vomiting and compulsive exercise. Men who practiced intermittent fasting were also more likely to report compulsive exercise.