adaptive cellular response in evolution

Fasting, Exercise and Mental Effort for Improved Health, Immunity and Brain Function

This blog article provides a cellular and biochemical basis for understanding why long-term caloric restriction (fasting), exercise and working-memory demanding mental effort all promote health, immunity and physical and mental performance, in a way that is complementary, sharing the same basic adaptive cellular stress response.

My original contribution is to interpret mental effort involving high cognitive load in the same stress response framework as caloric restriction and exercise. This provides a more foundational basis for combining planned  fasting and exercise with brain training.

Energetic Stressors in Evolution

In the environments of our distant ancestors, food was often scarce, and energy expenditure high. Three factors have all been powerful selective pressures in human evolution:

  • Caloric (energy) restriction (CR) in times of food scarcity
  • Physical energy expenditure ( e.g. for running, hunting, fighting, artifact making)
  • Mental energy expenditure (e.g. for learning, reasoning, strategizing) – known as mental effort.

As our species evolved, individuals that were mentally sharp,  physically fit, and disease or illness-free during periods of limited resource availability and could deal effectively with these energy stressors had an adaptive advantage.

Over time we have evolved adaptive cellular stress responses that optimize our physical and mental performance. The human body and brain is biochemically and neurophysiologically adapted to these three energetic challenges.

We can benefit from this adaptive stress response using the principle of hormesis.

Hormesis

Hormesis is the term for a beneficial biological response to low exposures to toxins and other stressors.  Smaller quantities have the opposite effect of larger quantities. The amount of the stressor matters of course, as this diagram of the hormesis response illustrates:

hormesis response 1

The scientific literature has a clear message based on harnessing the hormesis response: improved health, immunity and brain function result from appropriate amounts of caloric restriction, exercise and brain training involving mental effort.

There is an opposite principle also widely documented in the scientific literature: the deteriorating health, immune function and neuroplasticity that results from overeating, a sedentary lifestyle and the absence of mental effort.  This is of particular concern given that more than 60% of the populations of many industrialized countries, including the United States and the United Kingdom, are overweight. ‘Overweight’ is conventionally defined as having a body mass index (BMI) > 25.

Calculate your BMI by clicking here. Is it more than 25?

In this article I explain how using the principle of hormesis we can substantially improve overall health, immune function and brain function by practicing:

  • Caloric restriction (e.g. 75% daily calories or alternate day fasting)
  • Exercise (aerobic, resistance and/or high intensity interval training)
  • Focused mental effort (e.g. working memory brain training)

Of course the dose of these practices matters to ensure our systems are not over-stressed, and we will be looking at this too.

I. General Health Benefits from Fasting (Caloric Restriction) and Exercise

Numerous intervention studies have demonstrated  that caloric restriction (with a maintained balanced diet) results in:

  • reduced fat mass
  • increased insulin sensitivity and improves glucose metabolism
  • decreases blood pressure
  • increased heart rate variability (HRV) – a good index of overall mental and physical health
  • less oxidative damage during cell metabolism (due to free radicals) to tissues and DNA
  • less inflammation
  • better autophagy – the detoxification process whereby your cells eliminate waste material and repair themselves)
  • protection against multiple age-related diseases including cancers, cardiovascular disease, diabetes, a (amount of blood glucose is too high) and sarcopenia (degenerative loss of skeletal muscle mass)

Anti-Aging

Exercise has a comparatively little effect on the aging process Data from numerous animal studies show that restricted calories (by 25-55%) with adequate micronutrients compared to ‘free-for-all’ eating, can dramatically extend maximal life span and retard aging – by up to 65%.  In human terms that would be an extension of life expectancy around 80 years to 130 years. Mice and rats put on a low-calorie, nutrient-rich diet live far longer – and the same is true in monkeys.

Caloric restriction of 30% (with maintenance of nutrition) in monkeys protects against multiple age-related disorders. In the Wisconsin study of lifelong caloric restriction  in monkeys, over 20 years monkeys whose diets were not restricted were nearly three times more likely to have died than those whose calories were counted.  In the photos, the monkey on the two monkeys are the same age; the one on the left has not been calorie restricted, the one on the right is aging very well on a 30% restricted calorie diet.

calorie restricted fasting monkeys

“They don’t just live longer, they are healthier.  They actually aged biologically slower.  Their hair has gone gray less quickly.  Their hormones have stayed at their youthful profile and their immune function has stayed good.”  Dr. Susan Roberts  

A similar study is currently being conducted with humans – the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)  involving 132+ people who have been cutting their calories by 25% for a number of years now. Females consume around 1500 Cal/day rather than 2000, and males consume 1875 Cal/day rather than 2500. So far down the line, the biomarkers in this study have been consistent with the animal studies:

“I didn’t think calorie restriction worked in humans until I started working with people who’d been doing it for years. They are among the healthiest people I’ve ever known.  Their heart function is similar to people 15 years younger, they have very low levels of inflammation and very few get cancer.”  Dr. John Holloszy, M.D., lead CALERIE investigator   “… subjects have cholesterol around 160, blood pressure around 100 over 60, high HDL, low triglycerides and very low levels of inflammation. … here we have such a powerful intervention that is basically cleaning out the arteries.” Dr. Luigi Fontana & Dr. Susan Roberts, Washington University and Tufts University investigators for the NIH- funded CALERIE Study   

Caloric restriction with low animal protein diet

The life-extending effects of restricted diets found in other animals based on the adaptive cellular stress response is in large part due to the resulting lower levels of IGF-1 – a growth factor. It is known that higher levels of plasma  IGF-1 lead to more accelerated ageing and age-related diseases such as cancer, while low levels are protective. Luigi Fontana and colleagues found that caloric restriction (while maintaining nutrition) in human volunteers did not result in lowered IGF-1 levels.

But Humans tend to have high protein diets – well in excess of the recommended amount of protein of 0.8 grams per kg of body weight per day (e.g. 46 grams for the average US female and 56 grams for the average US male). Fontella and  found that reducing protein intake from an average of 1.67 g / kg / day to 0.95 g / kg / day for just 3 weeks in people practicing caloric restriction resulted in a reduction in IGF-1 by over 20%.

Higher fat animal proteins may be the culprit. Reducing the amount of animal protein we eat to 10% of calories eaten reduces risk factors for prostate, breast, and colon cancers, and neurodegenerative diseases. A 2014 University of Southern California study looking at the diets of more than 6000 people found that for 50-65 year olds a diet high in animal protein (more than 20% of daily calories) was associated with a 75% increase in overall mortality and afour-fold increase in the risk of dying from cancer. That is as big a risk factor as smoking.

This link was largely eliminated when the protein source was plant based. This study also found that for over 65s, a higher protein diet was linked to reduced cancer and overall mortality. A sensible recommendation for health and longevity is 10-15% primarily plant based protein intake up to one’s mid 60s, increasing to a 20-25% in later years. Good non-animal sources of protein can be found here.

Anti-cancer effects of exercise,caloric restriction and a low protein diet

Exercise training, decreased fat, and long-term consumption of a low-protein, low-calorie diet are associated with low plasma growth factors and hormones that are linked to an increased risk of cancer. A low protein diet has additional protective effects because it is associated with a greater decrease in circulating IGF-I than high levels of exercise alone. This diagram summarizes the adaptive response to caloric restriction or fasting that help fight cancer, adapted from this review article.

fasting cancer science

II. Brain Health & Performance Benefits from Fasting, Exercise & Mental Effort

Via the same adaptive cellular stress response that improves immune function, health and longevity reviewed above, caloric restriction, exercise and mental effort during brain training can all promote optimal brain function and resistance to age-related brain diseases, and does so via overlapping and complementary mechanisms. The diagram from this comprehensive review article illustrates at a neuron (brain cell) circuit level the three types of intervention (in red) that induce brain health and performance benefits from the adaptive cellular stress response.

adaptive cellular stress response

Three types of training regimes that help brain function in red. Triangles indicate synapses (communication points) between different brain cells (neurons).

In all three regimes – caloric restriction, aerobic exercise and mental effort – an adaptive hormesis response results in both neuroplasticity and cell protection – that is, both the strengthening of synapses via protein enzymes and neuron stress resistance via DNA repair enzymes, and antioxidant enzymes.

Mental effort is defined as energy mobilisation in the brain  in the service of cognitive goals. Mental effort facilitates performance in the presence of increased task demands (time pressure, multi-tasking, working memory load (e.g. n-back level) or inhibition habitual responses) as well as psychological stressors such as fatigue, sleep deprivation, drugs, noise. The brain has substantial energy requirements (approximately 20–30% of all energy expenditure at rest) and is dependent on a constant supply of glucose and oxygen from the bloodstream.  With more mental effort, there is more glucose and oxygen consumption. This can lead to an adaptive cellular stress response in the brain, which can be tapped via the principle of hormesis.

We will now look at specific brain benefits one by one. Much of this research can be found  in this excellent Cell Metabolism review paper.

Improved neuroplasticity

Neuroplasticity is defined as the changes that occur in neural pathways and synapses (the connecting points between neurons)  as adaptive responses to environmental challenges, including those that are voluntary (e.g., problem solving, learning skills, competing in sport) and those that are unwelcomed (e.g., a traumatic injury or disease).  Neuroplasticity is essential for learning and memory, and as the brain ages it tends to become less neuroplastic.

Neurogenesis

Neurogenesis is the creation of new brain cells (neurons) from  neural stem cells. The new neurons can  form synapses with existing neurons, thereby becoming part of a functional neural circuit.

Beneficial gene regulation

Going without food for even short periods of time switches on a number of ‘repair genes’.

Ketones – Superfuel and brain protection

Our biology is adapted for times of food scarcity. During these periods, the main goal of our system is to provide enough glucose to the brain and other tissues. If you’re not eating where does this glucose come from? Lack of food causes the brain to shift away from using glucose as a fuel to using ketones.  Ketones are produced when the body burns fat for fuel. Ketones act as a stand in for sugar in the brain. By reducing the body’s need for sugar, less protein is required, protecting muscle mass (the protein reservoir that might otherwise be used to power the brain).

Resilience to stress and emotional control

Countering cognitive decline: stress reactivity

Heightened susceptibility to stress (‘stress reactivity’) increases with aging. It is associated with atrophy of the hippocampus, age-related cognitive deficits such as memory loss, and increased risk for Alzheimer’s disease.

Countering cognitive decline: Neuroplasticity and brain function

Numerous studies show that both exercise and caloric restriction help maintain brain volume and buffer against loss of memory and other cognitive functions that is associated with loss of neuroplasticity with aging.

And for the benefits of cognitive challenges and brain training:

III. What Diet?

Caloric Restriction (CR) diet

Most of the studies reviewed above on caloric restriction have involved cutting daily calorie intake by 25%, ensuring that the diet has high nutritional value and all the recommended micronutrients are maintained. This is what hundreds of participants in the CALERIE study are doing – individuals who are showing excellent health biomarkers after a few years of this regime. And this is what CRON (Calorie Restriction with Optimal Nutrition) dieters are doing in their thousands.

A starting point to get you underway with a caloric restriction diet can be found at the Painless Calorie Restriction for People Who Love to Eat. The information on this site follows CALERIE guidelines, such as:

  • Sticking to the most nutrient-dense foods like fruits, vegetables, whole grains, and legumes–although the CALERIE study is not vegan or vegetarian.
  • Eating foods that are filling, appealing, low in calories, and nutrient-rich.
  • Eating lots of fiber–at least 50 grams a day (for me) without counting grams or even trying.  Fiber is key to keeping satisfied and full–and it likely activates the satiety receptors in the lower intestine.

In addition, it is important to reduce the amount of animal protein.

  • Reducing animal proteins (meat, fish, yoghurt, eggs and milk)  to 10% of calories eaten or less reduces risk factors for prostate, breast, and colon cancers, and neurodegenerative diseases.
1500 calorie diet

A 1500 calorie diet

 

Macronutrients in numbers

To calculate your required calorie intake, you can use this online calculator.   Then simply multiply your recommended Calories (to maintain current weight) by 0.75 to get your caloric restriction quota.

To get your macro breakdown, feed this diet-restricted number into this calculator, setting your protein intake to no more than 10% if you consume animal proteins.  For instance, 55% carbohydrates, 10% proteins, and 35% fats.  The exact carb-fat ratio is something you can experiment with or do further research on. If you consume mainly vegetable proteins and want a higher protein diet a 55/15/30  or 50/20/30 ratio may be preferred. Higher protein intake is recommended if you are over 65 or an athlete requiring high levels of strength.

Optimal weight range

It is important that you do not become underweight on a caloric restriction diet!  Being underweight – just like being overweight – can result in negative health and cognitive outcomes. For instance, being underweight long-term in adulthood and weight loss late in life is associated with poorer cognitive outcomes.

There seems to be a window of levels of energy intake and expenditure that promote optimal health and brain function; an energy balance that results in a BMI (body mass index) between 20 and 24 appears to be optimal for most people eating Western diets. You can calculate your current BMI here.

Intermittent fasting

Research has clearly demonstrated that many of the same health giving and brain enhancing genetic pathways and biochemical responses activated by caloric restriction are similarly engaged by fasting, even for relatively short periods of time. This review and this review (scroll down to paper) strongly indicate that “the reported beneficial health effects from caloric restriction… can be mimicked by alternating periods of short term fasting with periods of refeeding, without deliberately altering the total caloric intake.” One of the most comprehensive recent reviews of the benefits of caloric restriction (CR) concludes:

Incorporation of intermittent energetic challenges into our daily and weekly schedules should be a guiding principle for achieving optimal brain health.  a prescription of CR and regular exercise will improve the health and longevity of the brain and body. Individuals who are overweight and sedentary must reduce their energy intake and engage in regular vigorous exercise in order to improve their brain health and reduce their risk for neurodegenerative disorders. Those of normal weight can expect to optimize the performance of their brain by CR and exercise.

Intermittent fasting is more similar to the availability-scarcity cycles of our evolutionary past. As with exercise and mental effort, by periodically triggering the adaptive cellular stress response we can benefit from a planned hormesis response (see above). There are two popular varieties of intermittent fasting:

Alternate Day Fasting (ADF)

This requires eating what you want one day, then cutting down to a quarter of your normal calories the next. It does not seem to matter that much what you eat on non-fast days, provided your animal protein intake is not higher than 10%. Dr Krista Varady of the University of Illinois at Chicago carried out an eight-week trial comparing two groups of overweight patients on ADF. She observed: “If you were sticking to your fast days, then in terms of cardiovascular disease risk, it didn’t seem to matter if you were eating a high-fat or low-fat diet on your feed (non-fast) days”.

5:2 Diet

This is a less intensive and often more practical version of ADF.  Five days a week you eat normally (within recommended protein limits) and then for two days a week what you do is you cut down to a quarter of your normal calories as in ADF. The 5:2 diet has been popularized by the Michael Mosley in the BBC Horizon program Eat, Fast and Live Longer (also given a BBC feature here).  The feature is well worth a watch for an introduction to the science between restricted diet and intermittent fasting.

Mosley intermittent fasting

Michael Mosley having his health assessed before starting his 5:2 intermittent fasting diet. Click for video.

Recipes for 500-600 calorie intermittent fasting

I recommend Michael Mosley’s very affordable book The Fast Diet if you want a practical plan for adopting alternate day fasting or the 5:2 diet.  You can download it in an instant to your Kindle.

Examples of the fasting day diets are: Fast Diet

Breakfast: 1 boiled egg, half a grapefruit (125 calories)
Dinner: vegetarian chilli (378 calories)

Breakfast: Porridge with blueberries (197 calories)
Dinner: Chicken stir fry (306 calories)

Breakfast: strawberry smoothie (171 calories)
Dinner: Oven-baked smoked haddock (325 calories)

Same day intermittent fasting

Another variant suggested by Mark Mattson in his Cell Biology review paper on fasting and exercise is same day intermittent fasting, eating only during a short time window each day (e.g., not eating breakfast or lunch). One version of same day intermittent fasting has been adopted in Dave Asprey’s Bulletproof Intermittent Fasting. In this diet, you eat freely between 2pm and 8pm and fast for the remaining 18 hours in a day. Less research has been conducted looking directly at same-day intermittent fasting, but it triggers the same adaptive cellular stress response and hormesis principle as CR and ADF. Calorie Restricted dieting, alternate day fasting and same-day intermittent fasting schedules over a two day period are shown in the diagram.

types of caloric restriction diet

Recommendations

  • It is recommended that you research and experiment with different kinds of restricted calorie diet to find out what you can successfully make a part of your lifestyle.  These diets should be thought of as a long-term lifestyle change – not a temporary diet plan.  Many find CR too hard, and opt for some type of intermittent fasting. The 5:2 diet or same day IF may be the least stressful of the options.
  • The idea of caloric restriction/fasting is to create an energetic stressor to activate all the benefits of the hormesis response. If you overdo the fasting, or skimp on nutrients, you will cause the kind of system breakdown that you are trying to build resilience to – leading, for instance, to insulin resistance and poorer glucose metabolism.
  • The diet should, after a couple of weeks, be helping you feel “more energy, more bounce, …a greater zest for life” in the words of Dr Michael Mosley.  If you are feeling drained, faint, weak, stressed or unhealthy, or swinging in your moods and energy levels, then the diet is not working and should be adjusted.
  • Ensure that you don’t become weaker through muscle loss. Maintain at least 0.8 grams of (complete) protein per kilogram of body weight – e.g. 64 g for a 80 kg man (i.e. 256 calories) ;  45 g for a 56 kg woman (180 calories).  Ensure that most of your protein intake is plant based if you are consuming more than 10% protein in your overall calorie consumption.

IV. What Exercise?

[h3 align=’center’]Aerobic or resistance exercise[/h3] Most of the benefits reviewed above are based on aerobic exercise, not strength training. Some studies show greater benefits of aerobic training compared to resistance (strength) training. For example:

However,  this excellent article on the benefits of exercise reviews diverse evidence for the cognitive benefits of strength training among the elderly, and  suggests that while evidence is limited for the benefits of strength training, this may be due in part to lack of studies – not something intrinsic to the type of exercise.   The 2008 Physical Activity Guidelines for Americans and the Harvard School of Public Health recommends that healthy adults get:

High intensity

Intense exercise changes the body and muscles at a molecular level in ways that milder physical activity doesn’t match as reviewed in this New York Times feature.

High Intensity Circuit Training (HICT)

Scientific evidence indicates that high intensity circuit training (HICT) – the combines aerobic and strength training – is an efficient means of exercise to help decrease body fat, improve insulin sensitivity, and improve VO2max and muscular fitness. Interval training requires extremely intense activity intermingled with brief periods of recovery. This intermittently triggers the adaptive cellular stress response in a very efficient way.

There’s very good evidence” that high-intensity interval training provides “many of the fitness benefits of prolonged endurance training but in much less time.Chris Jordan, the director of exercise physiology at the Human Performance Institute in Orlando, Fla.  

Work by scientists at McMaster University in Hamilton, Ontario, and other institutions shows, for instance, that even a few minutes of training at an intensity approaching your maximum capacity produces molecular changes within muscles comparable to those of several hours of running or bike riding. The ‘7 minute workout’ has  been reviewed in the New York Times, and is a popular HICT option.  There are 12 exercises. Exercises are performed for 30 seconds, with 10 seconds of transition time between bouts. Total time for the entire circuit workout is approximately 7 minutes. The circuit can also be repeated 2 to 3 times, depending on time and fitness level. Variations on this workout.

7 minute workout

The side plank (no. 12) should be done on both sides. Modifications or extensions to this routine can easily be improvised – for instance, adding pull-ups or burpees.

 

V. What Mental Effort?

Most of the rodent studies demonstrating beneficial biochemical and cognitive outcomes from ‘cognitive challenges’ involve inducing  psychological stress in novel (‘enriched’) environments. Remembering that the brain is a huge energy consumer, this kind of energetic stressor I hypothesize taps exactly the same adaptive cellular stress response that is found in caloric restriction / fasting and intense exercise.

Any kind of intense mental effort that is incorporated into our lives, dealing with novel situations, requiring learning and involving some kind of adaptive stress response (e.g. writing articles or being in a drama club), should be beneficial to brain health and performance. The question here is, how can we maximize broad brain health and cognitive performance gains returns from this hormetic response to mental effort in a planned way.

How can we be efficient in our brain training in the way the high intensity circuit training is efficient?

The answer involves identifying and training a type of mental process that is stressful (but not too stressful),  effortful and high in energy demand, involves novelty that requires adaptive learning and is core to the broad range of cognitive processes underlying our fluid intelligence (the kind of intelligence that plans, problem solves and learns in novel situations).  The brain areas known to be important for fluid intelligence are part of an interconnected system associated with emotional arousal and the stress response.

The best candidate we have for this is working memory training.

Working memory is the ‘executive’ brain system for short term storage and control of the information needed for higher level cognitive tasks such as language comprehension, learning, and reasoning. It’s our ‘mental workspace’, and the more we load it with cognitive challenges, the more energy it consumes and the more we stimulate the adaptive cellular stress response. Studies on working memory training have shown:

  • Gamma (30–60 Hz) oscillations increase linearly with working memory load and gamma brainwaves are known to be associated with high energy demand, requiring both rapid adaptation of oxidative energy metabolism and sufficient supply with oxygen and nutrients.
  • The high metabolic demands of working memory activity explain the vulnerability of working-memory related functions to circulatory disturbances, genetic mitochondrial diseases, and neurodegeneration and why training working memory can help stimulate the adaptive cellular stress response to counter these vulnerabilities for better brain health, neuroplasticity and cognitive performance.
  • Prolonged (1 month) working memory training fulfils all the 5 criteria identified as critical for effective brain training by Dr Alvaro Fernandez and  the consumer research group SharpBrains.
  • This review of the benefits of working memory training concludes “The results of individual studies encourage optimism regarding the value of working memory training as a tool for general cognitive enhancement. …Studies of core training show improvements in a variety of areas of cognition (e.g. cognitive control, reading comprehension), persist even with the use of tightly matched controls, and are consistent with neuroimaging studies demonstrating activation changes in regions associated with domain-general cognitive performance. Core working memory training thus represents a favourable approach to achieve broad cognitive enhancement.”
  • The most popular ‘brain training’ providers on the market – much like the most popular ‘workouts’ and diets – do not work as energetic stressors that induce strong adaptive cellular stress responses. They are too easy and not stressful enough over a long-enough training period. Consequently the evidence for their benefits is lacking.

Recommended working memory training providers include the following:

  • IQ Mindware – my own brain training company, focusing on ‘core working memory training’ apps for IQ, emotion regulation, problem solving and skills learning.
  • CogMed –   Working memory training involving “systematic, focused, and rigorous training effort”.
  • BrainWorkshop – An academic-voluntary  provider, focusing specifically on variations of the n-back working memory task.

 

VI. Combinations of Fasting, Exercise and Brain Training

How should we combine caloric restriction, exercise and brain training? There are no studies showing that exercise while fasting is detrimental to health and performance, so various combinations can be experimented with. Dr Mark Mattson suggests combinations such as:

  • Alternate Day Fasting with a daily exercise period
  • Same day Intermittent Fasting, exercising every other day.
  • Eating in the morning and late afternoon/evening, and exercising at midday.

Brain training can be incorporated in similar overlapping or non-overlapping intervals, aiming at a total of perhaps 1 to 2 ½  hours working memory brain training per week, depending on intensity.   Your training mix should be based on reading your own energy levels and harnessing natural energy rhythms in my experience. As shown in the hormesis response diagram below, you have to experiment to ensure that you do not go into the ‘excessive stress’ zone. This is particularly true at the beginning of your training before you have built up more stress tolerance.

 

Hormesis response

Ensure that you do not overstress your brain and body’s biochemistry by combining multiple energetic stressors (fasting, exercise and brain training – perhaps also with stress in your work) all within the same short period.  In principle, however, if it feels right, combinations may have a synergetic benefits from the net adaptive cellular stress response. Experiment and find out! And if you have any insights or observations taking this overall approach to health and performance, please let me know about them.

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