Intervju med Mark Mattson

Hvor gunstig er periodisk faste?

Det å si at periodisk faste er en populær greie grenser til en underdrivelse. I perioder har det nesten virket som det er noe ‘alle’ helse og fitness folk har vært opptatt av og snakket om. Mens noen fremstår som sterkt imot det å hoppe over frokosten, så har andre omfavnet det å jobbe og trene på tom mage. Jeg er blant disse. Hvis jeg er veldig sulten om morgenen, så spiser jeg, men det er sjeldent tilfelle, og jeg pleier derfor å vente med å innta mat til litt utpå dagen.

Fra et evolusjonært perspektiv, så fremstår det å periodisk ‘gå på tom mage’ som normalen.

Dette virker kanskje radikalt for noen, spesielt med tanke på at vi i en årrekke har blitt fortalt at det viktigste måltidet er det vi spiser om morgenen, etter at vi har våknet opp. Fra et evolusjonært perspektiv derimot, så fremstår det som helt normalt å gå en del timer uten å spise. Fra et slikt ståsted, så er det det å spise hver tredje time, fra tidlig morgen av, som virker unormalt, ikke det å sporadisk holde seg unna matfatet. Dette har ikke fått særlig mye oppmerksomhet, noe jeg syntes er dumt, da det for meg fremstår som kjernepunktet i periodisk faste saken og noe mange kunne hatt nytte av å være oppmerksomme på.

Det å si at det ikke har fått så mye oppmerksomhet som det burde fått er dog ikke det samme som å si at det er ingen som har poengtert det. Én mann kan sies å være i en egen liga i denne forstand. Han heter Mark Mattson, og er bredt anerkjent for å være den fremste forskeren på periodisk faste. Gudfaren til IF (‘intermittent fasting’) om man vil. Ingen annen nevroforsker har i nyere tid blitt sitert i vitenskapelige sammenhenger oftere enn han, noe som sier litt om mengden arbeid han har lagt ned. Spesielt det at mange av hans artikler har et evolusjonært preg gjorde at jeg i 2019 kontaktet og gjennomførte et intervju med han – et intervju som Mattson etter å ha sett det på trykk gav uttrykk for at han var veldig fornøyd med.

1. Please tell us a little about yourself. I’m particularly interested in hearing about your research background and motivation for getting involved in neuroscience.

I received a B.S. degree in Zoology from Iowa State University and a Ph.D. in Biology from the University of Iowa where my thesis research project was aimed at understanding the signaling mechanisms involved in the neuroendocrine regulation of molting in crabs. There I gained a broad knowledge of how hormones and neurotransmitters are synthesized in endocrine cells and neurons, and how they elicit responses in their target cells.    

My postdoc training was in developmental neurobiology at Colorado State University where I discovered that the neurotransmitter glutamate regulates the outgrowth of dendrites and synapse formation in the developing embryonic rat brain. I focused on a brain region called the hippocampus which plays critical roles in learning and memory, and is adversely affected in Alzheimer’s disease, anxiety disorders and depression. 

I established a critical role for calcium influx in the regulation of dendrite outgrowth and synapse formation, and also showed that excessive activation of glutamate receptors can cause the degeneration and death of neurons in a process called excitotoxicity. Moreover, I discovered that neurotrophic factors can protect neurons from being damaged and killed by glutamate.  

This led to my interest in neuronal degeneration and Alzheimer’s disease. I then spent 11 years building my own independent research program as a Professor of Neuroscience at the University of Kentucky School of Medicine. There my team and I made major inroads towards understanding the reasons why neurons degenerate in Alzheimer’s disease. It was also there that we discovered that intermittent fasting can protect neurons in the brain against dysfunction and degeneration in rat and mouse models of Alzheimer’s and Parkinson’s diseases, and stroke.    

I was then recruited to the NIH to build and lead the neuroscience research program at the National Institute on Aging. It was there that we made major advances in understanding how IF affects cells and organ systems in ways that enhance their performance and increase their resistance to injury and disease.

2. How did you first become interested in intermittent fasting?

Aging is the major risk factor for Alzheimer’s and Parkinson’s diseases. Previous studies had shown that daily calorie restriction and every-other-day fasting can greatly increase lifespan in rats and mice. We therefore designed experiments to test the hypothesis that every-other-day fasting could protect neurons and improve functional outcome in animal models of neurodegenerative conditions.

The postdocs in my laboratory found that the IF protects neurons in the hippocampus against epileptic seizures and prevents memory impairment. We further showed that IF protects neurons against damage caused by a stroke. We went on to demonstrate that IF can counteract the disease processes in models of Alzheimer’s and Parkinson’s diseases.

3. Over the most recent decades, a number of studies linking intermittent fasting with a variety of health benefits have come out, some of which were conducted by you and your colleagues. As you see it, what is the most important takeaway message from this body of research?

Examples of functional effects and major cellular and molecular responses of various organ systems to IF. Figure derived from «Flipping the Metabolic Switch: Understanding and Applying Health Benefits of Fasting» by Mark Mattson et al.

IF improves general health and brain health by stimulating cells in ways that enhance their ability to prevent and repair damage to their molecules (DNA, protein and membranes). IF improves glucose regulation, promotes utilization of abdominal fat and ketones during the fasting period, and reduces inflammation.  

IF improves cardiovascular health as indicated by reduced blood pressure and resting heart rate, improved cardiovascular adaptation to stress and reduced LDL cholesterol and triglyceride levels. IF improves brain health by increasing the number of healthy mitochondria in neurons and by stimulating the production of a neurotrophic protein called BDNF. Others have shown robust suppression of tumor growth in animal models of various types of cancer and clinical trials of IF in cancer patients are in progress.

4. In nature, organisms have to “struggle” to survive and put in quite a bit of effort in order get a hold of something to eat. Up until not so long ago in our evolutionary history, we too took part in this evolutionary battle for existence. Our hunter-gatherer ancestors obviously didn’t eat three square meals every day, starting with an early carbohydrate-rich breakfast; rather, their food intake fluctuated depending on their hunting success, seasonal changes in food availability, and so forth. Most importantly, they relied on their senses, muscles, and cognitive faculties in order to track down and outsmart game animals, evade predators, and otherwise map and navigate their local environment in the search for something to eat. Hence, it’s not surprising, from a Darwinian point of view, that intermittent food deprivation not only doesn’t seem to undermine our physical and mental capabilities, but that it’s common to feel more focused, supple, alert, and creative on an empty stomach, than on a full one, particularly if the fast is coupled with aerobic activity. What requires more of an explanation though, is why intermittent periods of food shortage or avoidance appears to be important for maintaining health in the long term and steering clear of degenerative disease? Could you please talk a bit about that? If you could relate your answer to our evolutionary history and adaptive processes, then that would be great.

Our research on IF supports the evolutionary hypothesis that the brain and body function well, perhaps optimally, when the individual is in a food deprived/fasted state. After eating the cells in the body and brain utilize glucose which is stored in the liver. Upon depletion of the liver energy stores (10 -16 hours in humans) fat cells (adipocytes) release fatty acids into the blood which are then converted to the ketone bodies beta-hydroxybutyrate and acetoacetate in the liver. These ketones are used as the main energy source by cells during fasting.  

It turns out that compared to glucose, ketones are a more efficient fuel for cells and also stimulate cells in ways that enhance their performance. For example, we discovered that the ketone beta-hydroxybutyrate stimulates the production of BDNF in neurons in the brain and the BDNF, in turn, enhances learning and memory by strengthening synapses and promoting the formation of new synapses between neurons.

We have also published a paper in which we show that IF enhances endurance in runner mice which involves ketones and stimulation of an increase in the number of mitochondria in muscle cells. We find that these beneficial effects of IF are not immediate, but instead require 2-4 weeks. This is important for people who would like to try IF because they have to become adapted to the new intermittent eating pattern before they experience the benefits on brain and body performance. 

5. In your papers on intermittent challenges, you present evidence suggesting that intermittent fasting may help negate several disease processes. What diseases are particularly relevant in this respect?

Obesity, diabetes, cardiovascular disease and stroke, epilepsy, Alzheimer’s and Parkinson’s diseases, and cancers.

6. A large part of the reason why intermittent fasting has become so popular is that it has long been touted as being effective for weight loss. Is this reputation well-deserved? In as few words as possible, what’s your interpretation of the science pertaining to intermittent fasting and fat loss?

Examples of the influence of eating patterns on levels of glucose and ketones in the blood. The red arrows indicate the time of food consumption/meals during a 2 day period of time. Figure derived from «Impact of intermittent fasting on health and disease processes» by Mark Mattson et al.

Yes, IF is effective for weight loss if the person can make it long-term/lifelong eating pattern, and if the person avoids unhealthy foods (i.e. sugar, fructose and saturated fats). The reason for its effectiveness is well-established. People who eat three meals plus snacks spread out through the day may never deplete liver glucose stores and so do not utilize (“burn”) fat. People who have an IF eating pattern burn fat towards the end of the fasting period.

7. There are many possible ways to implement the principles you discuss in your research papers on intermittent fasting into one’s daily life. A popular approach is to fast for 14-18 hours every day, often skipping breakfast, and then eating during a 6-10 hour eating window. However, many other strategies exist, some of which include alternate day fasting or a more unplanned, irregular way of eating. Do you have any thoughts about this aspect of intermittent fasting? Do you favor a particular regimen over others in some instances? What would you recommend to the average Joe or Jen who’s looking to stay fit and healthy?

I would recommend restricting the time window during which one eats each day to 6-8 hours (fasting for 16-18 hours) every day. For many this is most easily accomplished by not eating breakfast (drinking non-caloric tea or coffee in the morning is good). I would also suggest (if possible) exercising towards the end of the fasting period – either in the morning or at midday.

However, our studies with Dr. Michelle Harvie have shown that eating only 500-600 calories (one moderate size meal) two days each week and eating normally the other 5 days (“5:2 diet”) is also effective for weight loss and improves glucose regulation and enables fat loss. Some people may find that the 5:2 regimen better fits their weekly schedule.

8. Intermittent fasting, while certainly being something that people who are looking to enhance their health and well-being should consider incorporating into their lives, is obviously not a panacea. Nor would it be expected to work equally well for everyone. Different subgroups of people would be expected to differ with respects to how they respond to intermittent food abstention. Some people, such as severely sick individuals, bodybuilders, and athletes, for example, have special nutritional requirements. Furthermore, men and women are dissimilar with respects to their physiological design and have historically had different roles and responsibilities. In hunter-gatherer societies, there’s a division of labor, with men doing most of the running and hunting, while women typically stay closer to camp, where they care for the young and collect tubers, berries, and/or fruit, among other things. This would be expected to cause inter-gender differences in adaptations and responses to endurance activity and fasting. Do you have any thoughts about this? I’ve seen it suggested that intermittent fasting may be more prudent for men than for women. As you see it, is this supported by the research? Is there any evidence to suggest that men and women respond differently to intermittent fasting?

This is an important question for which we do not as yet have a definitive answer. IF counteracts aging and extends lifespan in both male and female mice. Both male and female monkeys also benefited from caloric restriction/daily fasting. Our human studies in overweight women and women with asthma have shown that they benefit from IF.   

We do not know whether IF is “better” for normal weight men compared to normal weight women. Interestingly, women usually have a greater amount of body fat compared to men. From an evolutionary perspective this sex difference in fat mass may have enabled women to survive and bear children during periods of extended food scarcity.  

9. In your research papers, you’ve talked about other “intermittent challenges” besides intermittent fasting, including exposure to dietary phytochemicals and exercise. Could you briefly talk about some of these challenges/stresses and how they affect our health? If you could relate your answers to our evolutionary journey, then that would be spectacular. I’m particularly interested in hearing about things that generally don’t get much attention/things that most people don’t know much about.

Mechanisms by which the intermittent challenges of running, intermittent fasting and ingestion of hormetic phytochemicals may protect cells against injury and disease. This example focuses on the brain. Figure derived from «Challenging Oneself Intermittently to Improve Health» by Mark Mattson.

I have proposed that the reason vegetables and fruits are good for health is that they contain chemicals that function to prevent insects, herbivores and humans from eating any or too much of the plants. These chemicals, which always have a bitter taste, are concentrated in vital parts of the plant (buds, seeds and skins of fruits). Examples include sulforphane in broccoli, curcumin in turmeric, and even caffeine in coffee beans and tea leaves.  

However, it was advantageous for herbivores and humans to be able to consume these plant parts because they are a source of energy and other nutrients. And so our cells evolved to respond to these chemicals in ways that protect the cells against the potentially noxious effects of the chemicals.

Indeed, sulforaphane stimulates the production of antioxidant enzymes in cells, and caffeine stimulates the production of BDNF in neurons (which enhances learning and memory ability). Readers may be interested in reading the article I wrote on this topic for the magazine Scientific American which appeared in the July 2015 issue.

10. How would you go about implementing the things you discuss in your research on hormesis and intermittent cellular stress into health care and medical training and practise. If you were to formulate a short list (for example composed of 5 points) of action points, what would it look like?

Incorporate education of medical students and physicians on the basic science of IF – how it affects energy metabolism, the role of ketones, the adaptive stress responses, etc. This training should include the emerging clinical applications of IF in patients with obesity, diabetes, cardiovascular disease or cancers.

Health insurance should cover outpatient and inpatient programs in which patients can be “coached” on how to change their eating pattern to IF. The importance of the 2-4 week adaptation period should be emphasized so that patients understand that improvements in health, mood and cognition will not be immediate.

Employers should encourage healthy lifestyles in their employees and accommodate IF eating patterns be allowing employees to, for example, arrive and begin work one hour earlier than usual, and then allow the employees a 90 minute period midday when they can exercise and then eat. The “dark forces” of the processed food (including the breakfast food) industries and the pharmaceutical industries that encourage unhealthy food consumption and lifestyles should be reigned-in by government-enforced limitations on advertisements.  

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