The Molecular Mechanisms of Fasting – Excerpt from Periodic Fasting

The Molecular Mechanisms Of Fasting - Excerpt from Periodic Fasting


Optimal human condition goes beyond the current dangerously simplified approach which puts feeding and exercising at its core. Aligning the circadian clock, reducing non-native EMF radiation, improving sleep, improving hormone signaling, reducing the exposure to artificial light, improving redox potential, improving microbiota diversity, using cold thermogenesis are only few of the other important factors to be mentioned. Today these factors may be perceived as ‘exotic’ or ‘outrageous’, while tomorrow they may become the protocol.

The following is an excerpt from chapter 5 of my recently released book called Periodic Fasting. To read the rest of the chapter for free you can join the friends list.

Basic Concepts of Circa Rhythms

The human body, nowadays, mostly never experiences seasonality in terms of temperature. People living in colder climates have close to minimum exposure to low temperatures during winter due to their constant warm environments (cozy homes), due to commuting from one place to another in a warm car, due to less commuting, and due to warm clothing as well. They do not have to go hunting for their food and be exposed to cold for various hours in a row everyday. Food availability and the convenience of getting it have never been greater than today.

The human body mostly never experiences the dose of daily light exposure with which it was accustomed to for so many generations. Living in big cities where sun light may be partially blocked by buildings, staying indoors many hours during the day, and staying late at night being exposed to artificial light from TVs, light bulbs, tablets, smartphones and other devices prevents sound circadian rhythmicity.

And when you desynchronize your internal clock, when you are exposed to too much artificial light, when you are not exposed to stress coming from the environment (living in constant conditions 365 days a year), and when you sleep poorly, no wonder you are so vulnerable to many ailments.

When you consume food regularly everyday and when you do not sleep enough, your body mostly never goes into repair and maintenance mode, mainly because it has to focus on food digestion; hence the higher exposure to diseases; hence accelerated aging. I strongly think that eating frequently every day is not an optimal strategy.

The explosion of technology and the wide availability of information has lead to total chaos. But it’s never too late to put the pieces together and try to benefit from the wonders of high-tech and the comforts of modern-day life, while at the same time mitigating the bad effects and the risks that come in the same package.

As I get deeper into research, as I analyze more data from good and bad research studies, and as I experiment with different strategies myself, I come to realize that an optimal human condition has much more to do than the regular advice to focus on diet and exercise that most experts promote.

Dangerously simplified strategies of eating a certain way and exercising everyday, without doing a background analysis of the subject wanting to improve his/her lifestyle is one of the reasons most folks fall of the wagon. A personalized well-considered strategy may include thorough blood work, sleep improvement, circadian synchronization, reduced exposure to EMF (electro-magnetic-field) radiation, fasting, reduced artificial light exposure, and even genome analysis.

In this context, I would safely assume it matters little what you eat as long as you eat naturally, irregularly, and use these strategies along the way (including fasting). Of course, optimizing nutrition would provide increased benefits.

This is a holistic approach that I discussed in a previous book T-(Rx) – The Testosterone Protocol. I was able to increase my testosterone levels naturally with a strategy including a multitude of interventions. That way I mitigated the risks of unnaturally using hormone replacement therapies and/or steroid injections. What I’m trying to point out here is that personalized medicine is on its way to becoming very popular.

General guidelines are having less impact and I would encourage you to stay away from anyone (friends, family, media, government, etc) who tries to paint a simplistic picture of optimal health. I would also encourage you not to take any of my words for granted, but learn how to critically read studies, learn to discern from good and bad studies, and read as many of them so that you generate a more complex picture of optimal human condition. Many books may be biased.

To better understand the molecular mechanisms of fasting, one may have to get a good grasp on circadian rhythms. As I mentioned earlier, the circadian cycle encompasses biologic processes that take place with a 24-hour periodicity. Evolution has fine-tuned the human body for daily exposure to light and nightly exposure to dark. Metabolic processes in the body are tightly correlated to circadian rhythmicity.

Many hormones are secreted in a daily cyclical pattern. For example, in healthy people, cortisol levels are higher in the morning and gradually decreases throughout the day [107]. Testosterone levels usually peak between 8-10 A.M., while melatonin increases in the evening in the absence of light, preparing the body for sleep (repair and maintenance). Various biochemical processes in the human body are regulated in this fashion. But what happens when you’re exposed to artificial light at night and, on top of that, you consume food right before going to sleep?

One possible answer is that light exposure destroys melatonin production which disrupts the circadian cycle as it confuses the suprachiasmatic nucleus (SCN) inside your brain. SCN has been considered the master controller of circadian rhythms in mammals [108, 109]. Food consumption will make your body focus on digesting it instead of repairing damaged protein inside your body, building new cells, organizing memories, and doing maintenance work. This is a very simplified scenario as the picture and its implications are far more complex.

The oscillation of the suprachiasmatic nucleus (SCN) is not exactly 24 hours, which is why it needs to be entrained to external light/dark cycles so that it remains synchronized. Factors that entrain the clock are called zeitgebers. One of the most potent is light, as it enters the retina and its signal is transmitted to the SCN. Other factors entraining the circadian clock are food and/or feeding cycles [119].

Here’s an insightful illustration of the circadian clock [110]:

The Molecular Mechanisms Of Fasting - Excerpt from Periodic Fasting

These findings are heavily backed-up by research studies from the past few decades. Currently, there is an ever growing attention on the mechanisms of the circadian clock and their health implications in humans and other life forms. Sadly, the public is mostly unaware of the importance of circadian rhythms. Hence, many of us live in mismatched conditions, as I explained above.

Genetically modified animal models (mice) have exposed a certain correlation between metabolic disorders and the circadian clock [112]. Researchers have mutated and/or knocked-out clock genes (genes regulating the circadian clock) in mice and have observed how these animals become hyperphagic (eat a lot) and obese and develop signs of the metabolic syndrome, such as increased leptin levels, hyperlipidemia, increased glucose levels, as well as hepatic steatosis (fatty liver) [113].

Calorie restriction has the potential to reset a disrupted circadian clock, resulting in improved overall biochemistry, which in turn may increase life-span and the quality of life [114]. On the other hand, mice put on an intermittent energy restriction (IER/IF – alternate day) protocol even though they consume more food in their feeding days compared to mice that are fed continuously, they show better blood sugar management, improved cardiac function, improved neuronal function, as well as increased resistance to developing cancer [112].

Improved cardiovascular output was observed in humans who did intermittent fasting [115]. According to Froy (2011), calorie restriction may reset circadian rhythms in the periphery (cells and tissue specific circadian rhythms) and in the SCN (in the brain), while intermittent fasting resets circadian rhythms in the periphery and has the potential to extend life span [112].

In plants and animals there are two genes coding for the cryptochrome proteins CRY1 and CRY2. These proteins are sensitive to blue light and are components of the vast repository of the circadian clock.

In recent studies of CRY knock-out models (genetically engineered animal models with absent CRY proteins), researchers observed induced circadian arrhythmicity (disruption of the circadian clock), which lead to a constant expression of inflammatory cytokines. Such a scenario is also possible in people who disturb their circadian clock, like those traveling across multiple time zones at once, shift-workers, and also people who stay up late at night and are exposed to increased artificial light.

A constant level of chronic inflammation may eventually progress into full blown chronic diseases such as obesity, diabetes, and cancer [116, 117]. Yet again, intermittent fasting and calorie restriction have been shown to mitigate these negative effects [114]. Of course this does not give one free permission to constantly disrupt the circadian cycle and think that if they calorically restrict or fast intermittently, it will not have a negative impact on them.

But on the other hand, it may provide one with powerful tools of keeping the clock synchronized as much as possible when traveling, when working in shifts or in other disturbing circumstances. For example, when I traveled across continents, from Romania to Thailand (5 hours difference) or from Romania to America (7 hours difference), I suffered minimal jet-lag, possibly because I fasted mostly throughout these trips.

Conventional wisdom says that full recovery from jet-lag takes 1 day per every hour of time-zone difference. So it would have actually taken 5 days, respectively 7 days for me to fully recover from my travels. Yet, I was able to mitigate this pitfall with fasting. And of course, it’s much more convenient and cheaper because food is expensive in airports; and it would be impractical to carry packaged-food with me all the time.

Restricted feeding (RF) is another strategy very similar to intermittent fasting and refers to limiting the duration and the time of food availability without restricting calories. Animal models (mice) doing restricted feeding for 4 months express more robust circadian rhythmicity as well as lower levels of inflammatory markers (TNF-α, NFκB, IL-6, and others), concomitantly with increased levels of the anti-inflammatory cytokine IL-10 [118].

For some, it may be easier to follow a restricted feeding or intermittent fasting protocol daily over the long term, without having to tap into caloric restriction. However, I think that in time, if the food consumed is of higher quality and less/not processed, both RF and IF will progressively and naturally include calorie restriction.

Some researchers have also investigated the metabolic implications of circadian rhythms and obesity. According to Froy (2011), hormones such as insulin, glucagon, corticosterone, ghrelin, leptin, and adiponectin express circadian oscillation [119].

Leptin, for example, shows compelling circadian patterns in gene expression, with maximum levels during sleep [120]. Removing the adrenal glands or manipulating feeding times did not affect the rhythmic leptin secretion in rodents, but removal of the SCN did, marking a tight correlation between the SCN and circadian leptin secretion [121].

In human studies, researchers observed lower leptin levels over 24 hours in obese subjects, possibly suggesting a role of disrupted circadian rhythms in leptin resistance and obesity [122].

For folks not familiar with leptin and its action in the human body, you should know that leptin is a hormone secreted by your fat cells – affecting hunger and satiety. Its mechanism is similar to insulin and it is often mentioned in contexts regarding insulin resistance. Here’s how it is supposed to work:

Normal-weight subjects secrete leptin as a response to feeding. Leptin communicates with the hypothalamus telling your brain that it had enough food and that you should stop eating. In obese subjects, the adipose tissue releases more leptin and there is an inefficient communication between leptin and your brain, marking reduced leptin sensitivity (increased leptin resistance). Feeding cessation often occurs much later in obese subjects compared to lean subject, a mechanism that further promotes obesity.

Animal models with destroyed leptin receptors and humans with genetic mutations affecting leptin activity have shown to exhibit early onset morbid obesity, hyperinsulinemia, hyperphagia, increased circulating glucose levels and other conditions associated with the metabolic syndrome [123, 124, 125, 126, 127]. Of course, these may be extreme cases, but my point is to show you the critical importance of normal circulating leptin levels and how they may be affected by disrupted circadian rhythms.

Moreover, factors affecting the transport and the management of fatty acids (FATP1, ACS1, ADRP) are expressed diurnally (on a daily basis). Mice studies show that when they are activated (expressed) during nighttime (dark cycles), they lead to increased fatty acid uptake and higher adipogenesis [128]. Since mice are night-feeders, it may be more challenging to extrapolate these findings to human studies.

When the circadian rhythmicity of glucose metabolism is disrupted, it may lead to metabolic disorders, both in humans and rodents [129, 130, 131, 132, 133]. Some patients suffering from Type 2 Diabetes exhibit loss or non-functioning daily insulin secretion cycles and poor glucose tolerance [129]. I would suspect that constantly altering these cycles by consuming foods that increase glucose and insulin levels at inappropriate times of the day may contribute to the development of Type 2 Diabetes. After all, this condition is often induced by lifestyle.

In one study, healthy subjects had to move their last meal from 19-20 P.M. to 23-24 P.M. (midnight). After a period of 3 weeks, the overall daily glucose levels and insulin secretion increased significantly, marking a correlation between feeding cycles, circadian rhythms, and glucose and insulin secretion [134]. Subsequently, sleeping less than 6 hours or more than 9 hours per night has been associated with increased risk of developing poor glucose tolerance and T2D [135].

These studies suggest that we should not interfere with our circadian adapted metabolism, which has been polished and perfected over the thousands of generations of hominids on Earth. Constant exposure to artificial light, reduced sleep, and feeding at night may disrupt the processes involved in homeostasis and may actively participate in the development of diseased conditions.

Conversely, overnight fasting, restricted feeding, irregular feeding cycles, calorie restriction and a combination between these strategies may promote better preservation of health, a greater focus on healing and maintenance processes, increased lifespan, and healthier aging. This is what I delve into in the next section…


We recklessly concentrate on food and exercise alone, following the same strategies that were proved ineffective 50 years ago, while we blame others for our misfortunes. An optimal health condition encompasses much more than food and exercise. Aligning your circadian clock, reducing exposure to non-native (man-made) EMF radiation, reducing exposure to artificial light, improving sleep, using cold-thermogenesis, improving microbiota diversity, irregular feeding, and many others are important factors in this equation. If you want to learn more about this you can read the rest of this chapter for free by joining my friends list.

P.S. The day this blogpost is out, you can also get the kindle version of the book at half the price (~$5).


107. Weller, J. A., Buchanan, T. W., Shackleford, C., Morganstern, A., Hartman, J. J., Yuska, J., & Denburg, N. L. (2014). Diurnal cortisol rhythm is associated with increased risky decision-making in older adults. Psychology and aging, 29(2), 271.

108. Buijs, F. N., Cazarez, F., Basualdo, M. C., Scheer, F. A. J. L., Perusquía, M., Centurion, D., & Buijs, R. M. (2014). The suprachiasmatic nucleus is part of a neural feedback circuit adapting blood pressure response. Neuroscience, 266, 197-207.

109. Benarroch, E. E. (2008). Suprachiasmatic nucleus and melatonin Reciprocal interactions and clinical correlations. Neurology, 71(8), 594-598.

110. “Biological clock human” by NoNameGYassineMrabetTalk fixed by Addicted04 – The work was done with Inkscape by YassineMrabet. Informations were provided from “The Body Clock Guide to Better Health” by Michael Smolensky and Lynne Lamberg; Henry Holt and Company, Publishers (2000). Landscape was sampled from Open Clip Art Library (Ryan, Public domain). Vitruvian Man and the clock were sampled from Image:P human body.svg (GNU licence) and Image:Nuvola apps clock.png, respectively.. Licensed under CC BY-SA 3.0 via Wikimedia Commons –

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116. Narasimamurthy, R., Hatori, M., Nayak, S. K., Liu, F., Panda, S., & Verma, I. M. (2012). Circadian clock protein cryptochrome regulates the expression of proinflammatory cytokines. Proceedings of the National Academy of Sciences, 109(31), 12662-12667.

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2 Responses to The Molecular Mechanisms of Fasting – Excerpt from Periodic Fasting

  1. andy says:

    Hi Cristi, really loving the book on fasting,

    Wondering what strategies you propose for the sleep loss that happens in Ketosis. I understand that total sleep need may go down, but for me it goes down to almost 3 hours per night, and definitely do not feel rested or healthy for that matter. I have played around with adding higher carbs to the last meal of the day, but when I add enough to help my sleep it boots me out of ketosis.


    • Chris Chris says:

      Hey Andy, I’m not sure where you got the association of sleep loss and ketosis. It’s not the same thing to sleep less in ketosis and feel super energized, but feeling sleep deprived and fatigued may be due to a host of other associative conditions. There’s no actually a quick fix for anything in life from my perspective. What I’d do is to increase the nutrient richness of my diet, that is if you follow the dogma of ketogenic diets where you eat 80%+ fat and do not consume plenty of green vegetables that are rich in micronutrients. Magnesium may help for better sleep. Cold thermogenesis may as well. But these are tools…

      Not sure if this helps, but if it doesnt, please let me know your questions and I’ll follow-up.

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