Hormesis (which means exposure to stress to create a benefit) is proving to be an incredibly valuable tool in our health arsenal. From cold exposure to psychedelic micro-dosing and much more in between, the field has lots of potential. Part 3 in this 7 part series addresses fasting.
For a full introduction to Hormesis read part 1 of the Hormesis series.
Fasting, The Fasting-Mimicking Diet and Time-Restricted Eating
Various “dietary protocols” regarding advice to fast for days on end, restrict the eating window, or maintain a diet to exist in a permanent ketogenic state have exploded into mainstream debate.
While there is some interesting science and research behind all mentioned, and a larger body behind next weeks extension of this topic “calorie restriction”, and the recently popular “fasting-mimicking diet” (FMD), some of the claims regarding the benefits can pass the line into dangerous, and much of the research is very preliminary.
As a note, I am not covering the ketogenic diet in this series, despite speaking about ketones. While short term ketosis seems to have evidence supporting potential benefits, based on my knowledge of hormesis (and others more educated than myself), a permanent state of stress, which ketosis likely is, is unwise.
There exists research in which short term benefits of a high fat ketogenic diet are fascinating in the short term, and over longer periods the benefits fade, and larger issues are presented.
3-5 Day Fasts
I’ve been following fasting research for at least a couple of years now, but until last week I had never buckled down and tried one for myself. I just completed a 3-day water fast, kick-starting it with my last meal being a high fat, moderate protein intake following a soccer game, and worked out every day during the fast to maximize benefits.
My experiences were very different from what I have read, and I’ve considered some of the reasons behind this. During the fast, I consumed only water, lots of it, a multivitamin/ mineral, and twice-daily hydrogen water generated by our hydrogen tablets. I’ll note that the hydrogen water picked me up substantially, but only for an hour or two. I would “save” my hydrogen water dosages for when things were at a tough point.
First off, it was not one of the hardest things I have ever done. I don’t think it would make the top 100. This is perhaps the biggest surprise to me. I woke up morning 1 hungry and then subjected myself to a hard work out early day 1, and after that, the 16-24 hour mark was by far the hardest.
I considered giving up during this 8-hour window, but never actually came close as my thoughts and cravings were easily pushed down. By the time I woke up for day 2, my hunger pangs had subsided, and it became much easier. I even went to a movie the night of day 2. I stood in line staring at the treats and smelling the popcorn and other foods, trying to buy water, and didn’t consider folding.
Perhaps the temporariness of it, with a known end date, made it psychologically easier for me, but I found a 3-day fast much easier to stick to than even something as seemingly easy as a “no dessert or junk food for a month” protocol.
I experienced mental clarity, but no enlightened thought. What I did experience was overwhelming stupidity. My mind rarely goes blank. I cannot stop thinking, except when I initiate guided meditation/ relaxation hypnosis. I also have no issues focusing, usually.
During the fast, I was almost always not thinking, or struggling to remember what I was doing. Sometimes I would be completing a task and I would forget what my task was. Or I would finish, and my mind would go blank, spaced out into nothing.
I think what others experience is the high I felt. I presume as ketones are burning, releasing energy erratically and not constantly, waves of energy flow through the body. I would be lying down as if stuck in concrete, and suddenly, my whole body would warm and start tingling. My head would tingle, euphoric.
I want to say this is the “mental clarity” others have spoken to, but no advanced thought, no revelations, or creativity accompanied it. I was just useless for the last 2 days. 2 days later, and I am still “slower” than usual, my mind struggling to get back on track.
My workouts were absolutely arduous and putting myself through them was perhaps the hardest part of the fast. My recovery from the pathetic training sessions has been slow, as workouts where I would barely break a sweat usually, have my muscles “falling off the bone” when completing them during a fast.
Between the fast and the workouts, I’ve been able to solidly sleep two nights in a row of over 9 hrs a night. Great timing, as it is rounding out the Easter weekend (2019) as I write this.
Why I'd Consider Fasting Again
I would consider another fast, and likely will. First, let’s take a look at some of the reasons.
mTOR, or the mammalian target of rapamycin, is exploding on the research scene with very early research suggesting inhibition of its action has implications in aging.iiiiiivv Increased activation seems to be correlated in cancer progression and autophagy inhibition,vi and overactivation is tied closely to some of the pathologies of Alzheimer’s disease such as tauviiviii and beta-amyloid,ix although it is unclear of increased mTOR signaling leads to beta-amyloid, or if beta-amyloid secretion leads to increased mTOR activity.x
The drug candidate Rapamycin, which inhibits mTOR activity, is being heavily studied in all of these areas with human trials underway for cancer and Alzheimer’s but not yet complete and rodent trials already extending longevity in mice even when treated late stage of life.xixiixiiixiv
On study comparing the alterations in expressions and markers in rapamycin fed mice noted that some of the markers altered by dietary restrictions did not seem to be altered by rapamycin.xv It would be premature to suggest that dietary restrictions are superior or inferior to rapamycin, however, they share many common targets.
Autophagy is the natural process of cellular breakdown, removing damaged and improperly functioning cells, and recycling the “parts”. Yoshinori Ohsumi earned the 2016 Nobel Prize in Physiology or Medicine for his work and discoveries on the mechanisms of autophagy. The conceptual implications of the benefits of activating autophagy are very intuitive. So much so I believe I peaked in confidence on the Dunning-Kruger scale within half a dozen hours of reading on the subject.
In trying to follow along during Dr. Ohsumi’s recorded lectures, and reading significant portions of the literature, the last 20-30~ hours I’ve spent attempting to increase my understanding has been a straight nose dive into the valley of despair. Much of this is due to publications on the subject often being very technical, with references to pathways and mechanisms I had not previously been acquainted with.
Autophagy is implicated in both cell survival and cell death.xviiixix Further confounding my understanding on the overall implications is the notion that autophagy both suppresses and promotes cellular senescence.xx Since I previously “knew” that senescent cells are bad and one of the largest drivers in disease states and accelerated age-related degeneration,xxixxiixxiiixxiv how could a function that promotes them be good?
Cellular senescence can both be a protective barrier to cancer,xxv and dysfunction of cellular senescence can promote cancer via contributing to a chronic inflammatory state.xxvi In a similar paradox, autophagy seems to prolong the survival of cancers when apoptosis (programmed cell death) is impaired even leading to cancers believed to be eradicated reemerging, while impaired autophagy increases the rate of tumor growth.
Evidence also suggests that autophagy is protective in limiting tumor necrosis, or dead cells within the cancer that are particularly nasty, and inflammation, and mitigating genome damage in tumour cells in response to metabolic stress.xxvii
Regardless, others who are far more knowledgeable on the subject understand the implications of activation of autophagy more clearly than I do, and there is significant excitement. Autophagy is seemingly more harmful to more conditions when deactivated,xxviii and proper activation is a potent protector against cellular stress.xxixxxxxxxi
I am going out on a limb, but perhaps autophagy is neither good nor bad, but simply a system that needs homeostatic function such as our inflammatory defenses or our redox status. Senescence may even fit into this, to an extent. The default in most models could be under activation of autophagy and short term and intermittent fasting has shown to promote autophagy.xxxiixxxiii
AMPK activation is an interesting area of research that has been implicated as a mediator and necessary component of exercise-induced mitochondrial biogenesis via activation of PGC-1a, a key player inactivation of autophagy, and a regulator of our endogenous antioxidant defense systems.xxxiv AMPK activation, or rather the activation of the equivalent AAK-2 found in c elegans, has also shown to be necessary for the life extension of glucose restricted c elegans (worms).xxxvxxxvixxxvii
While much of the research on AMPK activation has centered around exercise and suggested it is possibly the most powerful activator,xxxviii fasting, or specifically nutrient and glucose starvation, is becoming a method which we are increasingly studying and learning can be utilized to activate it.xxxixxl
Since studies in mice tend to focus on 24hr fasts,xlixlii with energy requirements in mice being significantly higher per gram of body weight, 7 times higher in fact than humans,xliii we cannot directly convert fasting durations from mice to men and expect the same altered expressions to be consistent. A direct multiplication would imply a 7 day fast is necessary, which may be excessive.
A better standard could be the determination of glucose starvation by measurement of blood or urinary ketones. Personally, my ketone measurements via urine were roughly 1.5 mmol/L by hour 46, 4 mmol/L by hour 52 and in excess of 8 mmol/L when I broke my fast at the end of the third day. I did “kickstart” the fast with a high-fat meal after a soccer game, then a hard work out the next morning, and daily workouts and long walks throughout day 2 and 3, that said.
Ketone bodies have become an increasingly hot topic in mainstream media and discussion primarily due to the rising popularity of the ketogenic diet, controversy over its’ claims, and the ensuing release of countless products purporting to raise ketone levels. In the future, I will write a dedicated article to this, but for now, I will simply state that the data on ketones and their role, both beneficial and harmful, in different disease states such as cancer should warrant caution.
Ketones have shown to increase the rate of tumor growth and metastasis (the development of secondary growths), with ketone suppressants being a proposed drug candidate for cancer research,xliv Another study has shown that while initial beneficial signaling for anti-tumor effects occurred on a high fat ketogenic diet, prolonged exposure to this state ultimately leads to increased tumor development and faster growth.xlv
Conversely, a pair of rodent studies from the 80s show inhibited tumor growth from a low carb high-fat ketogenic dietxlvixlvii and more recent studies using human cancer cells in mice on a calorie-restricted ketogenic diet have been favorable in slowing tumor formation.xlviiixlixlli
It is unclear if the benefits come from the caloric restriction or the high fat low carbohydrate diet. Since evidence on the latter is contradictory in conclusions, and evidence regarding potential modes of action such as mTOR inhibition and autophagy activation are stronger in calorific restricted states, I would err on the side of the former.
There are a few small, early human studies on a high-fat ketogenic diet and tumor growth in cancer patients, although the durations have also been shorter and more acute, ranging from 2 weeks to 3 months.liiliiilivlv More studies are currently underway, as they are as well with fasting and the fasting-mimicking diet I cover next week.
Perhaps ketone bodies are an important piece of the puzzle. That said the evidence is currently much stronger in promoting acute exposure than maintaining an extended or permanent state. High-fat fed mice do not typically have high rates of health and survival over a lifetime, which is an important consideration as well. Luckily, there are several methods available where we can experiment with short exposures to ketosis such as fasting.
5x2 and 1x1 fasting
Two similar but different “fasting” diets have become popular in the last several years. I have my concerns with both regarding long term observance and impact on physical fitness, as well as the quality of the data.
The 5x2 diet suggests normal calorific intake 5 days per week and restriction to 25% of daily calories on 2 non-consecutive days. I was only able to find two publications on the 5x2 diet, by the same principal investigator, and while they showed benefits it was no more beneficial for weight loss than standard calorific reduction equally distributed throughout the week.lvilvii There were significant reductions in insulin resistance, that said, and a marked increase in ketones in the 5x2 method over the 25% reduction daily group. Of note, the 5x2 diet specified “non-consecutive days for fasting”, and this study utilized “consecutive days”. There was also a 23% drop out in just 3 months in the 5x2 group, not unusual for dietary intervention trials but indicative of the challenge in promoting a method like this for the broader population, permanently.
1:1 diets have amassed more evidence than the 5x2 diet, however many of the diets did not have a control group, or better yet a comparison to calorific reduction equally distributed through the days.lviiilix One study was a randomized crossover design, although again it was not compared to standard calorific restriction.lx
There is slightly more evidence for a hybrid between 1:1 and 5:2, with alternating days between calorific restriction but not total fasting, and normal intake. 7 studies fit this definition, with 4 being uncontrolled.lxilxiilxiiilxiv As such, we cannot draw any conclusions from these studies.
For the controlled studies, the earliest study I could find from 1998 had the control group at 1500-1800 calories a day, which at first looks to be calorific restriction, but upon inspection, the intervention group is on the same intake on their “normal feeding days”, with the increased reduction of intake on very restricted days.lxv
As such very little can be taken from this study, also. Two studies controlled with groups maintaining their typical eating habits.lxvilxvii One of the two study’s tries to give the appearance of being well controlled, with 4 total groups. On closer inspection, the groups are alternate day fasting, fasting + exercise, exercise alone with no dietary intervention, and the “control” neither exercising nor reducing their calories.
We know that exercise alone is a poor intervention for weight loss compared to calorific restriction and showing that fasting + exercise increases weight loss against either on their own or a control group with no intervention, does nothing to prove the efficacy of alternate-day fasting beyond other protocols restricting calories.
We really can’t draw any conclusions from the human data on these interventions. Additionally, I know from an athletic perspective it is very difficult to train on a severe calorific deficit, and muscles take significantly longer to recover post-training. Every other day fasting, and a 5x2 method, I believe would greatly reduce the ability to exercise and recover from exercise.
That said, if you are practicing one of these methods, have found you can exercise properly and experience benefits, by all means, continue.
Time-restricted eating is a strategy that is interesting, easy, and has a small amount of research supporting its’ efficacy. Personally, I have practiced time-restricted eating for years, however, in immersing myself with the published literature I believe I have been doing it all wrong.
I tend to eat within a 6-8 hour window, that window being in the afternoon to evening. I took up this habit as I find my mind works better on an empty stomach (until I have stress hunger), and I tend to overeat when I am not paying attention.
Much of the research on TRE revolves around our circadian rhythm as mice restricted to eat during their normal feeding hours, even with a high-fat diet, lower their risk of metabolic issues compared to mice fed ad libitum at an equivalent calorific intake.lxviii
Interestingly, when humans skip breakfast and consume the same calories at lunch as the breakfast eating control group, no weight loss or improvement in metabolic markers is observed. In fact, insulin sensitivity increased in the breakfast group.lxix Conversely, nighttime eating restrictions have shown improvements in human models.lxx
A pair of studies exist on the reduction of meal frequency to maximize the benefits of TRE.lxxilxxii While both showed weight loss and improvements in metabolic outcomes, I remain skeptical of the overall benefit.
The very reason I began delaying my first meal was the lethargy I feel after a large meal, no matter how nutritious and balanced that meal is. If we are to accept the circadian rhythm research, logic would suggest having a large meal earlier in the day, or mid-day. However, eating a day’s worth of calories in a single meal in the middle of the day would render me incapable of functioning, as I imagine it would most.
I’m attempting to make the switch to TRE of 10 hours a day, from 10 am to 8 pm, take an hour or so depending on the time of year. While my intuition is worth practically nothing (even expert intuition is practically useless, according to Prof. Daniel Kahneman), I would predict my energy expenditure and productivity would increase dividing my calories throughout several chunks over that 10 hours. Perhaps even a 3 meal system, we could call it a “breakfast, lunch and dinner”. Novel concept, I know.
Hormesis - Fasting Conclusion
Personally, out of what was discussed in this article I would favor a time-restricted eating schedule omitting meals in the evening hours, with the odd water fast, so long as it is done in a safe manner.
For anyone interested, please speak to your medical doctor first and consider and conditions you may have that could be exacerbated by any of these nutritional interventions.