Based on the multitude of headlines suggesting the health benefits of fasting, you probably already experimented with fasting or were curious about the real-world benefits. You also likely asked yourself: what type of fasting should I try? What should I monitor while fasting? What are the side effects (dizziness, low energy, headache)?  Will (fill in the blank) break my fast? Will the hungry cravings be overwhelming? Should I pair fasting with keto or any supplements? And so many other questions.

Today’s blog will give a brief overview of fasting and will go over an n-of-1 experiment, detailing Dom’s observations from previous 3-day fasts. By sharing his unique perspective, we hope to help you navigate this promising tool to improve markers of metabolic health and mental focus.

Although the scientific community does not have answers to all the questions above, we are continuously learning more about the benefits and mechanisms associated with fasting. As shown in the figures below, there has been a remarkable growth in both interest and research in the area of “fasting”. Since the metabolic and neurophysiological response to fasting varies between individuals, depending upon their existing metabolic health, it is even more important to monitor objective biomarkers, physical performance and subjective effects on things like energy levels, mood and mental clarity. Apps like Zero are working to develop methods for optimizing and personalizing the fasting experience.  Anecdotally, there appears to be a gender difference in metabolic response to fasting, and perhaps changes in dopamine and serotonin, which is currently being studied in women with eating disorders and food addiction.

Numbers represent search interest relative to the highest point on the chart for the given region and time. A value of 100 is the peak popularity for the term. A value of 50 means that the term is half as popular. A score of 0 means there was not enough data for this term. Source: Google Trends

Growth of Fasting research in peer-reviewed publications. Source: PubMed

Fasting Types

There are several fasting protocols to choose from with unique patterns and sometimes distinct health benefits, although most positive metabolic effects (eg. weight loss, reduced insulin) are due to creating a calorie deficit.  The figure below highlights the most common ones with a brief list of benefits reported. What we commonly call “Intermittent Fasting (IF)” is usually termed Time Restricted Feeding (TRF) in the scientific literature.

Adapted from: Fasting Science Review and Anton SD et al. Obesity 2018 [1]

One challenge is that there are few head-to-head studies comparing the different fasting approaches and how beneficial they can be for specific conditions or patient populations. With that in mind, whichever protocol you choose needs to work for your lifestyle and personal goals. We highly recommend getting bloodwork (CBC, CMP) and having a healthcare practitioner accompany you during the early stages of a fasting protocol, especially if it extends to 36hrs or beyond. Having a baseline health assessment also helps you track important changes that occur, and may vary between fasting protocols. There are a variety of commercially available devices (e.g. KetoMojo, Biosense) and home test kits (eg. ZRT or Base) you can find online to help you monitor things like blood ketones, glucose, insulin, hormones and other biomarkers. Dom uses a continuous glucose monitor (CGM) with Levels to track glucose levels and how this correlates with insulin over time.

Overlap between fasting and keto

Fasting is the quickest way to “flip the metabolic switch” from less glucose to greater fat and ketone metabolism [1]. In fasting, the suppression of insulin and elevation of glucagon liberates non-esterified fatty acids from our fat deposits into the bloodstream. This physiological response, largely driven by insulin suppression, contributes to the myriad of metabolic health benefits, including improved metabolic biomarkers, enhanced autophagic flux, mitophagy, and cellular senescence, mechanisms described in a previous blog focusing on longevity benefits of ketones.  Since context is important, it is important to note that fasting-induced metabolic changes can have a negative effect if taken too far, especially for underweight individuals, those with a poor nutritional status, or someone with a muscle wasting disease (eg. ALS, cachexia). With that said, fasting in cancer patients has been shown to reduce tumor progression and increase the effectiveness of chemotherapy. There are NIH-funded interventional clinical trials being done with various fasting protocols for prostate cancer (NCT04288336), melanoma (NCT04387084) and breast cancer (NCT05023967), to name a few.

Do keto and fasting go well together? Individuals following a ketogenic diet report feeling more satiated and less hungry, which may have practical benefits for those attempting to implement TRF [2] or other fasting protocols. In addition, the sustainment of ketosis can be maintained during TRF within the compressed eating window if ketogenic macronutrient ratios are maintained. Consumption of exogenous ketones has also been shown to acutely decrease hunger and desire to eat through suppressing hormones like ghrelin, suggesting a potential role for use in a “modified fasting protocol” and perhaps to further augment the therapeutic benefits of a ketogenic diet [3].

N-of-1 Experiment: Dom’s 72-hour fasting experience

Dom has discussed fasting on many podcasts including Tim Ferriss, on social media posts, and in previous KetoNutrition blogs, and summarizes his preferred approach below.  When not fasting, he chooses to consume most of his calories between 10am and 6pm, with a small snack in the evening. TRF is done once or twice/week, but doing it more often leads to unwanted weight loss.  He has tried 3-day, 5-day and 7-day fasting protocols with comprehensive bloodwork in addition to glucose and ketone monitoring throughout the process. Based on his goals (mental focus, work productivity), a 72hr fast offers the most benefits with little or no disruption in cortisol or testosterone (see table below). In addition, 72hr fasts produce minimal reductions in deadlift strength, which is probably the best index of muscle retention. That said, he has reported that strength endurance is often highest at the 16-20hr fasted state. With prolonged fasting (5-7 days) it can take a few weeks to fully recover strength back, which is why he now avoids these longer duration water-only fasts.

This table summarizes the results from one 7 day fast, three 72hr fasts, and a recent  “modified 72hr fast” that included an exogenous ketone salt product KetoStart and the MCT-based Nootropic product KetoBrainz to help maintain energy level during the fast and to increase ketone metabolism and signaling. Caffeine (coffee) with MCT enhances ketogenesis. It is largely unknown if further boosting ketosis influences biomarkers (especially insulin) associated with the beneficial effects of fasting. Although our current laboratory research is focused on things like ketone-induced autophagic flux, this was not the goal here. However, reaching a GKI of 1-2 or Biosense ACE reading of >20 after 72hrs may translate to autophagy due to the suppression of insulin signaling. Keep in mind that autophagy can be achieved with a caloric deficit alone, using any dietary approach, but fasting is the most rapid way to get there.  Also, fasting may achieve the greatest level of insulin suppression, which does not appear to be influenced by dietary fat or ketone supplementation (in small amounts).  Previously, Dom did note that higher protein meal increases insulin (2x higher than hypercaloric keto).

Summary and take-aways

Dom’s primary goal for fasting is not improving insulin sensitivity, fat loss or autophagy, although these are potential benefits. His motivation to fast is to maintain a state of “calm energy” and improved work productivity without significant reductions in strength (muscle) or hormone disruption. Activity during this period is generally low, and consists of long walks outside with bodyweight exercises.

Fasting produces relatively rapid (24-48hrs) “metabolic switching” towards greater fat and ketone metabolism and seems to suppress appetite and improve motivation. Interestingly, the homeostatic mechanisms that preserve blood glucose under energy restriction are powerful and maintain low-normal glucose levels, even in the context of starvation. For example, brain glucose transporters ensure optimal brain glucose uptake (GLUT3 has low Km and high Vmax), but ketones largely replace glucose during prolonged fasting. One of his 72hr fasts involved more physical activity, and this was associated with lower overall glucose and insulin levels, and greater loss in bodyweight- no doubt fat, but probably lean mass too. The use of ketone supplements boosts energy and motivation to exercise, which is even more noticeable in a fasted state.  Since ketones have an anti-catabolic effect, it is likely that a “modified fast” with ketone supplementation would help to preserve muscle in the context of a”fasted state”. It is likely that the benefits of fasting or even a fasting modified diet (5 day) will be experienced for several weeks after it is discontinued, as long as a eucaloric diet is maintained afterward.  At the time of this writing the insulin measurements from the 72hr modified fast (KetoStart + KetoBrainz) were not yet analyzed, but these values will be discussed when the data becomes available. Since this a complex topic and Dom has more experiments to share, we will continue it in another blog post, stay tuned.

References