Intermittent metabolic switching (IMS) via fasting: is it for you and how to do it?

Intermittent metabolic switching (IMS) via fasting is getting mainstream, spearheaded by an all-positive NEJM review published on Christmas Day 2019:

The article is ranked at the 99th percentile compared to other NEJM articles as of 01-02-2020,

Fasting is an example of hormesis. Hormesis is a term used by toxicologists to refer to a biphasic dose–response to an environmental agent: 1. a low dose stimulation or beneficial effect, 2. a high dose inhibitory or toxic effect. In the fields of biology and medicine hormesis is defined as an adaptive response of cells and organisms to a moderate (usually intermittent) stress. Examples include exercise, dietary energy restriction and exposures to low doses of certain phytochemicals. Source:

Intermittent metabolic switching (IMS) causes beneficial effects via a three-step process, illustrated below.

Effects of Fasting, Intermittent metabolic switching (IMS) (click to enlarge the image).

Fasting first causes the use of the glucose from the liver as a source of energy, produced via gluconeogenesis from glycogen from the stores in the liver. The glycogen is exhausted after 10-14 hours, then the glucose to ketone switch via ketogenesis is activated. The body fat releases fatty acids which the liver uses to makes ketones. This is illustrated in figure 2 here:,

The metabolic processes and the roles of the different organs are shown in figure 2 here:

Biochemical pathways involved in the metabolic switch are shown in figure 1 here:

Signalling pathways by which neurons respond to the metabolic switch during fasting and exercise, shown in figure 2 here:

Examples of effects of intermittent fasting on different organ systems are shown in figure 3 here:

Mark P. Mattson has reviewed hormetic plant chemicals here, see the figures:

Challenging oneself intermittently could improve health.

Fasting causes the following effects:

Increased: ketones, autophagy, DNA repair, mitochondrial stress, antioxidant defenses/sirtuins, neurotrophic factors - BDNF/cognition, increased parasympathetic tone/HRV

Decreased: glucose, insulin, IGF-1, mTOR/RAS/protooncogenes, protein synthesis, cholesterol, CRP, TNF, heart rate, BP, temperature

The recovery (eating) leads to ketone to glucose switch:

Increased: glucose, insulin, mTOR, protein synthesis, mitochondrial biogenesis. The reward: cell growth/CNS synaptic plasticity/neurogenesis, structural/functional tissue remodelling

Decreased: ketones, autophagy

3 meals plus snacks is abnormal eating pattern form evolutionary perspective (multiple glucose spikes, no ketones). See figure
1 here:

The intermittent metabolic switching (IMS) leads to long term adaptation:

Increased: insulin sensitivity, HRV. Healthier lipid profile and gut microbiome

Decreased: abdominal fat, inflammation (CRP), blood pressure

The long term reward includes a resilience of cells/organs to stress - metabolic, oxidative, ischemic, proteotoxic stress, enhanced cognition, mood, ANS function.

The adaptive responses of major organ systems to intermittent fasting are shown in figure 2 here:

Neural circuits and cellular signaling pathways that mediate adaptive responses of the brain to fasting are shown in figure 4 here:

A model for how intermittent metabolic switching may optimize brain performance and increase resistance to injury and disease, shown in figure 3 here:

Patterns of daily and weekly food consumption, shown in figure 3 here:

Mark Mattson recommended 5:2 diet with restricted time eating. 5:2 implies eating over a 6-hour time frame for 5 days, followed by 2 days of fasting. Fasting is defined as eating 50 calories per day, not water fasting. Mark Mattson advocates for this approach to be continued indefinitely, see figure 4 here:

Valter Longo proposed a fasting mimicking diet (FMD) which consists of low calories meals for 5 days, followed by a longevity diet, which is mostly plant-based diet. The fasting mimicking diet is eaten between every month to every 6 months based on the risk factors present in the patient. The fasting mimicking diet (Prolon) is available for purchased from Valter Longo's company and costs approximately $230 dollars for 5 days.

Most of the researchers involved in intermittent metabolic switching (IMS) via fasting are so convinced by the findings that they follow some fasting protocol or another. Discuss with your physician before trying fasting.


Effects of Intermittent Fasting on Health, Aging, and Disease | NEJM

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