Flipping the Metabolic Switch: Understanding and Applying the Health Benefits of Fasting

Abstract

Intermittent fasting (IF) is a term used to describe a variety of eating patterns in which no or few calories are consumed for time periods that can range from 12 hours to several days, on a recurring basis. Here we focus on the physiological responses of major organ systems, including the musculoskeletal system, to the onset of the metabolic switch – the point of negative energy balance at which liver glycogen stores are depleted and fatty acids are mobilized (typically beyond 12 hours after cessation of food intake). Emerging findings suggest the metabolic switch from glucose to fatty acid-derived ketones represents an evolutionarily conserved trigger point that shifts metabolism from lipid/cholesterol synthesis and fat storage to mobilization of fat through fatty acid oxidation and fatty-acid derived ketones, which serve to preserve muscle mass and function. Thus, IF regimens that induce the metabolic switch have the potential to improve body composition in overweight individuals. Moreover, IF regimens also induce the coordinated activation of signaling pathways that optimize physiological function, enhance performance, and slow aging and disease processes. Future randomized controlled IF trials should use biomarkers of the metabolic switch (e.g., plasma ketone levels) as a measure of compliance and the magnitude of negative energy balance during the fasting period.

Dietary Energy Restriction Ameliorates Cognitive Impairment in a Mouse Model of Traumatic Brain Injury

“…Both IF and CR significantly ameliorated this cognitive deficit. It was previously found that IF was neuroprotective in animal models of stroke and Alzheimer’s and Parkinson’s diseases (Anton et al 2018; Longo and Mattson 2014). Here, we show that both IF and CR preserve visual memory function in our closed mTBI mouse model.…”

Metabolic and molecular framework for the enhancement of endurance by intermittent food deprivation

“…Although high-fat diets can be ketogenic, they are typically high in saturated fats and protein and can be proinflammatory (55). In contrast, food deprivation in laboratory animals and voluntary fasting in humans mobilizes fatty acid ketone precursors in a regulated manner and also engages many adaptive signaling pathways that promote cellular stress resistance and resilience (4,5). With the latter thought in mind, our findings suggest that the impact of intermittent dietary energy restriction on the performance during prolonged highintensity interval regimens merits investigation in human subjects.…”

“…In rodents, IF reduces tumor incidence and growth (64,65) prevents and reverses type 2 diabetes (4), and protects the heart and brain against damage in models of myocardial infarction (66) and stroke (67,68). The signaling pathways and molecular mechanisms by which ADF affects cells has been previously investigated in studies of the brain and heart (4,5). The mechanisms include activation of trophic factor signaling pathways, autophagy and mitochondrial biogenesis, upregulation of protein chaperones and antioxidant defenses, and suppression of inflammation (4,5,(69)(70)(71).…”

“…Competition for limited food sources has been a driving force for evolution, with selection for individuals capable of high levels of physical performance under conditions of intermittent food deprivation (IF). In response to controlled energy restriction for more than 12 to 16 h and/or extended exercise, a major cellular fuel source switches from glucose to fats as liver glycogen stores are depleted, and fatty acids are metabolized to the ketones 3b-hydroxybutyrate (BHB) and acetoacetate (4)(5)(6). This switch to fatty acids as a fuel source manifests as a reduction in the respiratory exchange ratio (RER; ratio of CO 2 produced to O 2 consumed).…”

How active management survives

“…In rare areas of life, however, doing little or nothing is the dominant strategy. Fasting appears to have dramatic health benefits (Anton et al 2018;Mattson et al 2018). Meditation-doing nothing but observing one's thoughtscan be an effective complementary treatment for some psychiatric conditions (Shapero et al 2018).…”