APPENDIX D:

Intermittent Fasting: What is it, and how does it work?

Intermittent fasting: What is it, and how does it work? Johns Hopkins Medicine. (n.d.). Retrieved November 15, 2021, from https://www.hopkinsmedicine.org/health/ wellness-and-prevention/intermittent-fasting-what-is-it-and-how-does-it-work.

Excerpt:

“Research shows that the intermittent fasting periods do more than burn fat. Mattson explains, ‘When changes occur with this metabolic switch, it affects the body and brain.’

One of Mattson’s studies published in the New England Journal of Medicine revealed data about a range of health benefits associated with t he practice. These include a longer life, a leaner body and a sharper mind.

‘Many things happen during intermittent fasting that can protect organs against chronic diseases like type 2 diabetes, heart disease, age-related neurodegenerative disorders, even inflammatory bowel disease and many cancers,’ he says.

Here are some intermittent fasting benefits research has revealed so far:

• Thinking and memory. Studies discovered that intermittent fasting boosts working memory in animals and verbal memory in adult humans.
• Heart health. Intermittent fasting improved blood pressure and resting heart rates as well as other heart-related measurements.
• Physical performance. Young men who fasted for 16 hours showed fat loss while maintaining muscle mass. Mice who were fed on alternate days showed better endurance in running.
• Diabetes and obesity. In animal studies, intermittent fasting prevented obesity. And in six brief studies, obese adult humans lost weight through intermittent fasting.
• Tissue health. In animals, intermittent fasting reduced tissue damage in surgery and improved results.”

• The Intermittent Fasting Podcast

The Intermittent Fasting Podcast serves to demystify the intermittent fasting (IF) lifestyle: a pattern of eating in which you regulate the hours you eat each day, rather than the amount of food you eat. Intermittent fasting instigates effortless weight loss, health and vitality. The Intermittent Fasting Podcast was started by two self-published authors: Melanie Avalon (The What When Wine Diet: Paleo and Intermittent Fasting for Health and Weight Loss) and Gin Stephens (Delay, Don’t Deny: Living an Intermittent Fasting Lifestyle). Melanie and Gin both actively practice intermittent fasting lifestyles, personally choosing to eat one meal per day for dinner. With intermittent fasting, they have experienced effortless and substantial weight loss, as well as many health and other “life” benefits. They also answer listener questions through their podcast and website.

Effects of Intermittent Fasting on Health, Aging, and Disease Rafael de Cabo, Ph.D., and Mark P. Mattson, Ph.D. (2019). Effects of Intermittent Fasting on Health, Aging, and Disease. (381:2541-2551). 10.1056/NEJMra1905136.

Abstract:
Evidence is accumulating that eating in a 6-hour period and fasting for 18 hours can trigger a metabolic switch from glucose-based to ketone-based energy, with increased stress resistance, increased longevity, and a decreased incidence of diseases, including cancer and obesity.

Cardiometabolic Benefits of Intermittent Fasting
Krista A. Varady, Sofia Cienfuegos, Mark Ezpeleta, and Kelsey Gabel. (2021). Cardiometabolic Benefits of Intermittent Fasting. (Annual Review of Nutrition 41:1). pp 333-361. https://doi.org/10.1146/annurev-nutr-052020-041327.

Abstract:
This review aims to summarize the effects of intermittent fasting on markers of cardiometabolic health in humans. All forms of fasting reviewed here—alternate-day fasting (ADF), the 5:2 diet, and time-restricted eating (TRE)—produced mild to moderate weight loss (1–8% from baseline) and consistent reductions in energy intake (10–30% from baseline). These regimens may benefit cardiometabolic health by decreasing blood
pressure, insulin resistance, and oxidative stress. Low-density lipoprotein cholesterol and triglyceride levels are also lowered, but findings are variable. Other health benefits, such as improved appetite regulation and favorable changes in the diversity of the gut microbiome, have also been demonstrated, but evidence for these effects is limited. Intermittent fasting is generally safe and does not result in energy level disturbances or increased disordered eating behaviors. In summary, intermittent fasting is a safe diet therapy that can produce clinically significant weight loss (>5%) and improve several markers of metabolic health in individuals with obesity.

Glucose Tolerance and Skeletal Muscle Gene Expression in Response to Alternate Day Fasting.

Leonie K. Heilbronn, Anthony E. Civitarese, Iwona Bogacka, Steven R. Smith,
Matthew Hulver, Eric Ravussin. (2012). Glucose Tolerance and Skeletal Muscle Gene
Expression in Response to Alternate Day Fasting. (Volume 13, Issue 3). Pp 574-581.
https://doi.org/10.1038/oby.2005.61.
• Related: Carpenter, S. (2012, September). That gut feeling. Monitor on Psychology, 43(8). http://www.apa.org/monitor/2012/09/gut-feeling
Excerpt: Your gut holds 90% of your serotonin.

Abstract:
Objective: Alternate day fasting may extend lifespan in rodents and is feasible for short periods in nonobese humans. The aim of this study was to examine the effects of 3 weeks of alternate day fasting on glucose tolerance and skeletal muscle expression of genes involved in fatty acid transport/oxidation, mitochondrial biogenesis, and stress response.

Research Methods and Procedures: Glucose and insulin responses to a standard meal were tested in nonobese subjects (eight men and eight women; BMI, 20 to 30 kg/m2) at baseline and after 22 days of alternate day fasting (36 hour fast). Muscle biopsies were obtained from a subset of subjects (n = 11) at baseline and on day 21 (12-hour fast).

Results: Glucose response to a meal was slightly impaired in women after 3 weeks of treatment (p < 0.01), but insulin response was unchanged. However, men had no change in glucose response and a significant reduction in insulin response (p < 0.03). There were no significant changes in the expression of genes involved in mitochondrial biogenesis or fatty acid transport/oxidation, although a trend toward increased CPT1 expression was observed (p < 0.08). SIRT1 mRNA expression was increased after alternate day fasting (p = 0.01).

Discussion: Alternate day fasting may adversely affect glucose tolerance in nonobese women but not in nonobese men. The gene expression results indicate that fatty acid oxidation and mitochondrial biogenesis are unaffected by alternate day fasting. However, the increased expression in SIRT1 suggests that alternate day fasting may improve stress resistance, a commonly observed feature of calorie-restricted rodents.

Metabolic reactions activated during 58-hr fasting are revealed by non-targeted metabolomic analysis of human blood. Teruya, T., Chaleckis, R., Takada, J. et al. (2019). Metabolic reactions activated during 58-hr fasting are revealed by non-targeted metabolomic analysis of human blood. (Sci Rep 9). pp 854. https://doi.org/10.1038/s41598-018-36674-9

Abstract:
During human fasting, metabolic markers, including butyrates, carnitines, and branched chain amino acids, are upregulated for energy substitution through gluconeogenesis and use of stored lipids. We performed non-targeted, accurate semiquantitative metabolomic analysis of human whole blood, plasma, and red blood cells during 34–58 hr fasting of four volunteers. During this period, 44 of ~130 metabolites increased 1.5~60-fold. Consistently fourteen were previously reported. However, we identified another 30 elevated metabolites, implicating hitherto unrecognized metabolic mechanisms induced by fasting. Metabolites in pentose phosphate pathway are abundant, probably due to demand for antioxidants, NADPH, gluconeogenesis and anabolic metabolism. Global increases of TCA cycle-related compounds reflect enhanced mitochondrial activity in tissues during fasting. Enhanced purine/pyrimidine metabolites support RNA/protein synthesis and transcriptional reprogramming, which is promoted also by some fasting related metabolites, possibly via epigenetic modulations. Thus diverse, pronounced metabolite increases result from greatly activated catabolism and anabolism stimulated by fasting. Anti-oxidation may be a principal response to fasting.

Intermittent metabolic switching, neuroplasticity and brain health. Mattson MP, Moehl K, Ghena N, Schmaedick M, Cheng A. (2018). Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci. doi: 10.1038/nrn.2017.156. Epub 2018 Jan 11. Erratum in: Nat Rev Neurosci. 2020 Aug;21(8):445. PMID: 29321682; PMCID: PMC5913738.

Abstract:
During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted, and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signaling pathways
that promote neuroplasticity and resistance of the brain to injury and disease.