Science and Clinical Applications of Fasting

Educational Objectives

The goal of this program is to optimize utilization of fasting programs. After hearing and assimilating this program, the clinician will be better able to:

1. Differentiate among various types of fasting regimens.
2. Discuss the impacts of fasting on weight loss.
3. Identify appropriate candidates for fasting regimens.

Summary

Impacts of fasting on aging: several diseases, eg, diabetes mellitus (DM), heart disease (HD), cancer, dementia, are diseases of aging; anything that can slow or reverse aging can potentially reduce prevalence of these diseases; preliminary animal studies showed 20% to 25% longer lifespans with starvation; in human studies, it is difficult to identify reversal of the aging process at the cellular level; however, life expectancy is expected to increase with advances in medical technology

Intermittent fasting (IF): fasting for <48 hr; time-restricted eating (TRE) is the most popular type of IF because of ease of implementation; the most popular TRE regimen is 16/8, during which all calories for one day are consumed within 8 hr, followed by 16 hr fasting; other variants include the Warrior diet (20/4) and the 12/12 regimen; the 5:2 regimen involves observing regular eating habits for 5 days and dieting (complete fasting or modified fasting with reduced calories) for 2 days; alternate-day fasting (ADF) is another form of TRE

Prolonged (ie, periodic) fasting (PF): fasting for >48 hr; often performed for, eg, holistic, religious reasons; associated risks include compliance (the largest issue) and the risks for individuals with medical issues

Selection of regimen: IF vs PF — fasting for <48 hr leads to improvements in insulin sensitivity, blood pressure, and body weight; however, early animal studies show that PF promotes improvement in longevity (tissue repair, stem cell mobilization, cellular regeneration, and autophagy do not begin until 48 to 72 hr after fasting); TRE — choice of regimen is dependent on patient lifestyle; TRE should ideally be done ≥5 days a week to impart metabolic effects; for patients following a 5:2 regimen, 500 kcal/day for women and 600 kcal/day for men is ideal on the two days of stricter eating in lieu of a fully water-based fast, as basal metabolic rate is slightly lower for women than men; risks of PF — PF is associated with increased risks for, eg, dehydration, hypotension, hypoglycemia, muscle loss, fatigue, hunger, and gallstones, and risks are greater for the geriatric population and patients taking multiple medications; benefits of PF — the cell’s ability to self-repair is augmented with PF and is critical for prevention of HD and cancer; stem cell mobilization becomes more compromised with age, but initial studies demonstrate that PF can increase the proportion of mesenchymal circulating stem cells to ≤2.5%

Fasting mimicking diet (FMD): consists of eating specific foods for 5 days (≈1000 kcal/day) each month to induce a fasting state

Preclinical evidence: early studies showed that rodents fed a control diet weighed more and had decreased life expectancy, compared with rodents undergoing PF; primate studies showed lower incidences of age-related dermatologic issues and inflammation with PF vs standard diet; Bradhorst et al (2015) — rats exposed to FMD had decreased levels of visceral fat, compared with rats fed a control diet; evaluation of animals exposed to fasting showed significantly decreased prevalence of neoplasms and dermatologic conditions (including, eg, neoplasms, dermatitis), improved rates of mesenchymal stem cell circulation, and improved bone mineral density and overall survival

Cognitive performance: medications for dementia slow, but do not reverse, disease progression; during fasting, energy utilization changes; glycogen storage (mostly in the liver and muscles) is depleted 12 to 24 hr after eating, and the body then utilizes muscle or fat for energy, which generates ketone bodies; ketones are transported to the brain to induce expression of brain-derived neurotrophic factor (BDNF), a peptide which stimulates cognition and neural synapses; augmentation of BDNF helps in slowing the progression of dementia and other neurocognitive diseases; animal models have shown that fasting offers protection for neurons against degeneration, and studies have shown improved task performance

Autoimmune diseases: while medications may help to improve quality of life and function for patients with multiple sclerosis (MS; a progressive disease), decline and significant disability are still possible; Choi et al (2016) showed that fasting helped prevent neuronal damage in rats; a pilot trial by Choi et al (2016) revealed no improvement in self-reported quality of life and health among patients with MS with control diet vs ketogenic diet or FMD; there are ongoing larger trials to assess the role of fasting in MS

Impacts on weight loss: intermittent fasting — Trepanowski et al (2017) noted similar amounts of weight loss among individuals following daily caloric restriction or ADF; compared with control diet, patients who followed a fasting regimen maintained lower body weights at 12 mo; no particular form of fasting is known to be most superior; fasting mimicking diet — FMD helps prevent nutrient-sensing pathway activation and cell and tissue degeneration often seen with a traditional Western diet; in one cycle (30-day period) of FMD, fasting (or consumption of a particular combination of foods, comprising 800-1000 kcal/day) occurs for 5 consecutive days, and regular diet is consumed for 25 days; FMD still activates nutrient-sensing pathways but below the threshold that causes cellular degeneration; Wei et al (2017) noted significant weight loss (especially from the midsection), but not loss of lean muscle mass, following 3 cycles (90 days) of FMD; improvements in serum C-reactive protein level, BP, total cholesterol, and low-density lipoprotein were also noted at 3 mo with FMD; most benefits were sustained in 50% to 60% of patients 3 mo after returning to regular diet; one study showed that patients following FMD or Mediterranean diet exhibited similar metabolic benefits and changes in body composition

Patient selection: fasting is suitable for patients with overweight, obesity, borderline metabolic syndrome, who wish to avoid additional medications but see whether fasting is beneficial, or who can implement fasting as part of a healthy lifestyle; absolute contraindications include pregnancy, lactation, malnourishment, or unintentional weight loss; caution is advised for patients with type 1 or 2 DM, as fasting can cause hypoglyia, though the INTERFAST-2 trial (Obermayer et al, 2022) determined that IF is safe for patients with insulin-treated type 2 DM; caution is advised for patients who are immunocompromised, as transient depression of the immune system may occur during the initial phase of fasting; encourage hydration during active fasting (especially during the winter months when the thirst signal is diminished); side effects (including, eg, fatigue, weakness, dry mouth, constipation, brain fog, cravings) usually improve after the first few weeks

Readings

Brandhorst S, Choi IY, Wei M, et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 2015;22(1):86-99. doi:10.1016/j.cmet.2015.05.012; Choi IY, Piccio L, Childress P, et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep. 2016;15(10):2136-2146. doi:10.1016/j.celrep.2016.05.009; Cienfuegos S, Gabel K, Kalam F, et al. Effects of 4- and 6-h time-restricted feeding on weight and cardiometabolic health: a randomized controlled trial in adults with obesity. Cell Metab. 2020;32(3):366-378.e3. doi:10.1016/j.cmet.2020.06.018; Hajek P, Przulj D, Pesola F, et al. A randomised controlled trial of the 5:2 diet. PLoS One. 2021;16(11):e0258853. doi:10.1371/journal.pone.0258853; Obermayer A, Tripolt NJ, Pferschy PN, et al. Efficacy and safety of intermittent fasting in people with insulin-treated type 2 diabetes (INTERFAST-2) — a randomized controlled trial. Diabetes Care 1. 2023;46(2): 463–468. doi:10.2337/dc22-1622; Trepanowski JF, Kroeger CM, Barnosky A, et al. Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults: a randomized clinical trial. JAMA Intern Med. 2017;177(7):930-938. doi:10.1001/jamainternmed.2017.0936; Wei M, Brandhorst S, Shelehchi M, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017;9(377):eaai8700. doi:10.1126/scitranslmed.aai8700.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Hong was recorded at the 50th Annual USC Internal Medicine for PCPs and Subspecialists, held April 17-20, 2023 on Maui, HI, and presented by Keck School of Medicine of the University of Southern California. For information about upcoming CME activities from this presenter, please visit https://keckusc.cloud-cme.com/. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

IM702902

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.