Effects of Intermittent Fasting on Health, Aging, and Disease.

          Effects of Intermittent Fasting on Health, Aging, and Disease

       December 26, 2019

N Engl J Med 2019; 381:2541-2551
DOI: 10.1056/NEJMra1905136

  

According to Weindruch and Sohal in a 1997 article in the Journal, reducing food availability over a lifetime (caloric restriction) has remarkable effects on aging and the life span in animals.1 The authors proposed that the health benefits of caloric restriction result from a passive reduction in the production of damaging oxygen free radicals. At the time, it was not generally recognized that because rodents on caloric restriction typically consume their entire daily food allotment within a few hours after its provision, they have a daily fasting period of up to 20 hours, during which ketogenesis occurs. Since then, hundreds of studies in animals and scores of clinical studies of controlled intermittent fasting regimens have been conducted in which metabolic switching from liver-derived glucose to adipose cell–derived ketones occurs daily or several days each week. Although the magnitude of the effect of intermittent fasting on life-span extension is variable (influenced by sex, diet, and genetic factors), studies in mice and nonhuman primates show consistent effects of caloric restriction on the health span (see the studies listed in Section S3 in the Supplementary Appendix, available with the full text of this article at NEJM.org).

Figure 1.Cellular Responses to Energy Restriction That Integrate Cycles of Feeding and Fasting with Metabolism.

Studies in animals and humans have shown that many of the health benefits of intermittent fasting are not simply the result of reduced free-radical production or weight loss.2-5 Instead, intermittent fasting elicits evolutionarily conserved, adaptive cellular responses that are integrated between and within organs in a manner that improves glucose regulation, increases stress resistance, and suppresses inflammation. During fasting, cells activate pathways that enhance intrinsic defenses against oxidative and metabolic stress and those that remove or repair damaged molecules (Figure 1).5 During the feeding period, cells engage in tissue-specific processes of growth and plasticity. However, most people consume three meals a day plus snacks, so intermittent fasting does not occur.2,6

Preclinical studies consistently show the robust disease-modifying efficacy of intermittent fasting in animal models on a wide range of chronic disorders, including obesity, diabetes, cardiovascular disease, cancers, and neurodegenerative brain diseases.3,7-10Periodic flipping of the metabolic switch not only provides the ketones that are necessary to fuel cells during the fasting period but also elicits highly orchestrated systemic and cellular responses that carry over into the fed state to bolster mental and physical performance, as well as disease resistance.11,12

Here, we review studies in animals and humans that have shown how intermittent fasting affects general health indicators and slows or reverses aging and disease processes. First, we describe the most commonly studied intermittent-fasting regimens and the metabolic and cellular responses to intermittent fasting. We then present and discuss findings from preclinical studies and more recent clinical studies that tested intermittent-fasting regimens in healthy persons and in patients with metabolic disorders (obesity, insulin resistance, hypertension, or a combination of these disorders). Finally, we provide practical information on how intermittent-fasting regimens can be prescribed and implemented. The practice of long-term fasting (from many days to weeks) is not discussed here, and we refer interested readers to the European clinical experience with such fasting protocols.13

Be Well!

DrD


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