Impact of intermittent fasting on health and disease processes

Abstract

Humans in modern societies typically consume food at least three times daily, while laboratory animals are fed ad libitum. Overconsumption of food with such eating patterns often leads to metabolic morbidities (insulin resistance, excessive accumulation of visceral fat, etc.), particularly when associated with a sedentary lifestyle. Because animals, including humans, evolved in environments where food was relatively scarce, they developed numerous adaptations that enabled them to function at a high level, both physically and cognitively, when in a food-deprived/fasted state. Intermittent fasting (IF) encompasses eating patterns in which individuals go extended time periods (e.g., 16–48 h) with little or no energy intake, with intervening periods of normal food intake, on a recurring basis. We use the term periodic fasting (PF) to refer to IF with periods of fasting or fasting mimicking diets lasting from 2 to as many as 21 or more days. In laboratory rats and mice IF and PF have profound beneficial effects on many different indices of health and, importantly, can counteract disease processes and improve functional outcome in experimental models of a wide range of age-related disorders including diabetes, cardiovascular disease, cancers and neurological disorders such as Alzheimer’s disease Parkinson’s disease and stroke. Studies of IF (e.g., 60% energy restriction on 2 days per week or every other day), PF (e.g., a 5 day diet providing 750–1100 kcal) and time-restricted feeding (TRF; limiting the daily period of food intake to 8 h or less) in normal and overweight human subjects have demonstrated efficacy for weight loss and improvements in multiple health indicators including insulin resistance and reductions in risk factors for cardiovascular disease. The cellular and molecular mechanisms by which IF improves health and counteracts disease processes involve activation of adaptive cellular stress response signaling pathways that enhance mitochondrial health, DNA repair and autophagy. PF also promotes stem cell-based regeneration as well as long-lasting metabolic effects. Randomized controlled clinical trials of IF versus PF and isoenergetic continuous energy restriction in human subjects will be required to establish the efficacy of IF in improving general health, and preventing and managing major diseases of aging.

Introduction

The survival and reproductive success of all organisms depends upon their ability to obtain food. Accordingly, animals have evolved behavioral and physiological adaptations that enable them to survive periods of food scarcity or absence. When food is not available for extended time periods some organisms become dormant; for example, yeast enter a stationary phase, nematodes enter the dauer state, and ground squirrels and some bears hibernate (Calixto, 2015). Mammals have organs such as the liver and adipose tissue which function as energy depots that enable fasting/starvation for varying lengths of time depending upon the species. Importantly, metabolic, endocrine and nervous systems evolved in ways that enabled high levels of physical and mental performance when in the fasted state. In this article we review studies of the effects of regimens of intermittent fasting (IF) diets, which include eating patterns in which individuals go extended time periods (e.g., 16–48 h) with little or no energy intake, with intervening periods of normal food intake, on a recurring basis. To distinguish studies of short-term frequent fasting periods from studies of less frequent but longer fasting periods we use the term periodic fasting (PF) to refer to IF with periods of fasting or “fasting mimicking diets” (FMDs) lasting from 2 to as many as 21 or more days. The term time-restricted feeding (TRF) is used to describe an eating pattern in which food intake is restricted to a time window of 8 h or less every day. Studies of laboratory animals have elucidated the cellular and molecular mechanisms by which individuals respond to fasting in ways that can increase their overall fitness and their resistance to injury and a wide array of diseases (Longo and Mattson, 2014). Recent randomized controlled trials in human subjects have demonstrated that IF, including diets that mimic some aspects of FMDs, are achievable in humans and improve many health indicators in healthy individuals and in those with some chronic diseases.

In this article we focus on studies of the effects of IF, including PF and FMD, on animals and humans. Examples of specific IF diets include: complete fasting every other day (Bruce-Keller et al., 1999, Anson et al., 2003); 70% energy restriction every other day (Johnson et al., 2007, Varady et al., 2015); consuming only 500–700 cal two consecutive days/week (Harvie et al., 2011); and restricting food intake to a 6–8 h time period daily, which has also been termed ‘time restricted feeding’ (TRF) (Chaix et al., 2014). Examples of PF include a 4–5 day FMD (Brandhorst et al., 2015), 2–5 days of water only fasting (Raffaghello et al., 2008, Safdie et al., 2009), and 7 days of a FMD (Choi et al., 2016). The vast majority of IF animal studies have involved either alternate day fasting or TRF, and most randomized controlled human trials have involved either 60–75% energy restriction (500–800 kcal) on alternate days or 2 consecutive days/week. Rarely has more that one IF regimen been compared within the same study, and so it is not yet possible to make any clear conclusions as to whether one regimen is superior to another with regards to improving health and disease resistance.

Although results may differ quantitatively depending on the type of IF pattern and the species studied, all of the IF regimens described in the preceding paragraph result in several fundamental metabolic changes that define a fasting period including: maintenance of blood glucose levels in the low normal range, depletion or reduction of glycogen stores, mobilization of fatty acids and generation of ketones, a reduction of circulating leptin and often elevation of adiponectin levels (Johnson et al., 2007, Wan et al., 2010) (Fig. 1). Behavioral changes that occur during the fasting period of IF diets include increased alertness/arousal and increased mental acuity (Fond et al., 2013). As we describe in subsequent sections of this article, both the metabolic shift to ketone utilization, and adaptive responses of the brain and autonomic nervous system to food deprivation, play major roles in the fitness-promoting and disease-allaying effects of IF. Because overall calorie intake is often reduced during IF (e.g., weekly calorie intake in an individual on the ‘5:2′ diet is reduced by 25%; Harvie et al., 2011, Harvie et al., 2013a) it is important to know if and to what extent physiological responses to IF are mediated by the overall caloric restriction (CR). In some studies of animals or human subjects, groups maintained on IF or isocaloric CR diets have been compared directly and, in those cases we will describe the similarities and differences. Otherwise, we will not review studies of CR which are much more numerous than studies of IF, and have been reviewed elsewhere recently (Speakman and Mitchell, 2011, Mercken et al., 2012, Longo et al., 2015). It should be noted, however, that the most commonly used method for daily CR in rodent laboratory studies (limited daily feeding) is in fact a form of IF/TRF. Thus, the animals are housed singly and the average amount of food consumed each day when the animals are fed ad libitum is designated the ad libitum food intake. Animals are then randomly assigned to ad libitum control and CR groups, with the animals in the CR group being fed a designated percentage of their normal ad libitum intake (usually 60–80%; i.e., 20–40% CR). Animals on CR are typically provided their daily or, in some cases thrice weekly, food in one portion (Pugh et al., 1999). However, under these circumstances, the animals on CR often consume their entire allotment within a period of several hours of receiving the food and, accordingly, they are fasting intermittently for extended time periods of (for example, 16–20 h when fed daily, or 36 h or more when fed thrice weekly). The relative contributions of IF and CR to the lifespan extension and health-enhancing effects reported in studies of standard caloric restriction in these laboratory studies have not been investigated, and therefore represents a major knowledge gap in this field of research. Here we will focus on IF as the role of PF/FMDs on longevity and diseases in laboratory animals and humans. For more comprehensive recent reviews of the physiological and disease-modifying effects of fasting at the cellular and molecular levels, the reader is referred to Longo and Mattson (2014) and Longo and Panda (2016).