Cardiovascular benefits of intermittent fasting

Commentary on ‘Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese human’, by S. Stekovic et al., Cell Metabolism, 2019. ‘Tell me what you eat and I will tell you what you are’ that is how the French gastronome Brillat-Savarin once articulated that we are what we eat. Humans around the globe have long shared the same belief as they have and still do spend significant periods of their lifetime seeking ways to grow, gather, and prepare food. More recently though, it became widely recognized that not only what we eat, but also how much and even when we eat determine the health outcomes of our food. In this regard, there is a clear consensus that modern-day eating habits—especially if combined with a sedentary lifestyle—foster increased and ‘around-the-clock’ dietary intake, thereby facilitating the development of obesity and metabolic diseases. Accordingly, numerous experimental studies have shown that caloric restriction(definition) promotes health and protects from various diseases. It is believed that caloric restriction does so through steering cellular energy supplies from growth towards maintenance via activating several defensive and repair processes that improve homeostasis, stress resistance and quality control of damaged cells, including in the cardiovascular system.1 Among the common approaches to reduce caloric intake is intermittent fasting, which is a regiment characterized by prolonged periods of dietary restriction interrupted by ad libitum periods of eating.2 In line with other forms of caloric restriction, intermittent fasting has been shown to confer health benefits against various conditions, including obesity, dyslipidaemia, hypertension, and aging.3 However, despite the abundance of animal studies, clinical studies on the salutary effects of intermittent fasting are rather scarce. Moreover, available clinical evidence is primarily derived from studies on overweight and obese patients, which precludes generalizing these benefits to non-obese healthy individuals. To this end, Stekovic et al.4 carried out a clinical study examining the efficacy and safety of alternate-day fasting—a form of intermittent fasting where cycles of 36-h-long fasting are separated by 12 h of ad libitum eating (Figure 1)—in healthy non-obese individuals. The authors conducted a prospective cohort study in which they observed that individuals following alternate-day fasting for 6 months show sustained reduction of caloric intake by around 28.5%. This was associated with reduced levels of circulating lipids, including triglycerides as well as low- and very-low-density lipoproteins (LDL and VLDL cholesterol, respectively), but without changes in plasma levels of high-density lipoproteins. More importantly, the authors then randomized the non-fasting controls of their cohort study to perform a short-term controlled trial of alternate-day fasting. Here, the intervention group had decreased caloric intake by 37%, leading to a 3.5-kg reduction in body weight (i.e. about 4.5% of the initial weight) after 4 weeks of alternate-day fasting. Lean-to-fat ratio and body composition were also improved as the weight was disproportionately lost from the trunk fat. Furthermore, alternate-day fasting improved various parameters of cardiovascular health as it lowered resting heart rate and reduced systolic and diastolic arterial blood pressures, as well as pulse pressure and pulse wave velocity. Although short-term alternate-day fasting did not reduce blood lipids, it still significantly reduced the Framingham Risk Score, which estimates the 10-year risk for cardiovascular disease development. Finally, the authors could show that at least up to 6 months, alternate-day fasting does not reduce energy expenditure, nor does it compromise immune cell counts, bone mass, or mineral density. Taken together, the study clearly demonstrates that alternate-day fasting holds promise as a potentially safe dietary intervention that is beneficial for healthy non-overweight subjects for up to 6 months. Common variants of intermittent fasting. Most people in developed and developing countries adopted a Western lifestyle, which includes eating several high-calorie meals throughout the day leading to cardiometabolic complications and early onset of chronic diseases. A growing number of clinical trials examining the consequences of different forms of intermittent fasting, such as restricting food intake every other day or limiting it to a short window during the day (known as alternate-day fasting and time-restricted eating, respectively), indicate that the amount of food as well as the duration of time spent eating every day are important determinants of the effects of diet on our health and lifespan. Of note, the salutary effects of intermittent fasting are difficult to be explained by lower energy intake and associated leanness alone. In fact, some of the benefits of intermittent fasting (e.g. on insulin sensitivity and body composition) reportedly differ when compared to classical caloric restriction (i.e. continuous reduction in daily caloric intake without incurring malnutrition).5 Therefore, additional mechanisms have been proposed to contribute to the effects of intermittent fasting. The metabolic shifting in substrate utilization for energy production is one such mechanism. Specifically, intermittent fasting forces the body to rely on ketones and fatty acids—derived from adipose tissue breakdown—instead of glucose, which is reintroduced only during the eating periods. In support of this notion, Stekovic et al.4 reported higher circulating levels of the ketone body β-hydroxybutyrate and polyunsaturated free fatty acids. Such metabolic shifts occur periodically on a regular basis during intermittent fasting, thus, improving cellular metabolic flexibility and bioenergetic efficiency. Indeed, an elevated ketogenesis per se through ketogenic diet (i.e. without fasting) is suggested to exert cardiopr