Institute of Biochemistry, Food Science and Nutrition, Robert H. Smit Faculty of Agriculture, Food and Environment, The Hebrew University
Currently, about 12% of the population is 65 years or older and by the year 2030 that figure is expected to reach 21%. In order to promote the well-being of the elderly and to reduce the costs associated with health care demands, increased longevity should be accompanied by ageing attenuation. Caloric restriction (CR), which limits the amount of calories consumed to 60-70% of the daily intake, and intermittent fasting (IF), which allows the food to be available ad libitum every other day, extend the life span of mammals and prevent or delay the onset of major age-related diseases, such as cancer, diabetes and cataracts. We have shown that well-being can be achieved by resetting of the circadian clock and induction of robust catabolic circadian rhythms via timed feeding. As food components and feeding time have the ability to reset bodily rhythms, we may benefit from understanding what food components our body needs and at which time.
The circadian clock
Mammals have developed an endogenous circadian clock located in the brain suprachiasmatic nuclei (SCN) of the anterior hypothalamus that responds to the environmental light-dark cycle. Light is absorbed through the retina and this information is transmitted to the SCN, which in turn relays the information via neuronal connections or circulating humoral factors to peripheral clocks, such as the liver, heart and lungs, regulating cellular and physiological functions (1). Disruption of the coordination between the endogenous clock and the environment leads to symptoms of fatigue, disorientation and insomnia. Night-shift workers have disrupted circadian rhythms and they exhibit metabolic disorders, hormone imbalance (2), psychological and sleep disorders (3), and increased incidence of cancer and malignant growth (2). Others and we have shown that circadian rhythms change with normal ageing, including a shift in the phase and decrease in amplitude (4, 5). The circadian clock regulates metabolism and energy homeostasis in peripheral tissues (6). This is achieved by mediating the expression and/or activity of certain metabolic enzymes and transport systems (7, 8) involved in cholesterol metabolism, amino acid regulation, drug and toxin metabolism, the citric acid cycle, and glycogen and glucose metabolism (6, 9) (Fig.1).
Figure 1: The relationship between the circadian clock, feeding and metabolism
Effect of restricted feeding (RF) on circadian rhythms
Limiting the time and duration of food availability with no calorie reduction is termed restricted feeding (RF) (1). Restricting food to a particular time of day has profound effects on the behaviour and physiology. 2-4 h before the meal, the animals display food anticipatory behaviour, which is demonstrated by an increase in locomotor activity, body temperature, corticosterone secretion, gastrointestinal motility and activity of digestive enzymes (10), all are known output systems of the circadian clock. We have shown that long-term day-time RF can increase the amplitude of clock gene expression, increase expression of catabolic factors, and reduce the levels of disease markers leading to better health (11). RF regimen resembles the month of Ramadan, as Muslims abstain from eating and drinking during the activity period. The average low levels of cholesterol and triglycerides found during RF are in agreement with those found during Ramadan (12, 13). Aksungar and colleagues (14) demonstrated that Ramadan fasting has some positive effects on the inflammatory state and on risk factors for cardiovascular diseases.
Effect of calorie restriction (CR) on circadian rhythms
CR refers to a dietary regimen low in calories without malnutrition. CR restricts the amount of calories to 60-75% (15). It has been documented that calorie restriction significantly extends the life span of rodents by up to 50% (16, 17). In addition to the increase in life span, CR also delays the occurrence of age-related diseases, such as cancer, diabetes and cataracts (17-20). Theories on how CR modulates aging and longevity abound, but the exact mechanism is still unknown (17). The reduction of energy intake, and, as a result, in oxidative stress, is considered the critical beneficial factor in the CR regimen (17). CR during the daytime affects the temporal organization of the clockwork and circadian outputs in mice under light/dark cycle. In addition, CR affects photic responses of the circadian system, indicating that energy metabolism modulates gating of photic inputs in mammals (21). These findings suggest that synchronization of peripheral oscillators during CR could be achieved directly due to the temporal eating, as has been reported for RF (22-24), or by synchronizing the central clock (25), which entrains the peripheral tissues (26, 27).
Effect of intermittent fasting (IF) on circadian rhythms
IF allows food to be available ad libitum every other day. Similarly to calorically restricted animals, IF-fed animals exhibit increased life span as well as improved cardio- and neuro-protection and increased resistance to cancer (28). One suggested mechanism for its beneficial effects is the stimulation of cellular stress pathways induced by the IF regimen (28, 29). IF alters circadian rhythms depending on the time of food introduction. When food was introduced during the light period, mice exhibited almost arrhythmicity in clock gene expression in the liver. Unlike daytime feeding, night-time feeding yielded rhythms similar to those generated during ad libitum feeding (30).
Effect of high-fat diet on circadian rhythms
Obesity has become a serious and growing public health problem (31). Attempts to understand the causes of obesity and develop new therapeutic strategies have mostly focused on the imbalance between energy expenditure and caloric intake. However, studies in the last decade link energy regulation to the circadian clock at the behavioural, physiological, and molecular levels (6), emphasizing that the timing of food intake itself may play a significant role in weight gain (32). Obesity, which is characterized by the excess of fat accumulation in white adipose tissue, has been related to irregular sleep/wake schedules, high snacking frequency, or social jet lag known to disrupt the circadian clock (33). Several studies have shown that a high-fat diet leads to disruptions in locomotor activity in total darkness and to elevated food intake during the rest phase under light-dark conditions (34). These changes were also manifested by disrupted clock gene expression in the hypothalamus, liver and adipose tissue as well as altered cycling of hormones in mice, rats, and humans (35, 36). In addition, a high-fat diet induced a phase delay in clock and clock-controlled genes (35, 36). Combining high-fat diet with restricted feeding led to a leaner phenotype although the caloric intake was the same as mice fed a low-fat diet (37). Altogether, these studies demonstrate the importance of timing of feeding over its content.
Effect of breakfast on circadian metabolism
Breakfast has previously been demonstrated to be of major importance for the 24-h regulation of glucose (38). Indeed, skipping breakfast has been shown to be associated with weight gain and other adverse health outcomes, including insulin resistance and increased risk for developing type 2 diabetes. In contrast, consumption of a high-energy breakfast and a low-energy dinner resulted in a significant reduction of all-day postprandial glycaemia and body weight (39-41). The importance of breakfast has recently been demonstrated in type 2 diabetic patient who skipped breakfast and had increased postprandial hyperglycemia after both lunch and dinner in association with impaired insulin response (42).
Figure 2: Effect of feeding regimens on circadian rhythms and health. SCN, suprachiasmatic nuclei
Disruptions in clock genes and/or circadian rhythms promote ageing and shorten life span, whereas appropriate resetting of circadian rhythms leads to well-being and increased longevity. Life span extension has been a goal of research for several decades. CR, IF and RF reset circadian rhythms and promote better health (Fig. 2). In addition, breakfast consumption has been shown to affect all-day metabolism. Therefore, it is necessary to increase our understanding of circadian regulation over metabolism and longevity and to design new therapies based on this regulation.
This article was published in a special issue for World Food Day 2019