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S O U R C E : Cell Metabolism
Highlights
- For healthy, non-obese adults, ADF is safe to practice for several months
- 4-week ADF decreases the body weight by 4.5% and improves the fat-to-lean ratio
- Cardiovascular parameters and the CVD risk are improved upon ADF
- ADF reduces T3 and periodically depletes amino acids, while increasing PUFAs
Summary
Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.
CONTEXT AND SIGNIFICANCE
Of all the anti-aging and longevity-promoting interventions tested so far, calorie restriction (CR) seems to be the most conserved among species and robust. However, humans struggle to constantly achieve a certain level of CR. Here, we show in a clinical trial that a related intervention, alternate day fasting (ADF), also leads to striking reduction in overall calorie intake over the course of the study but is more easily tolerated than continuous CR and provokes similar beneficial changes on the cardiovascular system and on body composition while being safe for a period of >6 months. We also found positive alterations in cardiovascular disease risk factors and in fat mass after only 4 weeks of ADF. In the future, this practice, which is already growing in use as a lifestyle intervention, could eventually accommodate modern healthcare in various settings.
INTRODUCTION
While chronically increased caloric intake (and in particular one that is carbohydrate-centered) has negative effects on human health, caloric restriction (CR) is known to extend healthspan and lifespan in model organisms, including rhesus monkeys. The mechanisms of these longevity effects have not been fully elucidated yet. However, several clinical trials have been launched to translate the positive aspects of CR and fasting to humans. Thus, a recent study showed that CR reduced risk factors for cardiovascular diseases (CVD) and improved overall fitness and cardiac function parameters (i.e., blood pressure, heart rate, and energy expenditure). Conversely, continuous CR has also been associated with depleted circulating leukocytes, immunosuppression, and reduced bone density.
Among other CR alternatives, such as pharmacological mimicry of CR effects (Madeo et al., 2019) and periodic nutrient deprivation (Di Francesco et al., 2018), intermittent fasting (IF) could represent an easily manageable alternative to constant CR. Pre-clinical studies have shown that these dietary interventions reduce oxidative stress and metabolic rate, activate autophagy (which are biomarkers of CR-mediated lifespan extension), and expand healthspan and lifespan in various model organisms (Joslin et al., 2017, Madeo et al., 2015, Rubinsztein et al., 2011). However, there is still debate about the safety and efficiency of CR and IF, particularly on healthy humans. Among various forms of IF, alternate day fasting (ADF), defined as strict 36-h periods without caloric intake (“fast days”) followed by 12-h intervals with ad libitum food consumption (“feast days”), seems to be one of the most extreme dietary interventions (Antoni et al., 2018, Tinsley and La Bounty, 2015). In principle, a less stringent protocol of ADF allowing 25% calorie intake on fast days has been reported to be safe in obese patients (i.e., BMI ≥ 30) for at least 8 weeks, with only minimal adverse incidences (Hoddy et al., 2015). Other studies have conducted various lengths and forms of ADF in different cohorts, with little to no obvious adverse effects, though substantial hunger was reported by (Heilbronn et al., 2005) on fast days, which did not decrease throughout the 3 week trial.
At the same time, some studies have indeed shown adverse effects of recurring fasting periods on different outcomes. For instance, extended overnight fasting periods might increase the risk of gallstone disease (Sichieri et al., 1991). Additionally, although discussed controversially, skipping breakfast is associated with an elevated risk of coronary heart disease, type 2 diabetes and other adverse factors in some cohorts (Cahill et al., 2013, Ballon et al., 2019, Sievert et al., 2019). Inline, accumulating data indicate that not only are fasting periods per se important for maintenance and improvement of metabolic health but also the timing of meals matters, favoring early intake of calories (i.e., breakfast) rather than late (i.e., dinner) (Di Francesco et al., 2018).
Though many studies have addressed the application of IF on overweight participants with or without type 2 diabetes (Tinsley and La Bounty, 2015), mechanistic trials on healthy humans have been elusive. To fill this gap, we designed the present study to examine the effects of strict ADF on cardiovascular parameters, such as heart rate, blood pressure, cholesterol levels, CVD risk, body composition, and the metabolome and proteome of healthy, non-overweight adults, thereby assessing both the effectiveness and safety of such intervention. This is the first study, to the best of our knowledge, that comprehensively reports the effects of short- and long-term strict ADF on the physiology, cardiovascular system, and body composition in a non-obese cohort. Moreover, the comparison of a long-term ADF cohort with matched controls from the general healthy population is unique. We also examined the potential influence of ADF on the immune system, bone mineral density (BMD), and bone mass in both study arms.on fast days, which did not decrease throughout the 3 week trial.
At the same time, some studies have indeed shown adverse effects of recurring fasting periods on different outcomes. For instance, extended overnight fasting periods might increase the risk of gallstone disease (Sichieri et al., 1991). Additionally, although discussed controversially, skipping breakfast is associated with an elevated risk of coronary heart disease, type 2 diabetes and other adverse factors in some cohorts (Cahill et al., 2013, Ballon et al., 2019, Sievert et al., 2019). Inline, accumulating data indicate that not only are fasting periods per se important for maintenance and improvement of metabolic health but also the timing of meals matters, favoring early intake of calories (i.e., breakfast) rather than late (i.e., dinner) (Di Francesco et al., 2018).
Though many studies have addressed the application of IF on overweight participants with or without type 2 diabetes (Tinsley and La Bounty, 2015), mechanistic trials on healthy humans have been elusive. To fill this gap, we designed the present study to examine the effects of strict ADF on cardiovascular parameters, such as heart rate, blood pressure, cholesterol levels, CVD risk, body composition, and the metabolome and proteome of healthy, non-overweight adults, thereby assessing both the effectiveness and safety of such intervention. This is the first study, to the best of our knowledge, that comprehensively reports the effects of short- and long-term strict ADF on the physiology, cardiovascular system, and body composition in a non-obese cohort. Moreover, the comparison of a long-term ADF cohort with matched controls from the general healthy population is unique. We also examined the potential influence of ADF on the immune system, bone mineral density (BMD), and bone mass in both study arms.
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F O R T H E R E S T O F T H E S T U D Y , P L E A S E V I S I T T H E S O U R C E .
