Practicality of Intermittent Fasting in Humans and its Effect on Oxidative Stress and Genes Related to Aging and Metabolism

Abstract

Caloric restriction has consistently been shown to extend life span and ameliorate aging-related diseases. These effects may be due to diet-induced reactive oxygen species acting to up-regulate sirtuins and related protective pathways, which research suggests may be partially inhibited by dietary anti-oxidant supplementation. Because caloric restriction is not sustainable long term for most humans, we investigated an alternative dietary approach, intermittent fasting (IF), which is proposed to act on similar biological pathways. We hypothesized that a modified IF diet, where participants maintain overall energy balance by alternating between days of fasting (25% of normal caloric intake) and feasting (175% of normal), would increase expression of genes associated with aging and reduce oxidative stress and that these effects would be suppressed by anti-oxidant supplementation. To assess the tolerability of the diet and to explore effects on biological mechanisms related to aging and metabolism, we recruited a cohort of 24 healthy individuals in a double-crossover, double-blinded, randomized clinical trial. Study participants underwent two 3-week treatment periods-IF and IF with anti-oxidant (vitamins C and E) supplementation. We found strict adherence to study-provided diets and that participants found the diet tolerable, with no adverse clinical findings or weight change. We detected a marginal increase (2.7%) in SIRT3 expression due to the IF diet, but no change in expression of other genes or oxidative stress markers analyzed. We also found that IF decreased plasma insulin levels (1.01 μU/mL). Although our study suggests that the IF dieting paradigm is acceptable in healthy individuals, additional research is needed to further assess the potential benefits and risks.

Effects of intermittent fasting on glucose and lipid metabolism

“…100 % energy restriction) every other day, with fasting intervals ranging between 20 and 36 h. However, the long-term sustainability of this alternate day total fasting approach in human subjects is questionable due to the persistent hunger reported (24) . Subsequently, the IER protocols used by most human studies (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41) , and by some rodent studies (11,14,42) , have allowed a small amount of 'fast' day intake, so that energy is substantially (⩾70 %) but not completely restricted. This is often referred to as modified fasting, such that, the term fasting in this IER context denotes periods of severe (total or partial) energy restriction.…”

“…The most well-studied examples include alternate day modified fasting and the 5:2 diet, which entails two modified fast days a week (Table 1), although many variations exist. Intakes on non-restricted ('feed') days among these studies have ranged from ad libitum (27)(28)(29)(31)(32)(33)(34)36,38) , hypoenergetic (approximately 15-30 % of energy requirements) (34,41) , isoenergetic (30,37,40) or hyperenergetic (approximately 125-175 % of energy requirements) (35,39) . Compliance is reportedly high (29,37) , with both acute (5) and chronic (29,30,37,40) studies demonstrating a lack of full compensatory hyperphagia following modified fasting days.…”

“…In overweight/ obese (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)37,38,40,41) or combined healthy/overweight (36) cohorts, the average reported weight-loss through IER (70-100 % energy restriction) has ranged between approximately 4 and 10 % over dieting periods of 4-24 weeks. There are also some data demonstrating the successful applications of IER as a weight-maintenance strategy following weight-loss for periods of up to 1 year (37,39) .…”

“…To date, all IER studies allowing fast day intake have solely measured fasting blood markers of cardiometabolic risk. Some (27,(30)(31)(32)(33)(35)(36)(37)41) but not all of these studies (28,29,34,40) have included CER (standard treatment) or ad libitum (no intervention) control groups, whilst others have compared two or more different IER protocols (35,38,39) . In individuals with T2DM, IER has been shown to improve glycaemic control and lipid profiles (27) .…”

Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes

“…Alternative interventions that would mimic-at least partially-the molecular and physiological benefits of CR are thus of interest (Speakman and Mitchell 2011). Intermittent CR (or intermittent fasting) is one such alternative previously shown to decrease oxidative stress levels and improve insulin sensitivity in humans, but more research has yet to be done in this area (Wegman et al 2015). Polyphenols-a class of antioxidant phytochemicals mostly found in plant-derived produce such as fruits and vegetables (and their derivatives such as juices and wines), nuts, spices and grains (tea and chocolate)-represent another nutritional alternative to CR.…”