Circadian rhythms, aging, and life span in mammals.
Physiology (Bethesda, Md.)
Resetting the circadian clock leads to well being and increased life span, whereas clock disruption is associated with aging and morbidity. Increased longevity and improved health can be achieved by different feeding regimens that reset circadian rhythms and may lead to better synchrony in metabolism and physiology. This review focuses on recent findings concerning the relationships between circadian rhythms, aging attenuation, and life-span extension in mammals.
[Aging and homeostasis. Circadian rhythms and aging.]
Daily rhythms of physiological and behavioral processes such as sleep and arousal are controlled by the circadian clock. The expression of the clock genes oscillate rhythmically in daily manner, and this clock oscillator resides in almost all of the cells in the body. The circadian clock entrains to diurnal environmental changes by using light and food intake as external time cues. Timing of feeding and fasting strongly affects daily rhythms in the expression of circadian clock genes and key regulators of nutrient homeostasis. Understanding roles of the clock oscillator system and feeding-fasting cycles lets us recognize the importance of timing of feeding, ultimately to adjust the aging-related changes in circadian rhythms.
Crosstalk of the circadian clock, light response, feeding and aging.
Tsuyama Jun,Hatori Megumi
Nihon rinsho. Japanese journal of clinical medicine
Daily rhythms of many physiological and behavioral processes such as sleep and arousal are controlled by the circadian clock. The circadian clock entrains to environmental diurnal changes by using light and food intake as external time cues. Circadian photoentrainment is mediated by retinal ganglion cells expressing a blue-light sensitive photopigment mela- nopsin. Feeding and fasting drive daily rhythms in the expression of circadian clock genes and key regulators of nutrient homeostasis in peripheral tissues. Understanding melanopsin function and timing of feeding-fasting lets us recognize the importance of timing of blue light exposure and feeding based on the concept of the circadian clock, ultimately to adjust the age-related changes in daily rhythm.
Effect of feeding regimens on circadian rhythms: implications for aging and longevity.
Froy Oren,Miskin Ruth
Increased longevity and improved health can be achieved in mammals by two feeding regimens, caloric restriction (CR), which limits the amount of daily calorie intake, and intermittent fasting (IF), which allows the food to be available ad libitum every other day. The precise mechanisms mediating these beneficial effects are still unresolved. Resetting the circadian clock is another intervention that can lead to increased life span and well being, while clock disruption is associated with aging and morbidity. Currently, a large body of evidence links circadian rhythms with metabolism and feeding regimens. In particular, CR, and possibly also IF, can entrain the master clock located in the suprachiasmatic nuclei (SCN) of the brain hypothalamus. These findings raise the hypothesis that the beneficial effects exerted by these feeding regimens could be mediated, at least in part, through resetting of the circadian clock, thus leading to synchrony in metabolism and physiology. This hypothesis is reinforced by a transgenic mouse model showing spontaneously reduced eating alongside robust circadian rhythms and increased life span. This review will summarize recent findings concerning the relationships between feeding regimens, circadian rhythms, and metabolism with implications for ageing attenuation and life span extension.
Circadian rhythms, time-restricted feeding, and healthy aging.
Manoogian Emily N C,Panda Satchidananda
Ageing research reviews
Circadian rhythms optimize physiology and health by temporally coordinating cellular function, tissue function, and behavior. These endogenous rhythms dampen with age and thus compromise temporal coordination. Feeding-fasting patterns are an external cue that profoundly influence the robustness of daily biological rhythms. Erratic eating patterns can disrupt the temporal coordination of metabolism and physiology leading to chronic diseases that are also characteristic of aging. However, sustaining a robust feeding-fasting cycle, even without altering nutrition quality or quantity, can prevent or reverse these chronic diseases in experimental models. In humans, epidemiological studies have shown erratic eating patterns increase the risk of disease, whereas sustained feeding-fasting cycles, or prolonged overnight fasting, is correlated with protection from breast cancer. Therefore, optimizing the timing of external cues with defined eating patterns can sustain a robust circadian clock, which may prevent disease and improve prognosis.
Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease.
Wei Min,Brandhorst Sebastian,Shelehchi Mahshid,Mirzaei Hamed,Cheng Chia Wei,Budniak Julia,Groshen Susan,Mack Wendy J,Guen Esra,Di Biase Stefano,Cohen Pinchas,Morgan Todd E,Dorff Tanya,Hong Kurt,Michalsen Andreas,Laviano Alessandro,Longo Valter D
Science translational medicine
Calorie restriction or changes in dietary composition can enhance healthy aging, but the inability of most subjects to adhere to chronic and extreme diets, as well as potentially adverse effects, limits their application. We randomized 100 generally healthy participants from the United States into two study arms and tested the effects of a fasting-mimicking diet (FMD)-low in calories, sugars, and protein but high in unsaturated fats-on markers/risk factors associated with aging and age-related diseases. We compared subjects who followed 3 months of an unrestricted diet to subjects who consumed the FMD for 5 consecutive days per month for 3 months. Three FMD cycles reduced body weight, trunk, and total body fat; lowered blood pressure; and decreased insulin-like growth factor 1 (IGF-1). No serious adverse effects were reported. After 3 months, control diet subjects were crossed over to the FMD program, resulting in a total of 71 subjects completing three FMD cycles. A post hoc analysis of subjects from both FMD arms showed that body mass index, blood pressure, fasting glucose, IGF-1, triglycerides, total and low-density lipoprotein cholesterol, and C-reactive protein were more beneficially affected in participants at risk for disease than in subjects who were not at risk. Thus, cycles of a 5-day FMD are safe, feasible, and effective in reducing markers/risk factors for aging and age-related diseases. Larger studies in patients with diagnosed diseases or selected on the basis of risk factors are warranted to confirm the effect of the FMD on disease prevention and treatment.
Effect of Alternate-Day Fasting on Weight Loss, Weight Maintenance, and Cardioprotection Among Metabolically Healthy Obese Adults: A Randomized Clinical Trial.
Trepanowski John F,Kroeger Cynthia M,Barnosky Adrienne,Klempel Monica C,Bhutani Surabhi,Hoddy Kristin K,Gabel Kelsey,Freels Sally,Rigdon Joseph,Rood Jennifer,Ravussin Eric,Varady Krista A
JAMA internal medicine
Importance:Alternate-day fasting has become increasingly popular, yet, to date, no long-term randomized clinical trials have evaluated its efficacy. Objective:To compare the effects of alternate-day fasting vs daily calorie restriction on weight loss, weight maintenance, and risk indicators for cardiovascular disease. Design, Setting, and Participants:A single-center randomized clinical trial of obese adults (18 to 64 years of age; mean body mass index, 34) was conducted between October 1, 2011, and January 15, 2015, at an academic institution in Chicago, Illinois. Interventions:Participants were randomized to 1 of 3 groups for 1 year: alternate-day fasting (25% of energy needs on fast days; 125% of energy needs on alternating "feast days"), calorie restriction (75% of energy needs every day), or a no-intervention control. The trial involved a 6-month weight-loss phase followed by a 6-month weight-maintenance phase. Main Outcomes and Measures:The primary outcome was change in body weight. Secondary outcomes were adherence to the dietary intervention and risk indicators for cardiovascular disease. Results:Among the 100 participants (86 women and 14 men; mean [SD] age, 44  years), the dropout rate was highest in the alternate-day fasting group (13 of 34 [38%]), vs the daily calorie restriction group (10 of 35 [29%]) and control group (8 of 31 [26%]). Mean weight loss was similar for participants in the alternate-day fasting group and those in the daily calorie restriction group at month 6 (-6.8% [95% CI, -9.1% to -4.5%] vs -6.8% [95% CI, -9.1% to -4.6%]) and month 12 (-6.0% [95% CI, -8.5% to -3.6%] vs -5.3% [95% CI, -7.6% to -3.0%]) relative to those in the control group. Participants in the alternate-day fasting group ate more than prescribed on fast days, and less than prescribed on feast days, while those in the daily calorie restriction group generally met their prescribed energy goals. There were no significant differences between the intervention groups in blood pressure, heart rate, triglycerides, fasting glucose, fasting insulin, insulin resistance, C-reactive protein, or homocysteine concentrations at month 6 or 12. Mean high-density lipoprotein cholesterol levels at month 6 significantly increased among the participants in the alternate-day fasting group (6.2 mg/dL [95% CI, 0.1-12.4 mg/dL]), but not at month 12 (1.0 mg/dL [95% CI, -5.9 to 7.8 mg/dL]), relative to those in the daily calorie restriction group. Mean low-density lipoprotein cholesterol levels were significantly elevated by month 12 among the participants in the alternate-day fasting group (11.5 mg/dL [95% CI, 1.9-21.1 mg/dL]) compared with those in the daily calorie restriction group. Conclusions and Relevance:Alternate-day fasting did not produce superior adherence, weight loss, weight maintenance, or cardioprotection vs daily calorie restriction. Trial Registration:clinicaltrials.gov Identifier: NCT00960505.
Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota.
Cignarella Francesca,Cantoni Claudia,Ghezzi Laura,Salter Amber,Dorsett Yair,Chen Lei,Phillips Daniel,Weinstock George M,Fontana Luigi,Cross Anne H,Zhou Yanjiao,Piccio Laura
Multiple sclerosis (MS) is more common in western countries with diet being a potential contributing factor. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS model, experimental autoimmune encephalomyelitis (EAE). IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families and enhanced antioxidative microbial metabolic pathways. IF altered T cells in the gut with a reduction of IL-17 producing T cells and an increase in regulatory T cells. Fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF effects are at least partially mediated by the gut flora. In a pilot clinical trial in MS patients, intermittent energy restriction altered blood adipokines and the gut flora resembling protective changes observed in mice. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome.
Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.
Stekovic Slaven,Hofer Sebastian J,Tripolt Norbert,Aon Miguel A,Royer Philipp,Pein Lukas,Stadler Julia T,Pendl Tobias,Prietl Barbara,Url Jasmin,Schroeder Sabrina,Tadic Jelena,Eisenberg Tobias,Magnes Christoph,Stumpe Michael,Zuegner Elmar,Bordag Natalie,Riedl Regina,Schmidt Albrecht,Kolesnik Ewald,Verheyen Nicolas,Springer Anna,Madl Tobias,Sinner Frank,de Cabo Rafael,Kroemer Guido,Obermayer-Pietsch Barbara,Dengjel Jörn,Sourij Harald,Pieber Thomas R,Madeo Frank
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.