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Anti‐aging effects of intermittent fasting: a potential alternative to calorie restriction?

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Abstract

The multi-faceted process of aging encompasses various human pathologies such as diabetes, hypertension, neurological and cardiovascular diseases and cancer among many others. The hallmarks of aging has broadened the scope of eligible interventions aimed at delaying aging. Among the scores of anti-aging strategies, dietary restriction (DR) intervention has opened gamut of physiological benefits for humans. In this review, we elucidate briefly the two strict DR approaches practiced among humans especially for weight loss, but additionally for its metabolic benefits and lifespan elongating effects. Calorie restriction has been tried in diverse model organisms including humans, but CR has been challenging for humans due to its adverse effect. We discuss the metabolic pathways operating in case of intermittent fasting (IF) and calorie restriction (CR). Lastly we review a vital mechanism observed during fasting, ketogenesis, and scrutinize the latest emerging dieting trend keto diet with reference to IF.

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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.
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Dietary restriction (DR) is the most robust environmental manipulation known to increase active and healthy lifespan in many species. Despite differences in the protocols and the way DR is carried out in different organisms, conserved relationships are emerging among multiple species. Elegant studies from numerous model organisms are further defining the importance of various nutrient-signaling pathways including mTOR (mechanistic target of rapamycin), insulin/IGF-1-like signaling and sirtuins in mediating the effects of DR. We here review current advances in our understanding of the molecular mechanisms altered by DR to promote lifespan in three major invertebrate models, the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster.
Article
Calorie restriction (CR), a nutritional intervention of reduced energy intake but with adequate nutrition, has been shown to extend healthspan and lifespan in rodent and primate models. Accumulating data from observational and randomized clinical trials indicate that CR in humans results in some of the same metabolic and molecular adaptations that have been shown to improve health and retard the accumulation of molecular damage in animal models of longevity. In particular, moderate CR in humans ameliorates multiple metabolic and hormonal factors that are implicated in the pathogenesis of type 2 diabetes, cardiovascular diseases, and cancer, the leading causes of morbidity, disability and mortality. In this paper, we will discuss the effects of CR in non-obese humans on these physiological parameters. Special emphasis is committed to recent clinical intervention trials that have investigated the feasibility and effects of CR in young and middle-aged men and women on parameters of energy metabolism and metabolic risk factors of age-associated disease in great detail. Additionally, data from individuals who are either naturally exposed to CR or those who are self-practicing this dietary intervention allows us to speculate on longer-term effects of more severe CR in humans.
Article
An elaborate metabolic response to fasting is orchestrated by the liver and is heavily reliant on transcriptional regulation. In response to hormones (glucagon, glucocorticoids) many transcription factors (TFs) are activated and regulate various genes involved in metabolic pathways aimed at restoring homeostasis: gluconeogenesis, fatty acid oxidation, ketogenesis, and amino acid shuttling. We summarize recent discoveries regarding fasting-related TFs with an emphasis on genome-wide binding patterns. Collectively, the findings we discuss reveal a large degree of cooperation between TFs during fasting that occurs at motif-rich DNA sites bound by a combination of TFs. These new findings implicate transcriptional and chromatin regulation as major determinants of the response to fasting and unravels the complex, multi-TF nature of this response.
Article
Energy restriction induces physiological effects that hinder further weight loss. Thus, deliberate periods of energy balance during weight loss interventions may attenuate these adaptive responses to energy restriction and thereby increase the efficiency of weight loss (i.e. the amount of weight or fat lost per unit of energy deficit). To address this possibility, we systematically searched MEDLINE, PreMEDLINE, PubMed and Cinahl and reviewed adaptive responses to energy restriction in 40 publications involving humans of any age or body mass index that had undergone a diet involving intermittent energy restriction, 12 with direct comparison to continuous energy restriction. Included publications needed to measure one or more of body weight, body mass index, or body composition before and at the end of energy restriction. 31 of the 40 publications involved 'intermittent fasting' of 1-7-day periods of severe energy restriction. While intermittent fasting appears to produce similar effects to continuous energy restriction to reduce body weight, fat mass, fat-free mass and improve glucose homeostasis, and may reduce appetite, it does not appear to attenuate other adaptive responses to energy restriction or improve weight loss efficiency, albeit most of the reviewed publications were not powered to assess these outcomes. Intermittent fasting thus represents a valid - albeit apparently not superior - option to continuous energy restriction for weight loss.
Article
Intermittent fasting is a broad term that encompasses a variety of programs that manipulate the timing of eating occasions by utilizing short-term fasts in order to improve body composition and overall health. This review examines studies conducted on intermittent fasting programs to determine if they are effective at improving body composition and clinical health markers associated with disease. Intermittent fasting protocols can be grouped into alternate-day fasting, whole-day fasting, and time-restricted feeding. Alternate-day fasting trials of 3 to 12 weeks in duration appear to be effective at reducing body weight (≈3%–7%), body fat (≈3–5.5 kg), total cholesterol (≈10%–21%), and triglycerides (≈14%–42%) in normal-weight, overweight, and obese humans. Whole-day fasting trials lasting 12 to 24 weeks also reduce body weight (≈3%–9%) and body fat, and favorably improve blood lipids (≈5%–20% reduction in total cholesterol and ≈17%–50% reduction in triglycerides). Research on time-restricted feeding is limited, and clear conclusions cannot be made at present. Future studies should examine long-term effects of intermittent fasting and the potential synergistic effects of combining intermittent fasting with exercise.
Article
Periods of voluntary abstinence from food and drink (i.e., intermittent fasting) has been practiced since earliest antiquity by peoples around the globe. Books on ethnology and religion describe a remarkable variety of fasting forms and practices.1 Renewed interest in fasting regimens is evidenced by a plethora of popular press publications and diet recommendations. For example, in 2013, Mosley and Spencer published a best-selling book titled “The Fast Diet,” which touts the benefits of restricting energy intake severely for two days a week while eating normally the rest of the week.2 Dozens of books promote various fasting dietary patterns and the web offers hundreds of fasting-related sites. However, scientific evidence for the health benefits of intermittent fasting in humans is often extrapolated from animal studies, based on observational data on religious fasting (particularly Ramadan), or derived from experimental studies with modest sample sizes. The overall objective of this paper is to provide an overview of intermittent fasting regimens (Table 1) and summarize the evidence on the health benefits of intermittent fasting with a focus on human intervention studies. Because much of the data on intermittent fasting is from research in animal models, we briefly summarize key rodent studies and reviews. Health outcomes of interest are changes in weight and metabolic parameters associated with type 2 diabetes, cardiovascular disease, and cancer. We also present an overview of the major mechanisms hypothesized to link fasting regimens with human health: (1) circadian biology, (2) the gastrointestinal microbiota, and (3) modifiable lifestyle behaviors such as diet, activity, and sleep. Finally, we present conclusions regarding the evidence-base for intermittent fasting as an intervention for improving human health and propose a research agenda. Table 1 Types of intermittent fasting regimens that are hypothesized to impact health outcomes This paper provides a uniquely broad synthesis of the scientific evidence linking intermittent fasting with human health and a framework for future research on this topic.
Article
Reduced food intake, avoiding malnutrition, can ameliorate aging and aging-associated diseases in invertebrate model organisms, rodents, primates, and humans. Recent findings indicate that meal timing is crucial, with both intermittent fasting and adjusted diurnal rhythm of feeding improving health and function, in the absence of changes in overall intake. Lowered intake of particular nutrients rather than of overall calories is also key, with protein and specific amino acids playing prominent roles. Nutritional modulation of the microbiome can also be important, and there are long-term, including inter-generational, effects of diet. The metabolic, molecular, and cellular mechanisms that mediate both improvement in health during aging to diet and genetic variation in the response to diet are being identified. These new findings are opening the way to specific dietary and pharmacological interventions to recapture the full potential benefits of dietary restriction, which humans can find difficult to maintain voluntarily. Copyright © 2015 Elsevier Inc. All rights reserved.
Article
Beneficial effects on health of limiting food intake for certain periods of time have been recognized for a long time. While many diets can produce short-term weight loss, most fail to result in a long-lasting impact. Current data suggest that intermittent fasting may be beneficial for overall health and wellbeing. However, the lack of properly designed clinical studies makes it challenging to formulate evidence-based practice recommendations. Potential health risks of drastic changes in food intake are often ignored and might only be revealed after extensive follow-up. This review summarizes the popular intermittent dieting methods and their potential impact on fertility and reproduction.
Article
Time-restricted feeding (TRF), a key component of intermittent fasting regimens, has gained considerable attention in recent years. TRF allows ad libitum energy intake within controlled time frames, generally a 3–12 hour range each day. The impact of various TRF regimens on indicators of metabolic disease risk has yet to be investigated. Accordingly, the objective of this review was to summarize the current literature on the effects of TRF on body weight and markers of metabolic disease risk (i.e., lipid, glucoregulatory, and inflammatory factors) in animals and humans. Results from animal studies show TRF to be associated with reductions in body weight, total cholesterol, and concentrations of triglycerides, glucose, insulin, interleukin 6, and tumor necrosis factor-α as well as with improvements in insulin sensitivity. Human data support the findings of animal studies and demonstrate decreased body weight (though not consistently), lower concentrations of triglycerides, glucose, and low-density lipoprotein cholesterol, and increased concentrations of high-density lipoprotein cholesterol. These preliminary findings show promise for the use of TRF in modulating a variety of metabolic disease risk factors.
Article
Periods of deliberate fasting with restriction of solid food intake are practiced worldwide, mostly based on traditional, cultural or religious reasons. There is large empirical and observational evidence that medically supervised modified fasting (fasting cure, 200-500 kcal nutritional intake per day) with periods of 7-21 days is efficacious in the treatment of rheumatic diseases, chronic pain syndromes, hypertension, and metabolic syndrome. The beneficial effects of fasting followed by vegetarian diet in rheumatoid arthritis are confirmed by randomized controlled trials. Further beneficial effects of fasting are supported by observational data and abundant evidence from experimental research which found caloric restriction and intermittent fasting being associated with deceleration or prevention of most chronic degenerative and chronic inflammatory diseases. Intermittent fasting may also be useful as an accompanying treatment during chemotherapy of cancer. A further beneficial effect of fasting relates to improvements in sustainable lifestyle modification and adoption of a healthy diet, possibly mediated by fasting-induced mood enhancement. Various identified mechanisms of fasting point to its potential health-promoting effects, e.g., fasting-induced neuroendocrine activation and hormetic stress response, increased production of neurotrophic factors, reduced mitochondrial oxidative stress, general decrease of signals associated with aging, and promotion of autophagy. Fasting therapy might contribute to the prevention and treatment of chronic diseases and should be further evaluated in controlled clinical trials and observational studies. © 2014 S. Karger GmbH, Freiburg.
Article
Traditionally, the ketone body β-hydroxybutyrate (βOHB) has been looked upon as a carrier of energy from liver to peripheral tissues during fasting or exercise. However, βOHB also signals via extracellular receptors and acts as an endogenous inhibitor of histone deacetylases (HDACs). These recent findings support a model in which βOHB functions to link the environment, in this case the diet, and gene expression via chromatin modifications. We review the regulation and functions of ketone bodies, the relationship between ketone bodies and calorie restriction, and the implications of HDAC inhibition by the ketone body βOHB in the modulation of metabolism and in diseases of aging.
Article
Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects.
Article
Discovering the biological basis of aging is one of the greatest remaining challenges for science. Work on the biology of aging has discovered a range of interventions and pathways that control aging rate. A picture is emerging of a signaling network that is sensitive to nutritional status and that controls growth, stress resistance, and aging. This network includes the insulin/IGF-1 and target of rapamycin (TOR) pathways and likely mediates the effects of dietary restriction on aging. Yet the biological processes upon which these pathways act to control life span remain unclear. A long-standing guiding assumption about aging is that it is caused by wear and tear, particularly damage at the molecular level. One view is that reactive oxygen species (ROS), including free radicals, generated as by-products of cellular metabolism are a major contributor to this damage. Yet many recent tests of the oxidative damage theory have come up negative. Such tests have opened an exciting new phase in biogerontology in which fundamental assumptions about aging are being reexamined and revolutionary concepts are emerging. Among these concepts is the hyperfunction theory, which postulates that processes contributing to growth and reproduction run on in later life, leading to hypertrophic and hyperplastic pathologies. Here we reexamine central concepts about the nature of aging. Expected final online publication date for the Annual Review of Physiology Volume 75 is February 10, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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Life expectancy has increased across the globe and the number of aged people is increasing rapidly. With the rise in the average age of people, the prevalence of age related pathologies has also increased and thus the strategies to find anti-aging molecules assume significance. Anti-aging basically concerns the prevention or delaying the alterations taking place as a function of age which are manifested as age-associated illnesses. This review covers anti-aging strategies involving supplementation of dietary antioxidants such as polyphenols, vitamins E and C, lipoic acid, acetyl carnitine, carnosine and cysteine along with the application of mammalian target of rapamycin inhibitors and plasma membrane redox system activators. It also presents the use of different hormone supplementation, for example, melatonin, dehydroepiandrosterone, growth hormone and sex hormones as a tool against aging. The use of caloric restriction and calorie restriction mimetics as an anti-aging intervention is also reviewed. The concept, use and efficacy of different anti-aging approaches. Despite a lot of research and sustained ongoing efforts, finding a viable anti-aging therapy which can extend the maximum human lifespan remains elusive. However, several interventions aimed towards a longer healthy life seem promising.