Effects of Intermittent Fasting on Health, Aging, and Disease
25 Dec 2019-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 381, Iss: 26, pp 2541-2551
TL;DR: Effects of Intermittent Fasting on Health and Aging evidence is accumulating that eating in a 6-hour period and fasting for 18 hours can trigger a metabolic switch from glucose-based to ketone-base fasting.
Abstract: Effects of Intermittent Fasting on Health and Aging Evidence is accumulating that eating in a 6-hour period and fasting for 18 hours can trigger a metabolic switch from glucose-based to ketone-base...
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University College London1, Akershus University Hospital2, Discovery Institute3, Northwestern University4, University of Oxford5, National and Kapodistrian University of Athens6, Oslo University Hospital7, University of Oslo8, University of Tromsø9, Foundation for Research & Technology – Hellas10, University of Crete11, University of Cambridge12, Max Planck Society13
TL;DR: A recent review as discussed by the authors examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease, and discusses current preclinical evidence arguing for the use of auto-ophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases.
Abstract: Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease. In addition, we discuss current preclinical evidence arguing for the use of autophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases. Finally, we highlight key questions and propose novel research avenues that will likely reveal new links between autophagy and the hallmarks of aging. Understanding the precise interplay between autophagy and the risk of age-related pathologies across organisms will eventually facilitate the development of clinical applications that promote long-term health. This Review synthesizes recent research on the mechanisms and roles of autophagy in health, aging and disease and discusses how drugs that modulate the process of autophagy could be used to suppress age-associated diseases.
255 citations
TL;DR: It is suggested that 4- and 6-h TRF induce mild reductions in body weight over 8 weeks and show promise as interventions for weight loss and may also improve some aspects of cardiometabolic health.
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TL;DR: The underlying pathophysiological mechanisms linking NAFLD and CVD are described, the role ofNAFLD as a metabolic dysfunction associated cardiovascular risk factor is discussed, and common cardiovascular manifestations in NAFLd patients are focused on.
Abstract: Non-alcoholic fatty liver DISEASE (NAFLD) is the most common chronic liver disease in Western countries and affects approximately 25% of the adult population. Since NAFLD is frequently associated with further metabolic comorbidities such as obesity, type 2 diabetes mellitus, or dyslipidemia, it is generally considered as the hepatic manifestation of the metabolic syndrome. In addition to its potential to cause liver-related morbidity and mortality, NAFLD is also associated with subclinical and clinical cardiovascular disease (CVD). Growing evidence indicates that patients with NAFLD are at substantial risk for the development of hypertension, coronary heart disease, cardiomyopathy, and cardiac arrhythmias, which clinically result in increased cardiovascular morbidity and mortality. The natural history of NAFLD is variable and the vast majority of patients will not progress from simple steatosis to fibrosis and end stage liver disease. However, patients with progressive forms of NAFLD, including non-alcoholic steatohepatitis (NASH) and/or advanced fibrosis, as well as NAFLD patients with concomitant types 2 diabetes are at highest risk for CVD. This review describes the underlying pathophysiological mechanisms linking NAFLD and CVD, discusses the role of NAFLD as a metabolic dysfunction associated cardiovascular risk factor, and focuses on common cardiovascular manifestations in NAFLD patients.
216 citations
Cites background from "Effects of Intermittent Fasting on ..."
...Intermittent fasting with energy restriction for about 10-16 h is promising approach in this context, as it has been shown to mediate robust disease modifying effects on chronic metabolic disorders such as obesity, T2DM and CVD [156]....
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...Intermittent fasting with energy restriction for about 10-16 h is promising approach in this context, as it has been shown to mediate robust disease modifying effects on chronic metabolic disorders such as obesity, T2DM and CVD [156]....
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...In the liver, prolonged energy restriction results in a depletion of glycogen storage that subsequently triggers a metabolic switch towards the use of fatty acids and ketone bodies as energy sources [156]....
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...While growing evidence indicates that intermittent fasting is associated with numerous cardiovascular benefits, including reduced blood pressure, lipid levels, and reduced inflammatory marker, data on the effects of intermittent fasting in large cohorts of NAFLD patients are sparse [155, 156]....
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First Affiliated Hospital of Wenzhou Medical University1, Akershus University Hospital2, Durham University3, Duke University4, Fudan University5, Sun Yat-sen University6, University of New South Wales7, University of Gothenburg8, Zhejiang University9, Erasmus University Rotterdam10, National Institutes of Health11, Zhengzhou University12, Jinan University13, Peking Union Medical College14, Peking Union Medical College Hospital15, University of Macau16, Central South University17, Johns Hopkins University School of Medicine18, Peking University19, The Chinese University of Hong Kong20
TL;DR: Collectively, synergies across disciplines on policies, geriatric care, drug development, personal awareness, the use of big data, machine learning and personalized medicine will transform China into a country that enables the most for its elderly, maximizing and celebrating their longevity in the coming decades.
168 citations
TL;DR: On comparing low-fat and restricted diets, the scientific evidence supports the use of the Mediterranean Dietary Approaches to Stop Hypertension (DASH) diet intervention as the new paradigm for metabolic syndrome prevention and treatment.
Abstract: Metabolic syndrome is a cluster of metabolic risk factors, characterized by abdominal obesity, dyslipidemia, low levels of high-density lipoprotein cholesterol (HDL-c), hypertension, and insulin resistance. Lifestyle modifications, especially dietary habits, are the main therapeutic strategy for the treatment and management of metabolic syndrome, but the most effective dietary pattern for its management has not been established. Specific dietary modifications, such as improving the quality of the foods or changing macronutrient distribution, showed beneficial effects on metabolic syndrome conditions and individual parameters. On comparing low-fat and restricted diets, the scientific evidence supports the use of the Mediterranean Dietary Approaches to Stop Hypertension (DASH) diet intervention as the new paradigm for metabolic syndrome prevention and treatment. The nutritional distribution and quality of these healthy diets allows health professionals to provide easy-to-follow dietary advice without the need for restricted diets. Nonetheless, energy-restricted dietary patterns and improvements in physical activity are crucial to improve the metabolic disturbances observed in metabolic syndrome patients.
130 citations
References
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TL;DR: The results demonstrate that the lifespan response to a single level of DR exhibits wide variation amenable to genetic analysis and show that DR can shorten lifespan in inbred mice, raising the possibility that life extension by DR may not be universal.
Abstract: In 1935 McCay et al. (1935) reported that underfed rats “attained extreme ages beyond those of either sex that grew normally.” Since then, chronic reduction of food intake (dietary restriction or DR) has become the most common environmental intervention used to extend lifespan and probe mechanisms specifying longevity. DR extends lifespan across a variety of taxa (Weindruch & Walford, 1988; Finch, 1990; Masoro, 2003) and is considered to be among the most robust life-extending interventions (Weindruch & Walford, 1988; Masoro, 2005). Clinical studies are underway to test the effect of DR on various mortality risk factors in humans (Holloszy & Fontana, 2007), and members of one organization, the Calorie Restriction Society, practice self-imposed DR in an effort to extend their lives (Fontana et al., 2008).
However, life extension by DR may not be universal (Carey et al., 2002; Cooper et al., 2004). Several reports indicate that DR does not extend lifespan or has minimal effects in some rodent strains (Weindruch & Walford, 1988; Harper et al., 2006; Turturro et al., 1999). Others even report that DR shortens lifespan in some strains (Barrow & Roeder, 1965; Fernandes et al., 1976; Harrison & Archer, 1987; Forster et al., 2003), but these studies have not been conclusive given that other studies have shown lifespan extension under different conditions (Weindruch & Walford, 1988; Turturro et al., 1999). A systematic, unbiased screen to determine the efficacy of moderate DR across a range of genotypes is lacking. Here, we undertook such a study -- testing the hypothesis that the lifespan response to DR is subject to naturally-occurring genetic variation encompassing null or even negative effects.
This study used 41 ILSXISS recombinant inbred (RI) mouse strains (Williams et al., 2004) (formerly called LXS) originally developed to analyze genetic variation in alcohol sensitivity (Bennett et al., 2006). Mice were typically maintained 5/cage (Supplementary Table S1) and started at 2–5 months of age fed ad libitum (AL) or DR diets (60% of strain-specific AL intake) in a specific-pathogen-free vivarium dedicated to murine aging research (Ikeno et al., 2005). The DR rations, which were not implemented gradually, were calculated on the basis of AL food intake measured weekly for each strain, adjusted for wastage (Ikeno et al., 2005), and the rations were given daily just before lights out. At 12 months of age, the DR rations were fixed to avoid tracking the reduction of food intake that occurs during aging. We have followed this DR protocol at 60% of AL intake for over 30 years (Ikeno et al., 2005; Yu et al., 1982; McCarter et al., 2007). This level of restriction is one of the most common (Turturro et al., 1999; de Cabo et al., 2005), although DR levels from 40% to 80% of AL intake have been used to achieve life extension (Weindruch & Walford, 1988).
We found that the RI strains exhibited marked genetic variation in lifespan under both AL and DR conditions (Figs. 1 A, B; Supplementary Table S1). Mean lifespan under AL feeding ranged two- to three-fold: 504 to 1152 days in males and 407 to 1208 days in females. This variation in AL lifespan is comparable to that of 31 inbred strains selected for their genetic diversity (Yuan et al., 2009) (Supplementary Fig. S1). Strain variation of mean lifespan in mice under DR was even greater, ranging six- to ten-fold: 217 to 1215 days in males and 113 to 1225 days in females. Effect of strain on lifespan was significant for both sexes under both feeding conditions (p < 1×10−6, ANOVA). Heritability of lifespan under AL feeding was 28% (males) and 36% (females) and under DR was 55% (males) and 53% (females).
Fig. 1
Strain variation in mean lifespan of ILSXISS recombinant inbred (RI) mice under ad libitum (AL) and dietary restriction (DR) diets. Lifespans were typically obtained from 10 AL and 10 DR mice from each strain (5 males & 5 females per treatment ...
Strikingly, the majority of strains showed no extension of lifespan under the level of DR used in this study (Figs. 1C, D). Only 5% of the strains for males and 21% of the strains for females showed statistically significant life extension under DR, using single strain p values < 0.05. DR shortened lifespan in more strains (27% and 26%; males and females, respectively; p < 0.05 – 0.001). Although sample sizes were small, mean lifespans of males and females were significantly correlated under both AL (r = 0.50, p = 0.002) and DR (r = 0.42. p = 0.012) conditions. In addition, doubling sample size by combining the two sexes yielded a similar result: DR shortened life in more strains than showed lengthened life (Supplementary Fig. S2). Maximum lifespan (age at death of oldest mouse) was highly correlated with mean lifespan across strains under both AL and DR regimens (AL males, r = 0.81; AL females, r = 0.82; DR males, r = 0.92; DR females, r = 0.94; all p < 1×10−9), indicating that the strain variation in mean lifespan was not disproportionately affected by early deaths that can arise in DR mice. That early deaths in DR mice contributed to lifespan shortening is not supported by the finding that exclusion of deaths occurring before 12 months of age had negligible effect on the frequency of lifespan shortening (Supplementary Fig. S3). These results, using a large genetic screen, buttress previous but often overlooked results showing no extension or shortening of lifespan by DR (Weindruch & Walford, 1988; Harper et al., 2006; Turturro et al., 1999; Barrow & Roeder, 1965; Fernandes et al., 1976; Harrison & Archer, 1987; Forster et al., 2003). However, whether strains showing no increase in lifespan under 40% or other fixed level of DR show no increase in lifespan under less stringent level of DR remains to be determined.
Of note, the longest lifespans achieved under DR did not exceed the longest achieved under AL feeding (Figs. 1A, B). The average of the mean lifespans of the five longest-lived strains under DR (1103±40 and 1108±32 days in males and females) did not exceed that of the five longest-lived, albeit different, strains under AL feeding (1098±20 and 1088±31 days). Future studies are needed to determine why DR cannot further extend the lifespan of long-lived strains in this RI panel. One testable hypothesis is that the lifespan extending biochemical pathways modulated by DR are already maximally modulated in strains that are long-lived under AL conditions.
The biological basis for the strikingly different responses of lifespan to the commonly used level of DR, including life shortening, is important to determine. For example, some lines in this study may have unusual nutritional needs, and thus 40% DR could cause nutritional deficiencies that might outweigh the beneficial effects of DR. However, the possibility that some strains are vulnerable to a mineral or vitamin deficiency under DR is unlikely because, with the exception of selenium and choline, the diet used (Harlan-Teklad 7912) exceeded by several fold the minimum requirements established by the National Research Council (Nutrient Requirements of Laboratory Animals, 1995) (Supplementary Table S2). Also, even with diets supplemented with vitamins, the lifespan of male DBA/2J mice was either not extended (Forster et al., 2003) or minimally lengthened (Turturro et al., 1999). There also was no correlation between DR lifespan and the large strain variation in absolute food intake (Table 1), suggesting that the strains most likely to encounter deficiency were not more likely to have reduced survival under DR.
Table 1
Absence of correlation between lifespan under dietary restriction (DR) and lifespan, food consumption, fertility and ethanol sensitivity under ad libitum (AL) feeding.f
Considering the derivation of the ILSXISS strains, we tested whether the lifespan variation in response to DR might be related to the segregation of alleles for extreme differences in ethanol sensitivity, which could potentially reflect differences in vitality or stress resistance. However, there was no correlation between sensitivity to this stressor and lifespan in DR mice (Table 1). Another potential measure of vigor, female fertility, also showed no correlation with DR lifespan (Table 1). These results argue against the notion that strains in which DR shortened lifespan lacked overall vitality.
Many other testable possibilities exist to explain life-shortening of some strains under DR. These include vulnerability a) to stresses requiring energy expenditure, such as cold stress; b) to inbreeding depression (recessive alleles) not reflected by the variation in AL lifespan or fertility; and c) to a 40% reduction in food intake that would not be present at a 30% or 20% reduction. Nevertheless, the variable response of these strains to DR provides a valuable tool for identifying quantitative trait loci (genes) that modulate DR’s mechanism of action. In addition, mechanistic traits hypothesized to underlie the lifespan modulating effect of DR should correlate positively with the variation in the lifespan response to DR.
In summary, these findings, coupled with earlier reports, show that even though DR extends lifespan across a variety of taxa, a prolongevity effect may not be a foregone conclusion for many genotypes. The marked genetic variation among RI strains provides a tool for identifying genes and biochemical pathways that mediate lifespan modulation by DR. Finally, the results raise a cautionary note concerning the application of DR to humans and a critical need for predictors of efficacy.
440 citations
TL;DR: These two novel nucleotides have now been shown to be involved in a wide range of cellular functions including: cell cycle regulation in Euglena, a protist; gene expression in plants; and in animal systems, from fertilization to neurotransmitter release and long-term depression in brain.
Abstract: Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two Ca(2+) messengers derived from NAD and NADP, respectively. Although NAADP is a linear molecule, structurally distinct from the cyclic cADPR, it is synthesized by similar enzymes, ADP-ribosyl cyclase and its homolog, CD38. The crystal structure of the cyclase has been solved and its active site identified. These two novel nucleotides have now been shown to be involved in a wide range of cellular functions including: cell cycle regulation in Euglena, a protist; gene expression in plants; and in animal systems, from fertilization to neurotransmitter release and long-term depression in brain. A battery of pharmacological reagents have been developed, providing valuable tools for elucidating the physiological functions of these two novel Ca(2+) messengers. This article reviews these recent results and explores the implications of the existence of multiple Ca(2+) messengers and Ca(2+) stores in cells.
424 citations
"Effects of Intermittent Fasting on ..." refers background in this paper
...These include peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α), fibroblast growth factor 21,(22,23) nicotinamide adenine dinucleotide (NAD), sirtuins,(24) poly(adenosine diphosphate [ADP]–ribose) polymerase 1 (PARP1), and ADP ribosyl cyclase (CD38).(25) By influencing these major cellular pathways, ketone bodies produced Figure 2....
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TL;DR: The results suggest that an intermittent fasting program in which all calories are consumed in an 8-h window each day, in conjunction with resistance training, could improve some health-related biomarkers, decrease fat mass, and maintain muscle mass in resistance-trained males.
Abstract: Intermittent fasting (IF) is an increasingly popular dietary approach used for weight loss and overall health. While there is an increasing body of evidence demonstrating beneficial effects of IF on blood lipids and other health outcomes in the overweight and obese, limited data are available about the effect of IF in athletes. Thus, the present study sought to investigate the effects of a modified IF protocol (i.e. time-restricted feeding) during resistance training in healthy resistance-trained males. Thirty-four resistance-trained males were randomly assigned to time-restricted feeding (TRF) or normal diet group (ND). TRF subjects consumed 100 % of their energy needs in an 8-h period of time each day, with their caloric intake divided into three meals consumed at 1 p.m., 4 p.m., and 8 p.m. The remaining 16 h per 24-h period made up the fasting period. Subjects in the ND group consumed 100 % of their energy needs divided into three meals consumed at 8 a.m., 1 p.m., and 8 p.m. Groups were matched for kilocalories consumed and macronutrient distribution (TRF 2826 ± 412.3 kcal/day, carbohydrates 53.2 ± 1.4 %, fat 24.7 ± 3.1 %, protein 22.1 ± 2.6 %, ND 3007 ± 444.7 kcal/day, carbohydrates 54.7 ± 2.2 %, fat 23.9 ± 3.5 %, protein 21.4 ± 1.8). Subjects were tested before and after 8 weeks of the assigned diet and standardized resistance training program. Fat mass and fat-free mass were assessed by dual-energy x-ray absorptiometry and muscle area of the thigh and arm were measured using an anthropometric system. Total and free testosterone, insulin-like growth factor 1, blood glucose, insulin, adiponectin, leptin, triiodothyronine, thyroid stimulating hormone, interleukin-6, interleukin-1β, tumor necrosis factor α, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured. Bench press and leg press maximal strength, resting energy expenditure, and respiratory ratio were also tested. After 8 weeks, the 2 Way ANOVA (Time * Diet interaction) showed a decrease in fat mass in TRF compared to ND (p = 0.0448), while fat-free mass, muscle area of the arm and thigh, and maximal strength were maintained in both groups. Testosterone and insulin-like growth factor 1 decreased significantly in TRF, with no changes in ND (p = 0.0476; p = 0.0397). Adiponectin increased (p = 0.0000) in TRF while total leptin decreased (p = 0.0001), although not when adjusted for fat mass. Triiodothyronine decreased in TRF, but no significant changes were detected in thyroid-stimulating hormone, total cholesterol, high-density lipoprotein, low-density lipoprotein, or triglycerides. Resting energy expenditure was unchanged, but a significant decrease in respiratory ratio was observed in the TRF group. Our results suggest that an intermittent fasting program in which all calories are consumed in an 8-h window each day, in conjunction with resistance training, could improve some health-related biomarkers, decrease fat mass, and maintain muscle mass in resistance-trained males.
399 citations
TL;DR: It is shown that an every-other-day fasting (EODF) regimen selectively stimulates beige fat development within white adipose tissue and dramatically ameliorates obesity, insulin resistance, and hepatic steatosis.
394 citations
TL;DR: The ketone body β-hydroxybutyrate represents an essential carrier of energy from the liver to peripheral tissues when the supply of glucose is too low for the body's energetic needs, such as during periods of prolonged exercise, starvation, or absence of dietary carbohydrates.
Abstract: Various mechanisms in the mammalian body provide resilience against food deprivation and dietary stress. The ketone body β-hydroxybutyrate (BHB) is synthesized in the liver from fatty acids and represents an essential carrier of energy from the liver to peripheral tissues when the supply of glucose is too low for the body's energetic needs, such as during periods of prolonged exercise, starvation, or absence of dietary carbohydrates. In addition to its activity as an energetic metabolite, BHB is increasingly understood to have cellular signaling functions. These signaling functions of BHB broadly link the outside environment to epigenetic gene regulation and cellular function, and their actions may be relevant to a variety of human diseases as well as human aging.
388 citations
"Effects of Intermittent Fasting on ..." refers background in this paper
...Ketone bodies are not just fuel used during periods of fasting; they are potent signaling molecules with major effects on cell and organ functions.(21) Ketone bodies regulate the expression and activity of many proteins and molecules that are known to influence health and aging....
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