No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Intermittent fasting and longevity: From animal models to implication for humans
... resistance. [1][2][3][4][42][43][44] The same variability in results applies to ghrelin and leptin levels. Although some studies suggest an increase in plasma ghrelin levels during RF, others report no change or even a decrease. ...
... Food-related odors identification score 2.935 ± 0.674 (3, 3.145 ± 0.698 (3,(2)(3)(4) 3.516 ± 0.593 (4,(2)(3)(4) .0001 ...
... Food-related odors identification score 2.935 ± 0.674 (3, 3.145 ± 0.698 (3,(2)(3)(4) 3.516 ± 0.593 (4,(2)(3)(4) .0001 ...
Objective
The present study objectived to investigate the influence of Ramadan fasting (RF) on olfactory function.
Methods
Sixty‐two participants were included in the current prospective study. The odor threshold and identification performances were determined by using the Connecticut Chemosensory Clinical Research Center (CCCRC) test initially (day 0) and on the first and last day (30th) of RF. Body weight (BW)s were measured initially and at the end of the study. The results were analyzed statistically.
Results
The average of baseline and last‐day BWs were 78.38 ± 12.96 and 78.36 ± 12.39 kg, respectively. No significant difference was determined in terms of BWs (p = .932, p > .05). In the evaluation of CCCRC test outcomes, significant differences were observed in the scores of butanol thresholds (p = .0001), odor identification (p = .0001), food‐related odors identification (p = .0001), and the number of normosmic individuals (p = .0001) at different times (p < .05). The thresholds scores (p = .0001, p = .0001), the identification scores (p = .0001, p = .0001), food‐related odors identification scores (p = .0001, p = .0002), and the number of normomic individuals (p = .001, p = .001) detected on 30th day were significantly higher than on 0th and 1st days; respectively (p < .05). Additionally, the threshold scores (p = .0001), the identification scores (p = .003), food‐related odors identification scores (p = .007), and the number of normosmic individuals (p = .018) detected on day 1 were significantly higher than on day 0 (p < .05).
Conclusion
The current study demonstrated that Ramadan fasting enhances the olfactory detection threshold and odor identification scores, significantly improving the identification of food‐related odors. The results may indicate that Ramadan fasting improves olfactory performance.
Level of evidence
Level II.
... [17][18][19] Lastly, while more research is needed, some studies have suggested that IF may extend lifespan and improve overall health. [20,21] In recent years, researchers have explored the relationship between IF and cancer, investigating its potential roles in prevention, mitigation, and treatment. [22][23][24] Table 1 summarizes the types of IF interventions, their definitions, durations, and mechanistic modulation, as proposed by Kalam et al. [25] Elucidating the role of IF in cancer prevention, mitigation, and prevention is crucial. ...
Intermittent fasting (IF) has emerged as a potential adjunctive strategy in cancer prevention, mitigation, and treatment. This narrative review synthesizes existing literature to explore the relationship between IF and cancer across 3 dimensions: prevention, mitigation, and treatment. We examine the underlying mechanisms by which IF may reduce cancer risk, including its effects on insulin-like growth factor 1 suppression, autophagy induction, and chronic inflammation reduction. Furthermore, we discuss IF’s potential to enhance the efficacy of conventional cancer therapies by sensitizing cancer cells, promoting apoptosis, and reducing treatment-related side effects. While promising, the evidence is still limited, and further research is required to elucidate the long-term impact and optimal implementation of IF in cancer care. This review aims to provide health care professionals and patients with a comprehensive understanding of the potential benefits and risks associated with IF as a complementary approach in the oncology setting.
... Food insecurity-defined as limited and unpredictable access to nutritionally adequate food-is associated with obesity and poor health in humans (1,2). In contrast, intermittent fasting, which, like food insecurity can involve entire days without eating, is associated with weight loss and improved health (3)(4)(5). We hypothesise that the explanation for this apparent paradox lies in the distinction between starvation and fasting (6): whereas starvation is driven by extrinsic constraints, that are often unpredictable, fasting is internally driven and predictable. ...
1.
Summary
Food insecurity is associated with higher body weight in humans and other species, but the causal effect of unpredictable food availability on weight gain is unknown. We measured food intake and weight in starlings ( Sturnus vulgaris ) exposed to repeated irregular periods of food deprivation. We manipulated the predictability of deprivation between subjects with a 1-hour visual cue that either reliably preceded deprivation (Predictable), or was uncorrelated with deprivation (Unpredictable). During the cue, Predictable birds reduced their food intake and spent less time inactive, indicating that they had learnt the contingency. Despite these responses, they lost less weight during subsequent deprivation. They also ate less and gained less weight when food was returned. Birds with the largest behavioural response to the cue had the lowest overall variance in body weight. Consistent with the insurance hypothesis, food intake and body weight increased over time in both groups and body weight was higher in the Unpredictable group. Our results suggest that when food deprivation was predictable, birds were less reliant on stored fat and instead used conditioned hypometabolism to mitigate the effects of food deprivation. We discuss the implications of our findings for the differential health impacts of food insecurity and intermittent fasting.
... HG-induced oxidative stress in pancreatic β cells linked to the onset and progression of T2DM pathogenesis 34,35 . ...
Pancreatic β cells that produce insulin play a significant role in maintaining glucose homeostasis. However, high glucose (HG) causes oxidative stress, which leads to pancreatic β cell dysfunction. The synthesis of lipoic acid (LA) and plumbagin (PLU) conjugate (LA-PLU) was done and characterized using (1H) NMR, (13C) NMR, LC–ESI–MS/MS, and UV–visible spectroscopy techniques. ADME analysis confirmed the drug-like properties of LA-PLU. The present study revealed the protective effect of LA-PLU conjugate against HG (25 mM)-induced oxidative stress on pancreatic β cells. Cell viability was performed on RIN-5F cells and found that LA-PLU exhibits non-toxic up to 91.23 ± 2.61% of cell viability at 12.5 µM concentration. At 12.5 µM, LA-PLU protected pancreatic β cells up to 73.45 ± 3.72% under HG conditions. LA-PLU showed a protective effect on RIN-5F cells against HG-induced DNA damage, followed by preserving mitochondrial membrane potential and decreasing reactive oxygen species formation. Further, LA-PLU showed an anti-apoptotic effect by increasing the Bcl-2 (B cell lymphoma-2) level and decreasing the apoptotic proteins [Bcl-2 associated x (Bax), and cleaved caspase-3). Hence, the overall study concludes that LA-PLU could act as a potent antioxidant that protects the RIN-5F cells under HG conditions, resulting in the maintenance of glucose homeostasis.
... Intermittent fasting is a dietary approach that alternates between periods of eating and fasting. It has been associated with a wide range of health benefits including improved outcomes in various inflammatory conditions, such as obesity, diabetes, and inflammatory bowel diseases [1][2][3]. For example, intermittent fasting has been demonstrated to inhibit DSS-induced inflammation in mice by promoting intestinal regeneration and modulating inflammatory pathways [4,5]. ...
Intermittent fasting (IF) has been shown to ameliorate inflammation including DSS-induced colitis. It is well known that autophagy can limit inflammation and TFEB is a master transcriptional factor that regulates the processes of autophagy. However, whether TFEB is involved in the regulation of IF-mediated amelioration of inflammation and its mechanism remained unclear. In this study, we found that IF ameliorated DSS-induced colitis and induced TFEB. Nutrition deprivation induced TFEB puncta formation, which processes the characteristics of liquid–liquid phase separation (LLPS) showed by fluorescence recovery after photobleaching (FRAP) assay and 1,6-hexanediol treatment. We found the 24–33 amino acids of Coiled-Coil (CC) domain located in N terminus is essential for TFEB phase separation. Deletion of 24–33 amino acids within the CC domain inhibited TFEB-mediated target gene expression. In addition, we found transcription co-activators, EP300 and MED1, co-localized with TFEB condensate to formed a transcriptional hub that promotes the efficient expression of target genes. More importantly, TFEB inhibitor with ability to suppress TFEB puncta formation abolished the IF-mediated amelioration of DSS colitis. Together, these findings revealed a critical role of TFEB phase separation in the regulation of its transcriptional activity and anti-inflammatory functions induced by IF.
... Caloric restriction has been shown to reduce oxidative stress and extend lifespan in a variety of organisms [206,207], decreasing the overall metabolic rate and improving mitochondrial efficiency, meaning that less ROS is produced per unit of energy generated. Regular physical activity and avoiding smoking [166] and excessive alcohol consumption [208] can reduce oxidative stress. ...
Oxidative stress is the result of the imbalance between reactive oxygen and nitrogen species (RONS), which are produced by several endogenous and exogenous processes, and antioxidant defenses consisting of exogenous and endogenous molecules that protect biological systems from free radical toxicity. Oxidative stress is a major factor in the aging process, contributing to the accumulation of cellular damage over time. Oxidative damage to cellular biomolecules, leads to DNA alterations, lipid peroxidation, protein oxidation, and mitochondrial dysfunction resulting in cellular senescence, immune system and tissue dysfunctions, and increased susceptibility to age-related pathologies, such as inflammatory disorders, cardiovascular and neurodegenerative diseases, diabetes, and cancer. Oxidative stress-driven DNA damage and mutations, or methylation and histone modification, which alter gene expression, are key determinants of tumor initiation, angiogenesis, metastasis, and therapy resistance. Accumulation of genetic and epigenetic damage, to which oxidative stress contributes, eventually leads to unrestrained cell proliferation, the inhibition of cell differentiation, and the evasion of cell death, providing favorable conditions for tumorigenesis. Colorectal, breast, lung, prostate, and skin cancers are the most frequent aging-associated malignancies, and oxidative stress is implicated in their pathogenesis and biological behavior. Our aim is to shed light on the molecular and cellular mechanisms that link oxidative stress, aging, and cancers, highlighting the impact of both RONS and antioxidants, provided by diet and exercise, on cellular senescence, immunity, and development of an antitumor response. The dual role of ROS as physiological regulators of cell signaling responsible for cell damage and diseases, as well as its use for anti-tumor therapeutic purposes, will also be discussed. Managing oxidative stress is crucial for promoting healthy aging and reducing the risk of age-related tumors.
... Central to our review is the convergence of dietary interventions on key molecular pathways implicated in aging. By modulating nutrient-sensing pathways such as mTORC1, AMPK, and sirtuins, dietary regimens exert pleiotropic effects on cellular metabolism [92][93][94], stress resistance [95,96], and longevity [82,97]. ...
As the population ages, promoting healthy aging through targeted interventions becomes increasingly crucial. Growing evidence suggests that dietary interventions can significantly impact this process by modulating fundamental molecular pathways. This review focuses on the potential of targeted dietary strategies in promoting healthy aging and the mechanisms by which specific nutrients and dietary patterns influence key pathways involved in cellular repair, inflammation, and metabolic regulation. Caloric restriction, intermittent fasting, the Mediterranean diet, as well as the ketogenic diet showed promising effects on promoting healthy aging, possibly by modulating mTORC1 AMPK, an insulin signaling pathway. By understanding the intricate interplay between diet and molecular pathways, we can develop personalized dietary strategies that not only prevent age-related diseases, but also promote overall health and well-being throughout the aging process.
... Recent research indicates that dietary therapies and lifestyle changes that stimulate autophagy activation may have positive impacts on reproductive aging [60]. Studies have demonstrated that restricting caloric intake, practicing intermittent fasting, and supplementing the diet with chemicals that promote autophagy can increase autophagic activity and enhance reproductive outcomes in animal models [61,62]. Moreover, current research has demonstrated specific molecular pathways and regulatory systems that control autophagy during the process of reproductive aging ( Figure 3). ...
Rahman, M.H.; Alwasel, S.; Jalouli, M.; Kang, S.; Park, M.N.; Kim, B. Abstract: Autophagy, an evolutionarily conserved cellular mechanism essential for maintaining internal stability, plays a crucial function in female reproductive ability. In this review, we discuss the complex interplay between autophagy and several facets of female reproductive health, encompassing pregnancy, ovarian functions, gynecologic malignancies, endometriosis, and infertility. Existing research emphasizes the crucial significance of autophagy in embryo implantation, specifically in the endometrium, highlighting its necessity in ensuring proper fetal development. Although some knowledge has been gained, there is still a lack of research on the specific molecular impacts of autophagy on the quality of oocytes, the growth of follicles, and general reproductive health. Autophagy plays a role in the maturation, quality, and development of oocytes. It is also involved in reproductive aging, contributing to reductions in reproductive function that occur with age. This review explores the physiological functions of autophagy in the female reproductive system, its participation in reproductive toxicity, and its important connections with the endometrium and embryo. In addition, this study investigates the possibility of emerging treatment approaches that aim to modify autophagy, using both natural substances and synthetic molecules, to improve female fertility and reproductive outcomes. Additionally, this review intends to inspire future exploration into the intricate role of autophagy in female reproductive health by reviewing recent studies and pinpointing areas where current knowledge is lacking. Subsequent investigations should prioritize the conversion of these discoveries into practical uses in the medical field, which could potentially result in groundbreaking therapies for infertility and other difficulties related to reproduction. Therefore, gaining a comprehensive understanding of the many effects of autophagy on female fertility would not only further the field of reproductive biology but also open new possibilities for diagnostic and treatment methods.
Dietary therapy shows promise for diabetic kidney disease but requires personalization and further research.
Introduction: We conducted a systematic review and meta‐analysis to evaluate the effects of the 5:2 diet on weight loss and cardiovascular disease (CVD) risk factors in overweight and obese individuals.
Methods: Databases (PubMed, The Cochrane Library, Web of Science, Embase) were searched for randomized controlled trials of the intervention effects of the 5:2 diet in overweight and obese individuals. The search period was from database establishment to April 2024. RevMan 5.3 and Stata 14.0 were used for the meta‐analysis.
Results: A total of 20 articles with 1393 participants were finally included. There were 689 participants in the treatment groups and 704 in the control groups. The meta‐analysis showed that the 5:2 diet significantly reduces body weight, body mass index, waist circumference, body fat percentage, hip circumference, fat mass, fat‐free mass, low‐density lipoprotein, systolic blood pressure, and homeostasis model assessment‐insulin resistance levels relative to the control group ( p < 0.05). However, there was no significant difference in levels of visceral fat, total cholesterol, triglycerides, high‐density lipoprotein, diastolic blood pressure, insulin, fasting blood glucose, glycated hemoglobin A1c, and heart rate. Although there were no serious adverse events in the 5:2 diet group, participants in this group experienced mild physical and psychological side effects during the fasting period, which resolved spontaneously after fasting.
Conclusion: The 5:2 diet is effective for weight reduction and amelioration of CVD risk factors in overweight/obesity and is safe and feasible. However, the patient’s physical condition during the fasting period should be monitored and timely adjustments should be made accordingly.
This review examines the potential of fasting-mimicking diets (FMDs) in preventing and treating Alzheimer’s disease (AD). FMDs are low-calorie diets that mimic the physiological and metabolic effects of fasting, including the activation of cellular stress response pathways and autophagy. Recent studies have shown that FMDs can reduce amyloid-beta accumulation, tau phosphorylation, and inflammation, as well as improve cognitive function in animal models of AD. Human studies have also reported improvements in AD biomarkers, cognitive functions, and subjective well-being measures following FMDs. However, the optimal duration and frequency of FMDs and their long-term safety and efficacy remain to be determined. Despite these uncertainties, FMDs hold promise as a non-pharmacological approach to AD prevention and treatment, and further research in this area is warranted.
Organisms uptake energy from their diet and maintain a highly organized structure by importing energy and exporting entropy. A fraction of the generated entropy is accumulated in their bodies, thus causing ageing. Hayflick’s entropic age concept suggests that the lifespan of organisms is determined by the amount of entropy they generate. Organisms die after reaching their lifespan entropy generation limit. On the basis of the lifespan entropy generation concept, this study suggests that an intermittent fasting diet, which means skipping some meals without increasing the calories uptake in the other courses, may increase longevity. More than 1.32 million people died in 2017 because of chronic liver diseases, and a quarter of the world’s population has non-alcoholic fatty liver disease. There are no specific dietary guidelines available for the treatment of non-alcoholic fatty liver diseases but shifting to a healthier diet is recommended as the primary treatment. A healthy obese person may generate 119.9 kJ/kg K per year of entropy and generate a total of 4796 kJ/kg K entropy in the first 40 years of life. If obese persons continue to consume the same diet, they may have 94 years of life expectancy. After age 40, Child–Pugh Score A, B, and C NAFLD patients may generate 126.2, 149.9, and 272.5 kJ/kg K year of entropy and have 92, 84, and 64 years of life expectancy, respectively. If they were to make a major recommended shift in their diet, the life expectancy of Child–Pugh Score A, B, and C patients may increase by 29, 32, and 43 years, respectively.
Chronic dietary interventions have been known for decades to help prevent disease and extend longevity, yet most are difficult to adopt especially long-term. Brief periods of a diet that mimics fasting by regulating key starvation response genes including IGF-1, TOR-S6K and PKA lasting between 4 and 7 days and followed by long periods on a normal diet, are emerging as potentially effective pro-longevity interventions. These periodic fasting mimicking diets (FMD) provide low calories, sugars, and proteins and high levels of unsaturated fats. In mice, 4 day bi-monthly cycles of the FMD started at middle age extend longevity, reduce tumors by nearly 50%, reduce inflammatory diseases and increase cognitive performance at old ages. In humans, 3 monthly cycles of a 5 day FMD reduce markers or risk factors for aging, diabetes, cancer and cardiovascular disease including cholesterol, blood pressure, CRP, IGF-1, and fasting glucose, particularly in subjects with elevated levels of these markers at baseline. Here I will present our most recent mouse and clinical studies indicating that FMDs can help reverse insulin resistance, reduce risk factors/markers of aging and age-related diseases, and lower biological age.
Fasting and starvation were common occurrences during human evolution and accordingly have been an important environmental factor shaping human energy metabolism. Humans can tolerate fasting reasonably well through adaptative and well-orchestrated time-dependent changes in energy metabolism. Key features of the adaptive response to fasting are the breakdown of liver glycogen and muscle protein to produce glucose for the brain, as well as the gradual depletion of the fat stores, resulting in the release of glycerol and fatty acids into the bloodstream and the production of ketone bodies in the liver. In this paper, an overview is presented of our current understanding of the effects of fasting on adipose tissue metabolism. Fasting leads to reduced uptake of circulating triacylglycerols by adipocytes through inhibition of the activity of the rate-limiting enzyme lipoprotein lipase. In addition, fasting stimulates the degradation of stored triacylglycerols by activating the key enzyme adipose triglyceride lipase. The mechanisms underlying these events are discussed, with a special interest in insights gained from studies on humans. Furthermore, an overview is presented of the effects of fasting on other metabolic pathways in the adipose tissue, including fatty acid synthesis, glucose uptake, glyceroneogenesis, autophagy, and the endocrine function of adipose tissue.
Religious fasting is practiced by people of all faiths, including Christianity, Islam, Buddhism, Jainism, as well as Hinduism, Judaism, and Taoism. Individual/clinical, public, global, and planetary health has traditionally been studied as separate entities. Nevertheless, religious fasting, in conjunction with other religious health assets, can provide several opportunities, ranging from the individual to the population, environmental, and planetary levels, by facilitating and supporting societal transformations and changes, such as the adoption of healthier, more equitable, and sustainable lifestyles, therein preserving the Earth's systems and addressing major interconnected, cascading, and compound challenges. In this review, we will summarize the most recent evidence on the effects of religious fasting, particularly Orthodox and Ramadan Islamic fasting, on human and public health. Further, we will explore the potential effects of religious fasting on tackling current environmental issues, with a special focus on nutrition/food restriction and planetary health. Finally, specific recommendations, particularly around dietary intake during the fasting rituals, will be provided to ensure a sustainable healthy planet.
Background
As a cardiometabolic disease, hypertension has shown an obvious upward trend, becoming a global epidemic chronic disease. Lifestyle intervention is a fundamental method for lowering blood pressure. This systematic review and meta-analysis aimed to evaluate the effects of time-restricted eating (TRE) on blood pressure.
Methods
Studies were retrieved from the PubMed, Embase, Cochrane Library, and Web of Science databases to evaluate the effects of TRE on blood pressure. The time frame of search was from the start of database construction until July 14, 2022.There were no language restrictions. Meta-analysis and meta-regression were performed using Stata version 16. The weighted mean difference with 95% CI was used to assess the effect of TRE on blood pressure, heart rate, weight, blood glucose, total cholesterol, HDL-C, LDL-C, and triglycerides. The main ending of this article were blood pressure and heart rate, while the secondary ending were weight, blood glucose, total cholesterol, HDL-C, LDL-C, and triglycerides.
Results
Ten randomized controlled trials involving 694 patients were identified. TRE significantly reduced systolic blood pressure (SBP) (mean difference = −4.15; 95% CI: −6.73, −2.30; P < 0.0001), but had no significant effect on diastolic blood pressure (DBP) (mean difference = −2.06; 95% CI: −4.16, 0.02; P = 0.053) and no beneficial effect on heart rate (mean difference = 0.36; 95% CI: −2.83, 3.54; P = 0.0825). TRE promoted weight loss (mean difference = −1.63; 95% CI: −2.61, −0.64; P = 0.001) and decreased blood glucose levels (mean difference = −2.80; 95% CI: −4.64, −0.96; P = 0.003), but had no significant effect on total cholesterol (mean difference = 0.03, 95% CI: −10.01, 10.08; P = 0.995), HDL-C (mean difference = 0.85, 95% CI: −1.80, 3.49; P = 0.531), LDL-C (mean difference = −0.86, 95% CI: −6.47, 4.76; P = 0.764), or triglycerides (mean difference = −3.524, 95% CI: −9.49, 2.45; P = 0.248). In a separate meta-regression analysis, the degree of SBP change was related to weight loss (P = 0.044) but not to glucose improvement (P = 0.867).
Conclusions
The present meta-analysis suggests that TRE significantly reduced SBP, while no effect of reducing DBP was seen. The observed lower blood pressure may be attributed to significant weight loss. The effects of TRE on heart rate and blood lipid levels were not apparent.
The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer’s disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls. Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients. These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain.
Background:
Renal innate immune cell accumulation and inflammation are associated with hypertension. Time restricted feeding (TRF) has been reported to decrease inflammation and blood pressure. Whether TRF can decrease blood pressure by decreasing renal innate immune cells in hypertension is unknown.
Methods and results:
We determined whether TRF can decrease blood pressure in two separate mouse models of hypertension, N(G)-nitro-L-arginine methyl ester hydrochloride-induced hypertension (LHTN) and salt-sensitive hypertension (SSHTN). Once hypertension was established after 2 days, TRF (12-h food/12-h no food) for 4 weeks significantly decreased systolic blood pressure in both LHTN and SSHTN mice despite no differences in the amount of food eaten or body weight between groups. Activated macrophages and dendritic cells in the kidneys of both LHTN and SSHTN mice were decreased significantly in mice that underwent TRF. This was associated with an improvement in kidney function (decreased serum creatinine, decreased fractional excretion of sodium, and increased creatinine clearance) which achieved significance in LHTN mice and trended towards improvement in SSHTN mice.
Conclusions:
Our findings demonstrate that TRF can significantly decrease renal innate immune cells and blood pressure in two mouse models of hypertension.
Both ketogenic diets (KD) and time-restricted feeding (TRF) regimens have the ability to influence several parameters of physical health, including gut microbiome composition and circulating cytokine concentration. Moreover, both of these dietary interventions prevent common impairments associated with the aging process. However, significantly altering macronutrient intake, which is required for a KD, may be unappealing to individuals and decrease compliance to dietary treatments. In contrast to a KD, TRF allows individuals to continue eating the foods they are used to, and only requires a change in the time of day at which they eat. Therefore, we investigated both a KD and a diet with a more Western-like macronutrient profile in the context of TRF, and compared both diets to animals allowed access to standard chow ad libitum in young adult and aged rats. While limited effects on cytokine levels were observed, both methods of microbiome analysis (16S sequencing and metagenomics) indicate that TRF and KDs significantly altered the gut microbiome in aged rats. These changes were largely dependent on changes to feeding paradigm (TRF vs. ad libitum) alone regardless of macronutrient content for many gut microbiota, but there were also macronutrient-specific changes. Specifically, functional analysis indicates significant differences in several pathways, including those involved in the tricarboxylic acid (TCA) cycle, carbohydrate metabolism and neurodegenerative disease. These data indicate that age- and disease-related gut dysbiosis may be ameliorated through the use of TRF with both standard diets and KDs.
Caloric restriction is a popular approach to treat obesity and its associated chronic illnesses but is difficult to maintain for a long time. Intermittent fasting is an alternative and easily applicable dietary intervention for caloric restriction. Moreover, intermittent fasting has beneficial effects equivalent to those of caloric restriction in terms of body weight control, improvements in glucose homeostasis and lipid profiles, and anti-inflammatory effects. In this review, the beneficial effects of intermittent fasting are discussed.
(1) Background: Cardiometabolic disease, including insulin resistance, hyperlipidemia, and hypertension, are major contributors to adverse health outcomes. Fasting has gained interest as a nonpharmacological therapeutic adjunct for these disorders. (2) Methods: We conducted a prospective, single-center study on the effects of prolonged water-only fasting followed by an exclusively whole-plant-food refeeding diet on accepted measures of cardiovascular risk and metabolic health. Participants were recruited from patients who had voluntarily elected to complete a water-only fast in order to improve their overall health according to an established protocol at an independent, residential medical center. Median fasting and refeed lengths were 17 and 8 days, respectively. The primary endpoint was to describe the mean glucose tolerance as indicated by Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) scores at baseline, end-of-fast (EOF), and end-of-refeed (EOR) visits. Secondary endpoints were to describe the mean weight, body mass index (BMI), abdominal circumference (AC), systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid panel, and high-sensitivity C-reactive protein (hsCRP) at the same time points. (3) Results: The study enrolled 48 overweight/obese non-diabetic participants, of which 26 completed the full study protocol. At the EOF visit, the median SBP, AC, low-density lipoprotein (LDL), and hsCRP were decreased and triglycerides (TG) and HOMA-IR scores were increased. Conclusion: Prolonged water-only fasting and whole-plant-food refeeding holds potential as a clinical therapy for cardiometabolic disease but increased TG and HOMA-IR values after refeeding necessitate further inquiry.
Pregnant Muslim women are exempt from fasting during Ramadan; however a majority are reported to fast. The impact of this form of maternal intermittent fasting (IF) on fetal development and offspring health is not well defined. Using a rat model, we have shown previously that maternal IF results in fetal growth restriction accompanied by changes in placental nutrient transport function. The aim of this study was to assess cardiovascular, metabolic and renal function in adult offspring of IF-exposed dams. Food was withheld from Wistar rats from 17:00 to 09:00 daily throughout pregnancy; controls had ad libitum access to food. Birth weight was unaffected; however male IF pups grew more slowly up to 10 weeks of age (P < 0.01) whereas IF females matched their control counterparts. Systolic blood pressure (SBP), glucose tolerance and basal renal function at 14 weeks were not affected by IF exposure. When offered saline solutions (0.9–2.1%) to drink, females showed a greater salt preference than males (P < 0.01); however there were no differences between dietary groups. A separate group of pups was weaned onto a 4% NaCl diet. SBP increased in IF pups sooner, at 7 weeks (P < 0.01), than controls which became hypertensive from 10 weeks. Renal function did not appear to differ; however markers of renal injury were elevated in IF males (P < 0.05). Maternal IF does not affect resting cardiovascular, metabolic and renal function; but when challenged by dietary salt load male IF offspring are more prone to renal injury.
Elevated plasma levels of trimethylamine N-oxide (TMAO) have been proposed as a diet-derived biomarker of cardiometabolic disease risk. Caloric restriction is the most common dietary intervention used to improve cardiometabolic health; however, novel trends suggest a fasting-mimicking diet (FMD) as a more feasible alternative. FMD is a variation of intermittent fasting, based on caloric restriction and limitation of protein sources of animal origin, applied in daily cycles during a 5-day period. As TMAO is intensively produced by gut microbiota after the consumption of animal-derived products, we aim to investigate whether a 5-day FMD affects plasma TMAO levels and markers of metabolic health. To investigate whether an increase in vegetable intake possesses similar effects on TMAO levels and metabolic parameters, healthy volunteers (n = 24) were subjected to a 5-day FMD and 19 volunteers served as a reference group (VEG). This group of volunteers consumed an additional four servings of vegetables per day, but otherwise stayed on their usual diet. FMD resulted in a twofold decrease in plasma TMAO levels, which was not evident in the volunteers from the VEG group. Moreover, FMD led to a weight loss of 2.8 ± 0.2 kg and a subsequent reduction in BMI compared to baseline. The FMD group exhibited a significant elevation in plasma ketone bodies (14-fold compared to baseline) and a decrease in IGF-1 levels by 37 ± 8 ng/mL. Since fasting glucose and C-peptide levels decreased, all volunteers in the FMD group showed improved insulin sensitivity and a decreased HOMA-IR index. In contrast, in the VEG group, only a slight reduction in plasma levels of fasting glucose and triglycerides was noted. In conclusion, we show that FMD is a viable strategy to reduce plasma levels of TMAO by limiting caloric intake and animal-derived protein consumption. The reduction in the level of TMAO could be an additional benefit of FMD, leading to a reduced risk of cardiometabolic diseases.
Numerous human chronic pathological conditions depend on epigenetic modifications induced by environmental triggers throughout sensitive stages early in development. Developmental malnutrition is regarded as one of the most important risk factors in these processes. We present an overview of studies that the initiation and progression of many diseases are largely dependent on persisting epigenetic dysregulation caused by environmental insults early in life. For particular disorders, candidate genes were identified that underlie these associations. The current study assessed the most convincing evidence for the epigenetic link between developmental malnutrition and adult-life disease in the human population. These findings were obtained from quasi-experimental studies (so-called ‘natural experiments’), i.e. naturally occurring environmental conditions in which certain subsets of the population have differing levels of exposure to a supposed causal factor. Most of this evidence was derived on the DNA methylation level. We discussed DNA methylation as a key player in epigenetic modifications that can be inherited through multiple cell divisions. In this Perspective article, an overview of the quasi-experimental epidemiological evidence for the role of epigenetic mechanisms in the developmental programming by early-life undernutrition is provided.
Diet composition, calories, and fasting times contribute to the maintenance of health. However, the impact of very low-calorie intake (VLCI) achieved with either standard laboratory chow (SD) or a plant-based fasting mimicking diet (FMD) is not fully understood. Here, using middle-aged male mice we show that 5 months of short 4:10 VLCI cycles lead to decreases in both fat and lean mass, accompanied by improved physical performance and glucoregulation, and greater metabolic flexibility independent of diet composition. A long-lasting metabolomic reprograming in serum and liver is observed in mice on VLCI cycles with SD, but not FMD. Further, when challenged with an obesogenic diet, cycles of VLCI do not prevent diet-induced obesity nor do they elicit a long-lasting metabolic memory, despite achieving modest metabolic flexibility. Our results highlight the importance of diet composition in mediating the metabolic benefits of short cycles of VLCI. Understanding the contribution of diet composition, calories and length of fasting in health maintenance is still challenging. Here the authors compare the effects of cycles of intermittent very low calorie intake achieved with a plant-based fasting mimicking diet or standard laboratory chow to provide insights into the role played by diet composition in mediating the metabolic benefits of short cycles of very low-calorie intake in mice.
Cancer incidence increases with age and is a leading cause of death. Caloric restriction (CR) confers benefits on health and survival and delays cancer. However, due to CR’s stringency, dietary alternatives offering the same cancer protection have become increasingly attractive. Short cycles of a plant-based diet designed to mimic fasting (FMD) are protective against tumorigenesis without the chronic restriction of calories. Yet, it is unclear whether the fasting time, level of dietary restriction, or nutrient composition is the primary driver behind cancer protection. Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden. Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR.
Studies suggest that time-restricted feeding (TRF) may prevent obesity and its commodities. At present, little is known about how TRF impacts immune cells, and whether such an effect is linked to altered metabolic parameters under condition of a high-fat diet (HFD)-induced obesity. To address these issues, we conducted a study in which we determined whether TRF has therapeutic efficacy against weight gain, adiposity, as well as associated immune cell disturbance found in obese mice. Six-week-old male C57BL/6 mice were fed a low-fat diet (LFD) or HFD ad libitum for six weeks, after which time a subgroup of HFD mice was switched to the 10 h TRF paradigm (HFD-TRF) for additional eight weeks. We found that TRF intervention reduced HFD-induced weight gain. Even with comparable fat mass and mean adipocyte area, the HFD-TRF group had lower mRNA levels of proinflammatory cytokine Tnfα and chemokine Ccl8, along with reduced numbers of adipose tissue macrophages (ATM), CD11c+ ATM, and CD8+ T cell compared to the HFD group, while maintaining CD8+ to CD4+ ratio at levels similar to those in the LFD group. Furthermore, TRF intervention was effective in improving glucose tolerance and reducing HOMA-IR. Taken together, our findings suggest that TRF restores the obesity-induced alteration in immune cell composition, and this effect may in part contribute to health benefits (including insulin sensitivity) of practicing TRF.
Diet has long been the focus of attention as a leading risk factor for non-communicable diseases. As such, a better understanding of it is crucial to establish priorities for dietary guidelines and to inform, design, and implement strategies for preventing, helping manage, and stopping the progression of sleep and mental health-related symptoms/disorders. The aim of the current study is to conduct the largest investigation of diet, sleep, and mental health to date by utilizing the UK Biobank (UKB) dataset to identify the associations between diet and (i) sleep quality/health, and (ii) mental health symptomatology. This cross-sectional population-based study involved 502,494 middle-aged adults. UKB food frequency, sleep, and psychological factors and mental health questionnaires at baseline were used. Scores were also calculated for healthy diet, healthy sleep, mental health symptomatology, partial fibre intake, and milk intake. We observed positive associations with healthy diet and sleep and mental health, especially benefits of high intakes of vegetable, fruit, fish, water, and fibre. However, processed meat and milk intake were adversely associated with sleep and mental health. These findings make clear that there are health and wellbeing benefits and drawbacks of different diets, but do not, at this stage, demonstrate the clear causal relationships, which would support dietary interventions that might play a role in the treatment and also self-management of sleep and mental health disorders/symptoms. Further research is required to understand mechanisms of actions of which diet acts on to modulate sleep and mental health, while taking comorbidity of sleep and mental health disorders/symptoms into consideration.
Background: Religiously motivated Bahá'í fasting (BF) is a form of intermittent dry fasting celebrated by abstaining from food and drinks during daylight hours every year in March for 19 consecutive days.
Aim: To test the safety and effects of BF on hydration, metabolism, and the circadian clock.
Methods: Thirty-four healthy Bahá'í volunteers (15 women) participated in this prospective, exploratory cohort study. Laboratory examinations were carried out in four study visits: before fasting (V0), in the third week of fasting (V1) as well as 3 weeks (V3) and 3 months (V4) after fasting. Data collection included blood and urine samples, anthropometric measurements and bioelectrical impedance analysis. At V0 and V1, 24- and 12-hour urine and serum osmolality were measured. At V0–V2, alterations in the circadian clock phase were monitored in 16 participants. Our study was augmented by an additional survey with 144 healthy Bahá'í volunteers filling out questionnaires and with subgroups attending metabolic measurements (n = 11) and qualitative interviews (n = 13), the results of which will be published separately.
Results: Exploratory data analysis revealed that serum osmolality (n = 34, p < 0.001) and 24-hour urine osmolality (n = 34, p = 0.003) decreased during daytime fasting but remained largely within the physiological range and returned to pre-fasting levels during night hours. BMI (body mass index), total body fat mass, and resting metabolic rate decreased during fasting (n = 34, p < 0.001), while body cell mass and body water appeared unchanged. The circadian phase estimated by transcript biomarkers of blood monocytes advanced by 1.1 h (n = 16, p < 0.005) during fasting and returned to pre-fasting values 3 weeks after fasting. Most observed changes were not detectable anymore 3 months after fasting.
Conclusions: Results indicate that BF (Bahá'í fasting) is safe, has no negative effects on hydration, can improve fat metabolism and can cause transient phase shifts of circadian rhythms.
Trial Registration: https://www.clinicaltrials.gov/, identifier: NCT03443739.
Parkinson’s disease is one of the most common neurodegenerative disorders worldwide, characterized by a progressive loss of dopaminergic neurons mainly localized in the substantia nigra pars compacta. In recent years, the detailed analyses of both genetic and idiopathic forms of the disease have led to a better understanding of the molecular and cellular pathways involved in PD, pointing to the centrality of mitochondrial dysfunctions in the pathogenic process. Failure of mitochondrial quality control is now considered a hallmark of the disease. The peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family acts as a master regulator of mitochondrial biogenesis. Therefore, keeping PGC-1 level in a proper range is fundamental to guarantee functional neurons. Here we review the major findings that tightly bond PD and PGC-1s, raising important points that might lead to future investigations.
While prolonged fasting induces significant metabolic changes in humans and mice, less is known about systems-wide metabolic changes in response to short-term feed deprivation, which is used in experimental animal studies prior to metabolic challenge tests. We here performed a systems biology-based investigation of connections between gut bacterial composition and function, inflammatory and metabolic parameters in the intestine, liver, visceral adipose tissue, blood and urine in high-fat fed, obese mice that were feed deprived up to 12 h. The systems-wide analysis revealed that feed deprivation linked to enhanced intestinal butyric acid production and expression of the gene encoding the pro-thermogenic uncoupling protein UCP1 in visceral adipose tissue of obese mice. Ucp1 expression was also positively associated with Il33 expression in ileum, colon and adipose tissue as well as with the abundance of colonic Porphyromonadaceae, the latter also correlating to cecal butyric acid levels. Collectively, the data highlighted presence of a multi-tiered system of inter-tissue communication involving intestinal, immune and metabolic functions which is affected by feed deprivation in obese mice, thus pointing to careful use of short-feed deprivation in metabolic studies using obese mice.
Fasting is becoming an increasingly popular practice. Nevertheless, its clinical benefits and possible inconveniences remain limitedly evaluated. We observed the effects of a seven-day fast conducted in a non-medical center located in the Swiss Alps. Clinical parameters were measured on the first and last day of fasting (D1 and D7), and two months later (D60). Among the 40 participants, blood analyses were done on 25 persons with an increased metabolic risk, with the primary goal of assessing the lasting effect on low-density lipoprotein (LDL) cholesterol. By comparing D60 with D1, high-density lipoprotein cholesterol (HDL) (+0.15 mmol/L) and insulin-like growth factor-1 (IGF-1) (+2.05 mmol/L) increased (both p < 0.009), all other blood parameters (LDL, glucose, total cholesterol, triglycerides, C-reactive protein (CRP)) did not change; weight (−0.97 kg) and hearth rate (−7.31 min−1) decreased (both p < 0.006). By comparing D7 with D1, total cholesterol (+0.44 mmol/L), triglycerides (+0.37 mmol/L) and CRP (+3.37 mg/L) increased (all p < 0.02). The lack of LDL variation at D60 may be due to the low metabolic risk level of the participants. The increase of total cholesterol, triglycerides and CRP at D7 warrants studies to understand whether such fluctuations represent a stress reaction to the fasting state, which may vary in different fasting types.
Background
Time restricted eating (TRE) is an emerging dietary intervention for weight loss that is hypothesized to reinforce the metabolic benefits of nightly fasting/ketosis. This pilot study investigated the effectiveness of a daily 14-h metabolic fast (14:10 TRE beginning after dinner, a “fasting snack” at hour 12, and ending with breakfast 14 h later) combined with a commercial weight management program on body weight and fasting blood glucose (FBG) in individuals with obesity. We also investigated the effect of the low-calorie, high-fat, low-carbohydrate, and low-protein “fasting snack” on blood glucose.
Methods
This 8-week, randomized, controlled, clinical trial included men and women (BMI ≥ 30 kg/m ² ) between June and October 2020. Study procedures were conducted remotely. Participants were randomized to 14:10 or 12-h TRE (12:12, active comparator) and prescribed a diet (controlled for calories and macronutrient composition) and exercise program that included weekly customized counseling and support. The primary outcome was change from baseline in body weight in the 14:10 group.
Results
Of the 78 randomized participants, 60 ( n = 30/group) completed 8 weeks. The LS mean change from baseline in weight in the 14:10 group was −8.5% (95% CI −9.6 to −7.4; P < 0.001) and −7.1% (−8.3 to −5.8; P < 0.001) in the 12:12 group (between group difference −1.4%; −2.7 to −0.2; P < 0.05). There was a statistically significant LS mean change from baseline to week 8 in FBG in the 14:10 group of −7.6 mg/dl (95% CI −15.1 to −0.1; P < 0.05) but not in the 12:12 group (−3.1 mg/dl, −10.0 to 3.7; P = NS). Both interventions resulted in a larger reduction in FBG in participants with elevated FBG (≥100 mg/dl) at baseline (both P < 0.05).
Conclusions
In participants with obesity who completed 8 weeks of the 14:10 TRE schedule combined with a commercial weight loss program, there was statistically significant and clinically meaningful weight loss and improvements in FBG.
Background
Fasting-mimicking diet (FMD) has been recently promoted to achieve similar metabolic changes of fasting. The purpose of our study was to compare the effect of FMD versus continuous energy restriction (CER) on anthropometric measurements, body composition, glucose metabolism, and serum levels of leptin, neuropeptide Y (NPY), and total ghrelin.MethodsA randomized controlled trial (RCT) was conducted on 60 women with obesity aged 18–55 years. Subjects received either a 5-day FMD (low in energy, sugars, and proteins, but high in unsaturated fats) or a CER (an average daily energy deficit of 500 kcal) for 2 months. Anthropometric and biochemical factors were measured at baseline and the end of the study. Serum levels of leptin, total ghrelin, and NPY were tested with an ELISA kit. Physical activity and dietary intakes were also recorded.ResultsThere was no significant difference in weight loss between the two groups: mean weight change for CER was − 2.29 (standard deviation [SD], 1.95) kg compared to − 1.13 (2.27) kg for FMD (p = 0.06). There was more reduction in the basal metabolic rate (BMR) in the CER group (p = 0.045). Favorable effects on fat mass and muscle mass were only seen in the FMD group. Although insulin resistance was reduced in the FMD group compared to the CER group, results were not significant after adjustment. After controlling for potential confounders, there was a significant increase in serum levels of total ghrelin (p = 0.048) and NPY (p = 0.041) following CER; however, results for circulating leptin were not statistically significant (p = 0.48).Conclusions
There was no significant difference in weight loss following FMD and CER. However, FMD was more effective at reducing insulin resistance and regulating appetite-regulating hormones as well as preserving muscle mass and BMR.Trial RegistrationThis trial was registered at the Iranian Clinical Trial Registry (https://www.irct.ir/trial/40881) with the IRCT identification number IRCT20190717044244N1.
Myocardial infarction (MI) leading to heart failure (HF) is a major cause of death worldwide. Previous studies revealed that the circadian system markedly impacts cardiac repair post-MI, and that light is an important environmental factor modulating the circadian influence over healing. Recent studies suggest that gut physiology also affects the circadian system, but how it contributes to cardiac repair post-MI and in HF is not well understood. To address this question, we first used a murine coronary artery ligation MI model to reveal that an intact gut microbiome is important for cardiac repair. Specifically, gut microbiome disruption impairs normal inflammatory responses in infarcted myocardium, elevates adverse cardiac gene biomarkers, and leads to worse HF outcomes. Conversely, reconstituting the microbiome post-MI in mice with prior gut microbiome disruption improves healing, consistent with the notion that normal gut physiology contributes to cardiac repair. To investigate a role for the circadian system, we initially utilized circadian mutant Clock∆19/∆19 mice, revealing that a functional circadian mechanism is necessary for gut microbiome benefits on post-MI cardiac repair and HF. Finally, we demonstrate that circadian-mediated gut responses that benefit cardiac repair can be conferred by time-restricted feeding, as wake time feeding of MI mice improves HF outcomes, but these benefits are not observed in MI mice fed during their sleep time. In summary, gut physiology is important for cardiac repair, and the circadian system influences the beneficial gut responses to improve post-MI and HF outcomes.
Time-restricted feeding (TRF) regimens have grown in popularity; however, very few studies have examined their weight-loss efficacy. We conducted the first human trial (Clinicaltrials.gov NCT03867773) to compare the effects of two popular forms of TRF (4 and 6 h) on body weight and cardiometabolic risk factors. Adults with obesity were randomized to 4-h TRF (eating only between 3 and 7 p.m.), 6-h TRF (eating only between 1 and 7 p.m.), or a control group (no meal timing restrictions). After 8 weeks, 4- and 6-h TRF produced comparable reductions in body weight (∼3%), insulin resistance, and oxidative stress, versus controls. Energy intake was reduced by ∼550 kcal/day in both TRF groups, without calorie counting. These findings suggest that 4- and 6-h TRF induce mild reductions in body weight over 8 weeks and show promise as interventions for weight loss. These diets may also improve some aspects of cardiometabolic health.
Genetic and pharmacological interventions have successfully extended healthspan and lifespan in animals, but their genetic interventions are not appropriate options for human applications and pharmacological intervention needs more solid clinical evidence. Consequently, dietary manipulations are the only practical and probable strategies to promote health and longevity in humans. Caloric restriction (CR), reduction of calorie intake to a level that does not compromise overall health, has been considered as being one of the most promising dietary interventions to extend lifespan in humans. Although it is straightforward, continuous reduction of calorie or food intake is not easy to practice in real lives of humans. Recently, fasting-related interventions such as intermittent fasting (IF) and time-restricted feeding (TRF) have emerged as alternatives of CR. Here, we review the history of CR and fasting-related strategies in animal models, discuss the molecular mechanisms underlying these interventions, and propose future directions that can fill the missing gaps in the current understanding of these dietary interventions. CR and fasting appear to extend lifespan by both partially overlapping common mechanisms such as the target of rapamycin (TOR) pathway and circadian clock, and distinct independent mechanisms that remain to be discovered. We propose that a systems approach combining global transcriptomic, metabolomic, and proteomic analyses followed by genetic perturbation studies targeting multiple candidate pathways will allow us to better understand how CR and fasting interact with each other to promote longevity.
Murine studies showed that disruption of circadian clock rhythmicity could lead to cancer and metabolic syndrome. Time-restricted feeding can reset the disrupted clock rhythm, protect against cancer and metabolic syndrome. Based on these observations, we hypothesized that intermittent fasting for several consecutive days without calorie restriction in humans would induce an anticarcinogenic proteome and the key regulatory proteins of glucose and lipid metabolism. Fourteen healthy subjects fasted from dawn to sunset for over 14 h daily. Fasting duration was 30 consecutive days. Serum samples were collected before 30-day intermittent fasting, at the end of 4th week during 30-day intermittent fasting, and one week after 30-day intermittent fasting. An untargeted serum proteomic profiling was performed using ultra high-performance liquid chromatography/tandem mass spectrometry. Our results showed that 30-day intermittent fasting was associated with an anticancer serum proteomic signature, upregulated key regulatory proteins of glucose and lipid metabolism, circadian clock, DNA repair, cytoskeleton remodeling, immune system, and cognitive function, and resulted in a serum proteome protective against cancer, metabolic syndrome, inflammation, Alzheimer's disease, and several neuropsychiatric disorders. These findings suggest that fasting from dawn to sunset for 30 consecutive days can be preventive and adjunct therapy in cancer, metabolic syndrome, and several cognitive and neuropsychiatric diseases.
Significance
Our study has important clinical implications. Our results showed that intermittent fasting from dawn to sunset for over 14 h daily for 30 consecutive days was associated with an anticancer serum proteomic signature and upregulated key regulatory proteins of glucose and lipid metabolism, insulin signaling, circadian clock, DNA repair, cytoskeleton remodeling, immune system, and cognitive function, and resulted in a serum proteome protective against cancer, obesity, diabetes, metabolic syndrome, inflammation, Alzheimer's disease, and several neuropsychiatric disorders. Importantly, these findings occurred in the absence of any calorie restriction and significant weight loss. These findings suggest that intermittent fasting from dawn to sunset can be a preventive and adjunct therapy in cancer, metabolic syndrome and Alzheimer's disease and several neuropsychiatric diseases.
Fasting is deeply entrenched in evolution, yet its potential applications to today’s most common, disabling neurological diseases remain relatively unexplored. Fasting induces an altered metabolic state that optimizes neuron bioenergetics, plasticity, and resilience in a way that may counteract a broad array of neurological disorders. In both animals and humans, fasting prevents and treats the metabolic syndrome, a major risk factor for many neurological diseases. In animals, fasting probably prevents the formation of tumors, possibly treats established tumors, and improves tumor responses to chemotherapy. In human cancers, including cancers that involve the brain, fasting ameliorates chemotherapy-related adverse effects and may protect normal cells from chemotherapy. Fasting improves cognition, stalls age-related cognitive decline, usually slows neurodegeneration, reduces brain damage and enhances functional recovery after stroke, and mitigates the pathological and clinical features of epilepsy and multiple sclerosis in animal models. Primarily due to a lack of research, the evidence supporting fasting as a treatment in human neurological disorders, including neurodegeneration, stroke, epilepsy, and multiple sclerosis, is indirect or non-existent. Given the strength of the animal evidence, many exciting discoveries may lie ahead, awaiting future investigations into the viability of fasting as a therapy in neurological disease.
Intermittent fasting (IF) has been gaining popularity as a means of losing weight. The Ramadan fast (RF) is a form of IF practiced by millions of adult Muslims globally for a whole lunar month every year. It entails a major shift from normal eating patterns to exclusive nocturnal eating. RF is a state of intermittent liver glycogen depletion and repletion. The earlier (morning) part of the fasting day is marked by dominance of carbohydrate as the main fuel, but lipid becomes more important towards the afternoon and as the time for breaking the fast at sunset (iftar) gets closer. The practice of observing Ramadan fasting is accompanied by changes in sleeping and activity patterns, as well as circadian rhythms of hormones including cortisol, insulin, leptin, ghrelin, growth hormone, prolactin, sex hormones, and adiponectin. Few studies have investigated energy expenditure in the context of RF including resting metabolic rate (RMR) and total energy expenditure (TEE) and found no significant changes with RF. Changes in activity and sleeping patterns however do occur and are different from non-Ramadan days. Weight changes in the context of Ramadan fast are variable and typically modest with wise inter-individual variation. As well as its direct relevance to many religious observers, understanding intermittent fasting may have implications on weight loss strategies with even broader potential implications. This review examines current knowledge on different aspects of energy balance in RF, as a common model to learn from and also map out strategies for healthier outcomes in such settings.
Objective
This study aimed to assess the effects of 9‐hour time‐restricted feeding (TRF), early (TRFe) or delayed (TRFd), on glucose tolerance in men at risk for type 2 diabetes.
Methods
Fifteen men (age 55 ± 3 years, BMI 33.9 ± 0.8 kg/m²) wore a continuous glucose monitor for 7 days of baseline assessment and during two 7‐day TRF conditions. Participants were randomized to TRFe (8 am to 5 pm) or TRFd (12 pm to 9 pm), separated by a 2‐week washout phase. Glucose, insulin, triglycerides, nonesterified fatty acids, and gastrointestinal hormone incremental areas under the curve were calculated following a standard meal on days 0 and 7 at 8 am (TRFe) or 12 pm (TRFd).
Results
TRF improved glucose tolerance as assessed by a reduction in glucose incremental area under the curve (P = 0.001) and fasting triglycerides (P = 0.003) on day 7 versus day 0. However, there were no mealtime by TRF interactions in any of the variables examined. There was also no effect of TRF on fasting and postprandial insulin, nonesterified fatty acids, or gastrointestinal hormones. Mean fasting glucose by continuous glucose monitor was lower in TRFe (P = 0.02) but not TRFd (P = 0.17) versus baseline, but there was no difference between TRF conditions.
Conclusions
While only TRFe lowered mean fasting glucose, TRF improved glycemic responses to a test meal in men at risk for type 2 diabetes regardless of the clock time that TRF was initiated.
Intermittent fasting is increasing in popularity as a means of losing weight and controlling chronic illness. Patients with diabetes mellitus, both types 1 and 2, comprise about 10% of the population in the United States and would likely be attracted to follow one of the many methods of intermittent fasting. Studies on the safety and benefits of intermittent fasting with diabetes are very limited though, and health recommendations unfortunately today arise primarily from weight loss gurus and animal studies. Medical guidelines on how to manage therapeutic intermittent fasting in patients with diabetes are non-existent. The evidence to build such a clinical guideline for people with a diabetes diagnosis is almost non-existent, with just one randomized trial and several case reports. This article provides an overview of the available knowledge and a review of the very limited pertinent literature on the effects of intermittent fasting among people with diabetes. It also evaluates the known safety and efficacy issues surrounding treatments for diabetes in the fasting state. Based on those limited data and a knowledge of best practices, this paper proposes expert-based guidelines on how to manage a patient with either type 1 or 2 diabetes who is interested in intermittent fasting. The safety of each relevant pharmaceutical treatment during a fasting period is considered. When done under the supervision of the patient’s healthcare provider, and with appropriate personal glucose monitoring, intermittent fasting can be safely undertaken in patients with diabetes.
Only few studies document longer periods of fasting in large cohorts including non-obese participants. The aim of this study was to document prospectively the safety and any changes in basic health and well-being indicators during Buchinger periodic fasting within a specialised clinic. In a one-year observational study 1422 subjects participated in a fasting program consisting of fasting periods of between 4 and 21 days. Subjects were grouped in fasting period lengths of 5, 10, 15 and 20±2 days. The participants fasted according to the Buchinger guidelines with a daily caloric intake of 200–250 kcal accompanied by a moderate-intensity lifestyle program. Clinical parameters as well as adverse effects and well-being were documented daily. Blood examinations before and at the end of the fasting period complemented the pre-post analysis using mixed-effects linear models. Significant reductions in weight, abdominal circumference and blood pressure were observed in the whole group (each p<0.001). A beneficial modulating effect of fasting on blood lipids, glucoregulation and further general health-related blood parameters was shown. In all groups, fasting led to a decrease in blood glucose levels to low norm range and to an increase in ketone bodies levels (each p<0.001), documenting the metabolic switch. An increase in physical and emotional well-being (each p<0.001) and an absence of hunger feeling in 93.2% of the subjects supported the feasibility of prolonged fasting. Among the 404 subjects with pre-existing health-complaints, 341 (84.4%) reported an improvement. Adverse effects were reported in less than 1% of the participants. The results from 1422 subjects showed for the first time that Buchinger periodic fasting lasting from 4 to 21 days is safe and well tolerated. It led to enhancement of emotional and physical well-being and improvements in relevant cardiovascular and general risk factors, as well as subjective health complaints.
Fasting and especially intermittent fasting have been shown to be an effective intervention in many diseases, such as obesity and diabetes. The fasting-mimicking diet (FMD) has recently been found to ameliorate metabolic disorders. To investigate the effect of a new type of low-protein low-carbohydrate FMD on diabetes, we tested an FMD in db/db mice, a genetic model of type 2 diabetes. The diet was administered every other week for a total of 8 weeks. The intermittent FMD normalized blood glucose levels in db/db mice, with significant improvements in insulin sensitivity and β cell function. The FMD also reduced hepatic steatosis in the mice. Deterioration of pancreatic islets and the loss of β cells in the diabetic mice were prevented by the FMD. The expression of β cell progenitor marker Ngn3 was increased by the FMD. In addition, the FMD led to the reconstruction of gut microbiota. Intermittent application of the FMD increased the genera of Parabacteroides and Blautia while reducing Prevotellaceae, Alistipes and Ruminococcaceae. The changes in these bacteria were also correlated with the fasting blood glucose levels of the mice. Furthermore, intermittent FMD was able to reduce fasting blood glucose level and increase β cells in STZ-induced type 1 diabetic mouse model. In conclusion, our study provides evidence that the intermittent application of an FMD is able to effectively intervene in the progression of diabetes in mice.
Electronic supplementary material
The online version of this article (10.1186/s12986-018-0318-3) contains supplementary material, which is available to authorized users.
Lifespan of many organisms, from unicellular yeast to extremely complex human organism, strongly depends on the genetic background and environmental factors. Being among most influential target energy metabolism is affected by macronutrients, their caloric values, and peculiarities of catabolism. Mitochondria are central organelles that respond for energy metabolism in eukaryotic cells. Mitochondria generate reactive oxygen species (ROS), which are lifespan modifying metabolites and a kind of biological clock. Oxidized nicotinamide adenine dinucleotide (NAD+) and adenosine monophosphate (AMP) are important metabolic intermediates and molecules that trigger or inhibit several signaling pathways involved in gene silencing, nutrient allocation, and cell regeneration and programmed death. A part of NAD+ and AMP metabolism is tied to mitochondria. Using substances that able to target mitochondria, as well as allotopic expression of specific enzymes, are envisioned to be innovative approaches to prolong lifespan by modulation of ROS, NAD+, and AMP levels. Among substances, an anti-diabetic drug metformin is believed to increase NAD+ and AMP levels, indirectly influencing histone deacetylases, involved in gene silencing, and AMP-activated protein kinase, an energy sensor of cells. Mitochondrially targeted derivatives of ubiquinone were found to interact with ROS. A mitochondrially targeted non-proton-pumping NADH dehydrogenase may influence both ROS and NAD+ levels. Chapter describes putative how mitochondria-targeted drugs and NADH dehydrogenase extend lifespan, perspectives of creating drugs with similar properties and their usage as senotherapeutic pills are discussed in the chapter.
The metabolic syndrome consists of a constellation of clinical factors associated with an increased risk of cardiovascular disease, type 2 diabetes and cancer. Preclinical studies demonstrate that restricting the time during a 24 hour period when an obese animal eats (time restricted feeding) leads to metabolic benefits. These benefits, which may or may not be associated with weight loss, often lead to improvements in glucose tolerance and insulin sensitivity. Studies seeking to determine whether similar benefits result when humans restrict daily eating time (time restricted eating), are less mature and less consistent in their findings. In this commentary we outline some of the exciting preclinical findings, the challenges that preliminary studies in humans present, and efforts of the U.S. National Institutes of Health and specifically the National Cancer Institute to address the role of time restricted eating in cancer.
Intermittent fasting (IF) has been studied for its effects on lifespan and lifespan as well as the prevention or delay of age-related diseases upon the regulation of metabolic pathways. Mitochondria participate in key metabolic pathways and play important roles in maintaining intracellular signaling networks that modulate various cellular functions. Mitochondrial dysfunction has been described as an early feature of brain aging and neurodegeneration. Although IF has been shown to prevent brain aging and neurodegeneration, the mechanism is still unclear. This review focuses on the mechanisms by which IF improves mitochondrial function, which plays a central role in brain aging and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. The cellular and molecular mechanisms of IF in brain aging and neurodegeneration involve activation of adaptive cellular stress responses and signaling- and transcriptional pathways, thereby enhancing mitochondrial function, by promoting energy metabolism and reducing oxidant production.
This review aims to summarize the effects of intermittent fasting on markers of cardiometabolic health in humans. All forms of fasting reviewed here-alternate-day fasting (ADF), the 5:2 diet, and time-restricted eating (TRE)-produced mild to moderate weight loss (1-8% from baseline) and consistent reductions in energy intake (10-30% from baseline). These regimens may benefit cardiometabolic health by decreasing blood pressure, insulin resistance, and oxidative stress. Low-density lipoprotein cholesterol and triglyceride levels are also lowered, but findings are variable. Other health benefits, such as improved appetite regulation and favorable changes in the diversity of the gut microbiome, have also been demonstrated, but evidence for these effects is limited. Intermittent fasting is generally safe and does not result in energy level disturbances or increased disordered eating behaviors. In summary, intermittent fasting is a safe diet therapy that can produce clinically significant weight loss (>5%) and improve several markers of metabolic health in individuals with obesity.
The global human population has recently experienced an increase in life expectancy with a mounting concern about the steady rise in the incidence of age-associated chronic diseases and socio-economic burden. Calorie restriction (CR), the reduction of energy intake without malnutrition, is a dietary manipulation that can increase health and longevity in most model organisms. However, the practice of CR in day-to-day life is a challenging long-term goal for human intervention. Recently, daily fasting length and periodicity have emerged as potential drivers behind CR’s beneficial health effects. Numerous strategies and eating patterns have been successfully developed to recapitulate many of CR’s benefits without its austerity. These novel feeding protocols range from shortened meal timing designed to interact with our circadian system (e.g., daily time-restricted feeding) to more extended fasting regimens known as intermittent fasting. Here, we provide a glimpse of the current status of knowledge on different strategies to reap the benefits of CR on metabolic health in murine models and in humans, without the rigor of continuous reduction in caloric intake as presented at the USU State of the Science Symposium.
Intermittent and periodic fasting (IF and PF, respectively) are emerging as safe strategies to affect longevity and healthspan by acting on cellular aging and disease risk factors, while causing no or minor side effects. IF lasting from 12 to 48 hours and repeated every 1 to 7 days and PF lasting 2 to 7 days and repeated once per month or less have the potential to prevent and treat disease, but their effect on cellular aging and the molecular mechanisms involved are only beginning to be unraveled. Here, we describe the different fasting methods and their effect on longevity in organisms ranging from yeast to humans, linking them to the major nutrient-sensing signaling pathways and focusing on the benefits of the fasting and the refeeding periods. We also discuss both the therapeutic potential and side effects of IF and PF with a focus on cancer, autoimmunity, neurodegeneration and metabolic and cardiovascular disease.
Over the past 10 to 15 years, intermittent fasting has emerged as an unconventional approach to reduce body weight and improve metabolic health beyond simple calorie restriction. In this review, we summarize findings related to Ramadan and Sunnah fasting. We then discuss the role of caloric restriction not only as an intervention for weight control, but importantly, as a strategy for healthy aging and longevity. Finally, we review the four most common intermittent fasting (IF) strategies used to date for weight management and to improve cardiometabolic health. Weight loss is common after IF but does not appear to be different than daily caloric restriction when compared directly. IF may also provide additional cardiometabolic benefit, such as insulin sensitization, that is independent from weight loss. While no specific fasting regimen stands out as superior at this time, there is indeed heterogeneity in responses to these different IF diets. This suggests that one dietary regimen may not be ideally suited for every individual. Future studies should consider strategies for tailoring dietary prescriptions, including IF, based on advanced phenotyping and genotyping prior to diet initiation.
Intermittent fasting (IF) is a widely practiced dietary method that encompasses periodic restriction of food consumption. Due to its protective benefits against metabolic diseases, aging, and cardiovascular and neurodegenerative diseases, IF continues to gain attention as a preventative and therapeutic intervention to counteract these chronic diseases. Although numerous animal studies have reported positive health benefits of IF, its feasibility and efficacy in clinical settings remain controversial. Importantly, since dietary interventions such as IF have systemic effects, thoroughly investigating the tissue-specific changes in animal models is crucial to identify IF's mechanism and evaluate its potential adverse effects in humans. As such, we will review and compare the outcomes and underlying mechanisms of IF in both animal and human studies. Moreover, the limitations of IF and inconsistencies between preclinical and clinical studies will be discussed to provide insight into the gaps between translating research from bench to bedside.
Dietary patterns, such as the Dietary Approaches to Stop Hypertension and the Mediterranean diet, have been shown to improve cardiac health. Intermittent fasting is another type of popular dietary pattern that is based upon timed periods of fasting. Two different regimens are Alternative Day Fasting and Time-Restricted Eating. Although there are no large, randomized control trials examining the relationship between intermittent fasting and cardiovascular outcomes, current human studies that suggest this diet could reduce the risk for cardiovascular disease with improvement in weight control, hypertension, dyslipidemia and diabetes. Intermittent fasting may exert its effects through multiple pathways including reducing oxidative stress, optimization of circadian rhythms and ketogenesis. This review evaluates current literature regarding the potential cardiovascular benefits of intermittent fasting and proposes directions for future research.
Objective:
To examine the evidence for intermittent fasting (IF), an alternative to calorie-restricted diets, in treating obesity, an important health concern in Canada with few effective office-based treatment strategies.
Data sources:
A MEDLINE and EMBASE search from January 1, 2000, to July 1, 2019, yielded 1200 results using the key words fasting, time restricted feeding, meal skipping, alternate day fasting, intermittent fasting, and reduced meal frequency.
Study selection:
Forty-one articles describing 27 trials addressed weight loss in overweight and obese patients: 18 small randomized controlled trials (level I evidence) and 9 trials comparing weight after IF to baseline weight with no control group (level II evidence). Studies were often of short duration (2 to 26 weeks) with low enrolment (10 to 244 participants); 2 were of 1-year duration. Protocols varied, with only 5 studies including patients with type 2 diabetes.
Synthesis:
All 27 IF trials found weight loss of 0.8% to 13.0% of baseline weight with no serious adverse events. Twelve studies comparing IF to calorie restriction found equivalent results. The 5 studies that included patients with type 2 diabetes documented improved glycemic control.
Conclusion:
Intermittent fasting shows promise for the treatment of obesity. To date, the studies have been small and of short duration. Longer-term research is needed to understand the sustainable role IF can play in weight loss.
Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI. Systemic chronic inflammation increases with age and is linked to the development of several diseases, as presented in this Perspective.
The therapeutic use of ketone bodies (KB) against acute brain injury and neurodegenerative disorders has been lately suggested by many studies. Several mechanisms responsible for the protective action of KB have been described, including metabolic, anti-inflammatory and epigenetic. However, it is still not clear whether a specific mechanism of action can be associated with a particular neurological disorder. Different strategies to induce ketosis including the ketogenic diet (KD), caloric restriction (CR), intermittent fasting (IF), as well as the administration of medium chain triglycerides (MCTs), exogenous ketones or KB derivatives, have been used in animal models of brain injury and in humans. They have shown different degrees of success to prevent neuronal damage, motor alterations and cognitive decline. However, more investigation is needed in order to establish safe protocols for clinical application. Throughout the present review, we describe the different approaches that have been used to elevate blood KB and discuss their effectiveness considering their advantages and limitations, as tested in models of brain injury, neurodegeneration and clinical research. We also describe the mechanisms of action of KB in non-pathologic conditions and in association with their protective effect against neuronal damage in acute neurological disorders and neurodegenerative diseases.
Every organism must adapt and respond appropriately to the source of nutrients available in its environment. Different mechanisms and pathways are involved in detecting the intracellular and extracellular levels of macronutrients including amino acids. Detection of amino acids in food sources is provided by taste cells expressing T1R1 and T1R3 type receptors. Additionally, cells of the intestine, pancreas or heart sense amino acids extracellularly. Neuronal and hormonal regulation integrates and coordinates the signals at the organismal level. Amino acid-sensitive mechanisms including GCN2 protein, mTOR and LYNUS machinery adjust cellular process according to the availability of specific amino acids. Triggering these mechanisms by genetic manipulations or by external manipulations with diets has a significant impact on lifespan. In model organisms, the restriction of protein or specific amino acids within the diet leads to lifespan-extending effects. However, the translation of results from model organisms to application in humans has to take into account lifestyle, psychology, social aspects and the possibility to choose what to eat and how it is cooked.
