ArticleLiterature Review

Time restricted feeding for prevention and treatment of cardiometabolic disorders

March 2017
The Journal of Physiology 595(12)

Authors:

San Diego State University

The soaring prevalence of obesity and diabetes is associated with an increase in comorbidities, including elevated risk for cardiovascular diseases (CVD). CVDs continue to be among the leading causes of death and disability in the United States. While increased nutrition intake from an energy dense diet is known to disrupt metabolic homeostasis and contributes to the disease risk, circadian rhythm disruption is emerging as a new risk factor for CVD. Circadian rhythms coordinate cardiovascular health via temporal control of organismal metabolism and physiology. Thus, interventions that improve circadian rhythms are prospective entry points to mitigate cardiometabolic disease risk. Although light is a strong modulator of neural circadian clock, time of food intake is emerging as a dominant agent that affects circadian clocks in metabolic organs. We discovered that imposing a time-restricted feeding (TRF) regimen in which all caloric intakes occur within a consistent ≤12 h every day exerts many cardiometabolic benefits. TRF prevents excessive body weight gain, improves sleep, and attenuates age- and diet- induced deterioration in cardiac performance. Using an integrative approach that combines Drosophila melanogaster (fruit fly) genetics with transcriptome analyses it was found that the beneficial effects of TRF are mediated by circadian clock, ATP dependent TCP/TRiC/CCT chaperonin and mitochondrial-ETC components. Parallel studies in rodents have shown TRF reduces cardiometabolic disease risks by maintaining metabolic homeostasis. As modern humans continue to live under extended periods of wakefulness and ingestion events, daily eating pattern offers a new potential target for lifestyle intervention to reduce CVD risk. This article is protected by copyright. All rights reserved

Mitochondrial epigenetic modifications and nuclear-mitochondrial communication: A new dimension towards understanding and attenuating the pathogenesis in women with PCOS

Article

Full-text available

Jan 2023
REV ENDOCR METAB DIS

Mitochondrial DNA (mtDNA) epigenetic modifications have recently gained attention in a plethora of complex diseases, including polycystic ovary syndrome (PCOS), a common cause of infertility in women of reproductive age. Herein we discussed mtDNA epigenetic modifications and their impact on nuclear-mitochondrial interactions in general and the latest advances indicating the role of mtDNA methylation in the pathophysiology of PCOS. We highlighted epigenetic changes in nuclear-related mitochondrial genes, including nuclear transcription factors that regulate mitochondrial function and may be involved in the development of PCOS or its related traits. Additionally, therapies targeting mitochondrial epigenetics, including time-restricted eating (TRE), which has been shown to have beneficial effects by improving mitochondrial function and may be mediated by epigenetic modifications, have also been discussed. As PCOS has become a major metabolic disorder and a risk factor for obesity, cardiometabolic disorders, and diabetes, lifestyle/behavior intervention using TRE that reinforces feeding-fasting rhythms without reducing caloric intake may be a promising therapeutic strategy for attenuating the pathogenesis. Furthermore, future perspectives in the area of mitochondrial epigenetics are described.

Circadian‐mediated regulation of cardiometabolic disorders and aging with time‐restricted feeding

Article

Full-text available

Jan 2023

Circadian rhythms are present throughout biology, from the molecular level to complex behaviors such as eating and sleeping. They are driven by molecular clocks within cells, and different tissues can have unique rhythms. Circadian disruption can trigger obesity and other common metabolic disorders such as aging, diabetes, and cardiovascular disease, and circadian genes control metabolism. At an organismal level, feeding and fasting rhythms are key drivers of circadian rhythms. This underscores the bidirectional relationship between metabolism and circadian rhythms, and many metabolic disorders have circadian disruption or misalignment. Therefore, studying circadian rhythms may offer new avenues for understanding the etiology and management of obesity. This review describes how circadian rhythm dysregulation is linked with cardiometabolic disorders and how the lifestyle intervention of time‐restricted feeding (TRF) regulates them. TRF reinforces feeding‐fasting rhythms without reducing caloric intake and ameliorates metabolic disorders such as obesity and associated cardiac dysfunction, along with reducing inflammation. TRF optimizes the expression of genes and pathways related to normal metabolic function, linking metabolism with TRF's benefits and demonstrating the molecular link between metabolic disorders and circadian rhythms. Thus, TRF has tremendous therapeutic potential that could be easily adopted to reduce obesity‐linked dysfunction and cardiometabolic disorders.

A Time to Rest, A Time to Dine: Sleep, Time-Restricted Eating, and Cardiometabolic Health

Article

Full-text available

Jan 2022

Cardiovascular disease (CVD) poses a serious health and economic burden worldwide. Modifiable lifestyle factors are a focus of research into reducing the burden of CVD, with diet as one of the most investigated factors. Specifically, the timing and regularity of food intake is an emerging research area, with approaches such as time-restricted eating (TRE) receiving much attention. TRE involves shortening the time available to eat across the day and is associated with improved CVD outcomes compared with longer eating windows. However, studies that have examined TRE have not considered the impact of sleep on CVD outcomes despite recent evidence showing that sleep duration can influence the timing and amount of food eaten. In this article, we argue that as TRE and sleep influence each other, and influence the same cardiometabolic parameters, experiencing inadequate sleep may attenuate any positive impact TRE has on CVD. We examine the relationship between TRE and CVD, with sleep as a potential mediator in this relationship, and propose a research agenda to investigate this relationship. This will provide necessary evidence to inform future interventions aimed at reducing the burden of CVD.

Translation, adaptation and validation of the Chrononutrition Profile - Questionnaire (CP-Q) in Brazilian Portuguese

Article

Mar 2023
CHRONOBIOL INT

Chrononutrition is a science that studies the relationship between mealtimes and sleep/wake habits. However, these behaviors are not evaluated by a single questionnaire. Therefore, this study aimed to translate and culturally adapt the Chrononutrition Profile - Questionnaire (CP-Q) into Portuguese and validate the Brazilian version. The translation and cultural adaptation process consisted of: translation; synthesis of translations; backtranslation; expert committee and pre-test. The validation was performed with 635 participants (32.4 ± 11.2 years) who answered the CPQ-Brazil and Pittsburgh Sleep Quality Index (PSQI); Munich Chronotype Questionnaire (MCTQ); Night Eating questionnaire; Quality of life and health index (SF-36) and 24 h-recall. The participants were mostly female, single, from the northeastern region, a eutrophic profile, and average quality of life score of 55.8 ± 17.9. Moderate to strong correlations were observed in the sleep/wake schedules between CPQ-Brazil, PSQI and MCTQ, both for work/study days and free days. The correlations between largest meal, skipping breakfast, eating window, nocturnal latency, and last eating event with the same variables in the 24 h-recall showed moderate to strong positive correlations. The translation, adaptation, validation and reproducibility of the CP-Q generates a valid and reliable questionnaire to assess the sleep/wake and eating habits in the Brazilian population.

Intermittent Fasting as Possible Treatment for Heart Failure

Article

Jun 2022
CURR VASC PHARMACOL

Western-style diet often leads to food overconsumption, which triggers the development of comorbidities such as obesity, insulin resistance, hypercholesterolemia, hypertriglyceridemia, type 2 diabetes, and heart failure (HF). Several studies suggested that intermittent fasting (IF) protects against the development of those morbidities. This study presents evidence of the beneficial effects of IF on HF. Based on the current evidence, we discuss the potential molecular mechanisms by which IF works and where liver ketone bodies (KBs) play important roles. There is evidence that IF promotes a metabolic switch in highly metabolic organs, such as the heart, which increases the use of KBs during fasting. However, besides their role as energy substrates, KBs participate in the signaling pathways that control the expression of genes involved in oxidative stress protection and metabolism. Several molecular factors, such as adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor, fibroblast growth factor 21 (FGF21), sirtuins, and nuclear factor erythroid 2-related factor 2 (Nrf2) are involved. Furthermore, IF appears to maintain circadian rhythms, essential in highly metabolically active organs. Finally, we highlight the important research topics that need to be pursued to improve current knowledge and strengthen the potential of IF as a preventive and therapeutic approach to HF.

Time-Limited Eating and Continuous Glucose Monitoring in Adolescents with Obesity: A Pilot Study

Article

Full-text available

Oct 2021

Due to its simplicity, time-limited eating (TLE) may represent a more feasible approach for treating adolescents with obesity compared to other caloric restriction regimens. This pilot study examines the feasibility and safety of TLE combined with continuous glucose monitoring (CGM) in adolescents. Fifty adolescents with BMI ≥95th percentile were recruited to complete a 12-week study. All received standard nutritional counseling, wore a CGM daily, and were randomized to: (1) Prolonged eating window: 12 h eating/12 h fasting + blinded CGM; (2) TLE (8 h eating/16 h fasting, 5 days per week) + blinded CGM; (3) TLE + real-time CGM feedback. Recruitment, retention, and adherence were recorded as indicators of feasibility. Weight loss, dietary intake, physical activity, eating behaviors, and quality of life over the course of the intervention were explored as secondary outcomes. Forty-five participants completed the study (16.4 ± 1.3 years, 64% female, 49% Hispanic, 75% public insurance). There was high adherence to prescribed eating windows (TLE 5.2 d/wk [SD 1.1]; control 6.1 d/wk [SD 1.4]) and daily CGM wear (5.85 d/wk [SD 4.8]). Most of the adolescents (90%) assigned to TLE reported that limiting their eating window and wearing a CGM was feasible without negative impact on daily functioning or adverse events. There were no between-group difference in terms of weight loss, energy intake, quality of life, physical activity, or eating behaviors. TLE combined with CGM appears feasible and safe among adolescents with obesity. Further investigation in larger samples, with a longer intervention duration and follow-up assessments are needed.

Snack quality and snack timing are associated with cardiometabolic blood markers: the ZOE PREDICT study

Article

Full-text available

Sep 2023
EUR J NUTR

Background Snacking is a common diet behaviour which accounts for a large proportion of daily energy intake, making it a key determinant of diet quality. However, the relationship between snacking frequency, quality and timing with cardiometabolic health remains unclear. Design Demography, diet, health (fasting and postprandial cardiometabolic blood and anthropometrics markers) and stool metagenomics data were assessed in the UK PREDICT 1 cohort ( N = 1002) (NCT03479866). Snacks (foods or drinks consumed between main meals) were self-reported (weighed records) across 2–4 days. Average snacking frequency and quality [snack diet index (SDI)] were determined ( N = 854 after exclusions). Associations between snacking frequency, quality and timing with cardiometabolic blood and anthropometric markers were assessed using regression models (adjusted for age, sex, BMI, education, physical activity level and main meal quality). Results Participants were aged (mean, SD) 46.1 ± 11.9 years, had a mean BMI of 25.6 ± 4.88 kg/m ² and were predominantly female (73%). 95% of participants were snackers (≥ 1 snack/day; n = 813); mean daily snack intake was 2.28 snacks/day (24 ± 16% of daily calories; 203 ± 170 kcal); and 44% of participants were discordant for meal and snack quality. In snackers, overall snacking frequency and quantity of snack energy were not associated with cardiometabolic risk markers. However, lower snack quality (SDI range 1–11) was associated with higher blood markers, including elevated fasting triglycerides (TG (mmol/L) β ; – 0.02, P = 0.02), postprandial TGs (6hiAUC (mmol/L.s); β ; – 400, P = 0.01), fasting insulin (mIU/L) ( β ; – 0.15, P = 0.04), insulin resistance (HOMA-IR; β ; – 0.04, P = 0.04) and hunger (scale 0–100) ( β ; – 0.52, P = 0.02) ( P values non-significant after multiple testing adjustments). Late-evening snacking (≥ 9 pm; 31%) was associated with lower blood markers (HbA1c; 5.54 ± 0.42% vs 5.46 ± 0.28%, glucose 2hiAUC; 8212 ± 5559 vs 7321 ± 4928 mmol/L.s, P = 0.01 and TG 6hiAUC; 11,638 ± 8166 vs 9781 ± 6997 mmol/L.s, P = 0.01) compared to all other snacking times (HbA1c remained significant after multiple testing). Conclusion Snack quality and timing of consumption are simple diet features which may be targeted to improve diet quality, with potential health benefits. Clinical trial registry number and website NCT03479866, https://clinicaltrials.gov/ct2/show/NCT03479866?term=NCT03479866&draw=2&rank=1

Time-Restricted Feeding and Weight Loss in Obesity: A Mini Review on the Impacts on Skeletal Muscle Mass

Article

Full-text available

Aug 2023

Across the globe, obesity is a significant concern for public health, a disease characterized by excessive accumulation of body fat, with a negative impact on health. Time-restricted feeding (TRF), in which food accessibility is restricted to a variable period of 8–10 h, especially in the active phase, inducing a prolonged fasting period, is a strategy with potential effects in preventing obesity. Evidence in preclinical studies demonstrated that TRF attenuates the impacts of metabolic disturbances related to high-fat diet feeding in rodents. Through these discoveries, there has been growing interest in revealing the effects associated with TRF in preventing obesity and its comorbidities, as well as investigating its effects in humans. Although TRF is a promising alternative to reduce the impact of obesity, it is necessary to investigate the results on skeletal muscle tissue. Muscle tissue is important for body energy expenditure; however, caloric restriction can negatively impact protein turnover and induce loss of muscle mass, influencing the basal metabolic rate and weight loss. This mini review examined the scientific literature exploring the effects of time-restricted feeding (TRF) on muscle mass. Although still incipient, the findings related to TRF applied to obese individuals highlight the importance of carrying out dietary control, as well as the consumption and fractionation of proteins, to maintain a balanced protein turnover and, consequently, muscle mass.

Enhancing circadian rhythms—the circadian MEGA bundle as novel approach to treat critical illness

Article

Full-text available

Jun 2023

Circadian rhythms are essential to physiological homeostasis, but often disrupted in the intensive care unit (ICU) due to the absence of natural zeitgebers and exposure to treatments which affect circadian regulators. This is increasingly recognized as a contributor to morbidity and mortality across a variety of medical conditions including critical illness. Maintenance of circadian rhythms is particularly relevant to critically ill patients, who are restricted not only to the ICU environment but often bed bound. Circadian rhythms have been evaluated in several ICU studies, but effective therapies to maintain, restore, or amplify circadian rhythms have not been fully established yet. Circadian entrainment and circadian amplitude enhancement are integral to patients' overall health and well-being, and likely even more important during response to and recovery from critical illness. In fact, studies have shown that enhancing the amplitude of circadian cycles has significant beneficial effects on health and wellbeing. In this review, we discuss up-to-date literature on novel circadian mechanism that could not only restore but enhance circadian rhythms in critical illness by using a MEGA bundle consisting of intense light therapy each morning, cyclic nutrition support, timed physical therapy, nighttime melatonin administration, morning administration of circadian rhythm amplitude enhancers, cyclic temperature control and a nocturnal sleep hygiene bundle.

The impact of sleep quality, meal timing, and frequency on diet quality among remote learning university students during the COVID-19 pandemic

Article

Full-text available

Jun 2023

Our objective is to assess the relationship between meal timing, frequency, sleep quality, and diet quality (DQ) among university students engaged in remote learning during the COVID-19 pandemic. To achieve this, a cross-sectional study was conducted in April 2021. We employed a self-administered electronic questionnaire to gather data. Participants self-reported their anthropometric and sociodemographic information. Physical activity (PA) levels were evaluated using the International PA Questionnaire (IPAQ), while sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). DQ was determined using a short-form Food Frequency Questionnaire (FFQ), and the data were stratified into quartiles. A total of 311 students completed the questionnaire. Half of the participants (53.2%) exhibited a moderate DQ. Interestingly, female participants had a higher proportion of individuals with high DQ (22.5%) compared to males (9.8%). Conversely, males had a higher percentage of participants with moderate DQ (68.9%) compared to females (49.4%) (P=0.016). Participants with high DQ reported significantly more consistent meal timing, such as fixed meal times, waking up early, going to bed early, feeling hungry during breakfast and lunchtime, and having breakfast in the morning (P<0.001). Participants with low DQ reported moderate to low levels of PA and poor sleep quality (P<0.001). Our findings are consistent with relevant studies conducted in different regions of the world. In conclusion, remote learning during the COVID-19 pandemic has been associated with adverse changes in meal timing and frequency, as well as compromised sleep quality. Furthermore, it has been linked to a prevalence of moderate DQ among university students.

Automated evaluation of cardiac contractile dynamics and aging prediction using machine learning in a Drosophila model

Preprint

Full-text available

Feb 2023

The Drosophila model has proven tremendously powerful for understanding pathophysiological bases of several human disorders including aging and cardiovascular disease. Relevant high-speed imaging and high-throughput lab assays generate large volumes of high-resolution videos, necessitating next-generation methods for rapid analysis. We present a platform for deep learning-assisted segmentation applied to optical microscopy of Drosophila hearts and the first to quantify cardiac physiological parameters during aging. An experimental test dataset is used to validate a Drosophila aging model. We then use two novel methods to predict fly aging: deep-learning video classification and machine-learning classification via cardiac parameters. Both models suggest excellent performance, with an accuracy of 83.3% (AUC 0.90) and 77.1% (AUC 0.85), respectively. Furthermore, we report beat-level dynamics for predicting the prevalence of cardiac arrhythmia. The presented approaches can expedite future cardiac assays for modeling human diseases in Drosophila and can be extended to numerous animal/human cardiac assays under multiple conditions. Significance · Current analysis of Drosophila cardiac recordings is capable of limited cardiac physiological parameters and are error-prone and time-consuming. · We present the first deep-learning pipeline for high-fidelity automatic modeling of Drosophila contractile dynamics. · We present methods for automatically calculating all relevant parameters for diagnosing cardiac performance in aging model. · Using the machine and deep learning age-classification approach, we can predict aging hearts with an accuracy of 83.3% (AUC 0.90) and 77.1% (AUC 0.85), respectively.

Time-restricted feeding promotes muscle function through purine cycle and AMPK signaling in Drosophila obesity models

Article

Full-text available

Feb 2023

Obesity caused by genetic and environmental factors can lead to compromised skeletal muscle function. Time-restricted feeding (TRF) has been shown to prevent muscle function decline from obesogenic challenges; however, its mechanism remains unclear. Here we demonstrate that TRF upregulates genes involved in glycine production (Sardh and CG5955) and utilization (Gnmt), while Dgat2, involved in triglyceride synthesis is downregulated in Drosophila models of diet- and genetic-induced obesity. Muscle-specific knockdown of Gnmt, Sardh, and CG5955 lead to muscle dysfunction, ectopic lipid accumulation, and loss of TRF-mediated benefits, while knockdown of Dgat2 retains muscle function during aging and reduces ectopic lipid accumulation. Further analyses demonstrate that TRF upregulates the purine cycle in a diet-induced obesity model and AMPK signaling-associated pathways in a genetic-induced obesity model. Overall, our data suggest that TRF improves muscle function through modulations of common and distinct pathways under different obesogenic challenges and provides potential targets for obesity treatments.

The Effect of Diet on the Cardiac Circadian Clock in Mice: A Systematic Review

Article

Full-text available

Dec 2022

Circadian rhythms play important roles in regulating physiological and behavioral processes. These are adjusted by environmental cues, such as diet, which acts by synchronizing or attenuating the circadian rhythms of peripheral clocks, such as the liver, intestine, pancreas, white and brown adipose tissue, lungs, kidneys, as well as the heart. Some studies point to the influence of diet composition, feeding timing, and dietary restriction on metabolic homeostasis and circadian rhythms at various levels. Therefore, this systematic review aimed to discuss studies addressing the effect of diet on the heart clock in animal models and, additionally, the chronodisruption of the clock and its relation to the development of cardiovascular disorders in the last 15 years. A search was conducted in the PubMed, Scopus, and Embase databases. The PRISMA guide was used to construct the article. Nineteen studies met all inclusion and exclusion criteria. In summary, these studies have linked the circadian clock to cardiovascular health and suggested that maintaining a robust circadian system may reduce the risks of cardiometabolic and cardiovascular diseases. The effect of time-of-day-dependent eating on the modulation of circadian rhythms of the cardiac clock and energy homeostasis is notable, among its deleterious effects predominantly in the sleep (light) phase and/or at the end of the active phase.

Are We Ready to Implement Circadian Hygiene Interventions and Programs?

Article

Full-text available

Dec 2022
Int J Environ Res Publ Health

Circadian hygiene, a concept not to be confused with the notion of public or social hygiene, should be discussed among experts and society. Light–dark cycles and other possible synchronizers of the human circadian timing system affect ways of life, including sleeping, eating, working and physical activity. Some of these behaviors have also been investigated individually as synchronizers (e.g., eating times). Therefore, the knowledge held today about circadian rhythms, and their implications for health, allows future perspectives in this field to be mapped. The present article summarizes the latest knowledge on factors influencing circadian rhythms to discuss a perspective for the future of health promotion based on circadian hygiene. However, it is important to highlight that circadian hygiene is the product of an imbrication of individual and societal involvement. First, it is important to adopt practices and devise public health policies in line with circadian hygiene. Second, individual healthy habits require internal rhythms to be examined. Last, the research agenda on circadian hygiene can be developed on a public as well as individual level, raising the question as to how much society is willing to embrace this change.

Chrono-communication and cardiometabolic health: The intrinsic relationship and therapeutic nutritional promises

Article

Full-text available

Sep 2022

Circadian rhythm, an innate 24-h biological clock, regulates several mammalian physiological activities anticipating daily environmental variations and optimizing available energetic resources. The circadian machinery is a complex neuronal and endocrinological network primarily organized into a central clock, suprachiasmatic nucleus (SCN), and peripheral clocks. Several small molecules generate daily circadian fluctuations ensuring inter-organ communication and coordination between external stimuli, i.e., light, food, and exercise, and body metabolism. As an orchestra, this complex network can be out of tone. Circadian disruption is often associated with obesity development and, above all, with diabetes and cardiovascular disease onset. Moreover, accumulating data highlight a bidirectional relationship between circadian misalignment and cardiometabolic disease severity. Food intake abnormalities, especially timing and composition of meal, are crucial cause of circadian disruption, but evidence from preclinical and clinical studies has shown that food could represent a unique therapeutic approach to promote circadian resynchronization. In this review, we briefly summarize the structure of circadian system and discuss the role playing by different molecules [from leptin to ghrelin, incretins, fibroblast growth factor 21 (FGF-21), growth differentiation factor 15 (GDF15)] to guarantee circadian homeostasis. Based on the recent data, we discuss the innovative nutritional interventions aimed at circadian re-synchronization and, consequently, improvement of cardiometabolic health.

Tackling Atherosclerosis via Selected Nutrition

Article

Full-text available

Jul 2022
INT J MOL SCI

The development and pathogenesis of atherosclerosis are significantly influenced by lifestyle, particularly nutrition. The modern level of science and technology development promote personalized nutrition as an efficient preventive measure against atherosclerosis. In this survey, the factors were revealed that contribute to the formation of an individual approach to nutrition: genetic characteristics, the state of the microbiota of the gastrointestinal tract (GIT) and environmental factors (diets, bioactive components, cardioprotectors, etc.). In the course of the work, it was found that in order to analyze the predisposition to atherosclerosis associated with nutrition, genetic features affecting the metabolism of nutrients are significant. The genetic features include the presence of single nucleotide polymorphisms (SNP) of genes and epigenetic factors. The influence of telomere length on the pathogenesis of atherosclerosis and circadian rhythms was also considered. Relatively new is the study of the relationship between chrono-nutrition and the development of metabolic diseases. That is, to obtain the relationship between nutrition and atherosclerosis, a large number of genetic markers should be considered. In this relation, the question arises: “How many genetic features need to be analyzed in order to form a personalized diet for the consumer?” Basically, companies engaged in nutrigenetic research and choosing a diet for the prevention of a number of metabolic diseases use SNP analysis of genes that accounts for lipid metabolism, vitamins, the body’s antioxidant defense system, taste characteristics, etc. There is no set number of genetic markers. The main diets effective against the development of atherosclerosis were considered, and the most popular were the ketogenic, Mediterranean, and DASH-diets. The advantage of these diets is the content of foods with a low amount of carbohydrates, a high amount of vegetables, fruits and berries, as well as foods rich in antioxidants. However, due to the restrictions associated with climatic, geographical, material features, these diets are not available for a number of consumers. The way out is the use of functional products, dietary supplements. In this approach, the promising biologically active substances (BAS) that exhibit anti-atherosclerotic potential are: baicalin, resveratrol, curcumin, quercetin and other plant metabolites. Among the substances, those of animal origin are popular: squalene, coenzyme Q10, omega-3. For the prevention of atherosclerosis through personalized nutrition, it is necessary to analyze the genetic characteristics (SNP) associated with the metabolism of nutrients, to assess the state of the microbiota of the GIT. Based on the data obtained and food preferences, as well as the individual capabilities of the consumer, the optimal diet can be selected. It is topical to exclude nutrients of which their excess consumption stimulates the occurrence and pathogenesis of atherosclerosis and to enrich the diet with functional foods (FF), BAS containing the necessary anti-atherosclerotic, and stimulating microbiota of the GIT nutrients. Personalized nutrition is a topical preventive measure and there are a number of problems hindering the active use of this approach among consumers. The key factors include weak evidence of the influence of a number of genetic features, the high cost of the approach, and difficulties in the interpretation of the results. Eliminating these deficiencies will contribute to the maintenance of a healthy state of the population through nutrition.

Article

Full-text available

May 2022

The aim of the study was to investigate whether time-related eating patterns are associated with the daily intake of calories and macronutrients in Brazilian male military police officers (n = 81; 29-day and 52-night workers; mean age: 36.4 ± 0.9 and 38.5 ± 0.7 years, respectively). Energy and macronutrient intake were determined by a non-consecutive 3-day food recall. Time-related eating patterns, such as the time of the first and the last meals, eating duration, and caloric midpoint, were evaluated. Individuals were classified as “early” or “late” eaters according to the median caloric midpoint. Night shift workers showed a later eating time for the last meal (p < 0.001), longer eating duration (p < 0.001), and later caloric midpoint (p = 0.037) than day workers. Late eaters from both workgroups consumed more 24 h energy (p = 0.028), fat in calories (p = 0.006) and protein (calories: p < 0.001; percentage of total calories: p = 0.042), and less carbohydrates in calories (p = 0.010) intake than early eaters. The time of the first meal was negatively correlated with 24 h energy (p = 0.024) and carbohydrate (p = 0.031) intake only in day workers. The time of the last meal was positively correlated with 24 h energy (day workers: β = 0.352; p = 0.044; night workers: β = 0.424; p = 0.002) and protein (day workers: β = 0.451; p = 0.013; night workers: β = 0.536; p < 0.001) intake for both shift workers, and with carbohydrate (β = 0.346; p = 0.016) and fat (β = 0.286; p = 0.042) intake only in night workers. Eating duration was positively correlated with energy (day workers: β = 0.473; p = 0.004; night workers: β = 0.320; p = 0.023) and carbohydrate (day workers: β = 0.418; p = 0.011; night workers: β = 0.364; p = 0.010) intake in both groups. Thus, time-related eating patterns indicative of intake later at night are associated with increased daily energy and macronutrient intake.

Macrophage Meets the Circadian Clock: Implication of the Circadian Clock in the Role of Macrophages in Acute Lower Respiratory Tract Infection

Article

Full-text available

Feb 2022

The circadian rhythm is a biological system that creates daily variations of physiology and behavior with a 24-h cycle, which is precisely controlled by the molecular circadian clock. The circadian clock dominates temporal activity of physiological homeostasis at the molecular level, including endocrine secretion, metabolic, immune response, coupled with extrinsic environmental cues (e.g., light/dark cycles) and behavioral cues (e.g., sleep/wake cycles and feeding/fasting cycles). The other side of the clock is that the misaligned circadian rhythm contributes to the onset of a variety of diseases, such as cancer, metabolic diseases, and cardiovascular diseases, the acceleration of aging, and the development of systemic inflammation. The role played by macrophages is a key mediator between circadian disruption and systemic inflammation. At the molecular level, macrophage functions are under the direct control of the circadian clock, and thus the circadian misalignment remodels the phenotype of macrophages toward a 'killer' mode. Remarkably, the inflammatory macrophages induce systemic and chronic inflammation, leading to the development of inflammatory diseases and the dampened immune defensive machinery against infectious diseases such as COVID-19. Here, we discuss how the circadian clock regulates macrophage immune functions and provide the potential risk of misaligned circadian rhythms against inflammatory and infectious diseases.

Beneficial effects of time‐restricted feeding on gentamicin cytotoxicity in mouse cochlea and vestibular organs

Article

Full-text available

Feb 2022

Objective: Time restricted feeding (TRF), which is an intermittent fasting protocol, has been reported to decrease the toxicity and mortality rate associated with systemic gentamicin (GM) administration. The aim of this study is to evaluate the effect of TRF on GM-induced vestibular and auditory function in mice. Methods: Japan Central Laboratory for Experimental Animals:Institute of Cancer Research (Jcl:ICR) mice were housed in a light-dark (LD) cycle (12:12) and were divided into three groups: (1) GM treatment at a dose of 220 mg/kg with TRF (feeding time: 8 h [9:00-17:00] during the light phase [7:00-19:00]) (GM + TRF group), (2) GM treatment at a dose of 220 mg/kg without TRF (GM group), and (3) saline injection with TRF (NS + TRF group). GM or saline was injected subcutaneously for 18 days (three courses of 5 days' injection + 2 days' rest, and an additional 3 days' injection). The auditory brainstem response (ABR) and vestibular evoked potential (VsEP) were tested after the treatments. The number of sensory hair cells in the cochlear organs and the vestibular organs were quantified using microscopic images. Results: All animals survived until the end of the experiment. One day after the last injection, GM + TRF mice showed significantly lower ABR thresholds at 4 kHz compared to GM mice, and there was no significant difference between the GM + TRF and NS + TRF groups. There was a significant difference of VsEP between GM and GM + TRF mice only in symmetric parabolic waves with linear acceleration and ramps waveform stimulation. GM + TRF mice showed significantly less outer and inner hair cell loss compared to GM mice. GM + TRF mice showed significantly less type II hair cell loss in the utricle and the ampulla compared to GM mice. Conclusion: TRF with daytime feeding reduced GM cytotoxicity in the cochlea and vestibular organs of ICR mice. Level of evidence: NA.

Chronoradiobiology of Breast Cancer: The Time Is Now to Link Circadian Rhythm and Radiation Biology

Article

Full-text available

Jan 2022
INT J MOL SCI

Circadian disruption has been linked to cancer development, progression, and radiation response. Clinical evidence to date shows that circadian genetic variation and time of treatment affect radiation response and toxicity for women with breast cancer. At the molecular level, there is interplay between circadian clock regulators such as PER1, which mediates ATM and p53-mediated cell cycle gating and apoptosis. These molecular alterations may govern aggressive cancer phenotypes, outcomes, and radiation response. Exploiting the various circadian clock mechanisms may enhance the therapeutic index of radiation by decreasing toxicity, increasing disease control, and improving outcomes. We will review the body’s natural circadian rhythms and clock gene-regulation while exploring preclinical and clinical evidence that implicates chronobiological disruptions in the etiology of breast cancer. We will discuss radiobiological principles and the circadian regulation of DNA damage responses. Lastly, we will present potential rational therapeutic approaches that target circadian pathways to improve outcomes in breast cancer. Understanding the implications of optimal timing in cancer treatment and exploring ways to entrain circadian biology with light, diet, and chronobiological agents like melatonin may provide an avenue for enhancing the therapeutic index of radiotherapy.

Fasting-Mimicking-Diet does not reduce skeletal muscle function in healthy young adults: a randomized control trial

Article

Full-text available

Mar 2022
EUR J APPL PHYSIOL

Purpose The aim of this study was to evaluate the short- and long-term effects of the Fasting-Mimicking-Diet (FMD) intervention on neuromuscular parameters of force production in healthy young men. Methods Twenty-four physically active men completed the study. Participants were randomly assigned to Fasting-Mimicking (FMD) or Normal Diet (ND) and asked to follow three cycles of dietary intervention. Neuromuscular parameters of force production during maximal voluntary isometric contractions (MVCs) with the leg extensors muscles and anthropometrics were measured at baseline (T0), at the end of the first cycle (T1), and 7–10 days after the 3rd cycle of the nutritional intervention (T2). The study was registered on Clinicaltrials.gov (No. NCT04476615). Results There was a significant decrease in body mass at T1 for FMD (− 2.6 kg, ∆ from baseline, on average; p < 0.05) but not in ND (− 0.1 kg;). Neuromuscular parameters of force production, muscle volume, and MVC torque did not change or differ between groups across visits. Results were similar even when parameters were normalized by muscle volume. Conclusion The consumption of FMD in a group of young healthy male subjects showed to be feasible, and it did not affect neuromuscular parameters of force production. The results suggest that FMD could be safely adopted by strength athletes without detrimental effects on force and muscle volume. Further research in clinical population at risk of muscle mass loss, such as elderly and obese subjects with sarcopenia, is warranted.

Assessing temporal eating pattern in free living humans through the myCircadianClock app

Article

Jan 2022
INT J OBESITY

The quality and quantity of nutrition impact health. However, chrononutrition, the timing, and variation of food intake in relation to the daily sleep-wake cycle are also important contributors to health. This has necessitated an urgent need to measure, analyze, and optimize eating patterns to improve health and manage disease. While written food journals, questionnaires, and 24-hour dietary recalls are acceptable methods to assess the quantity and quality of energy consumption, they are insufficient to capture the timing and day-to-day variation of energy intake. Smartphone applications are novel methods for information-dense real-time food and beverage tracking. Despite the availability of thousands of commercial nutrient apps, they almost always ignore eating patterns, and the raw real-time data is not available to researchers for monitoring and intervening in eating patterns. Our lab developed a smartphone app called myCircadianClock (mCC) and associated software to enable long-term real-time logging that captures temporal components of eating patterns. The mCC app runs on iOS and android operating systems and can be used to track multiple cohorts in parallel studies. The logging burden is decreased by using a timestamped photo and annotation of the food/beverage being logged. Capturing temporal data of consumption in free-living individuals over weeks/months has provided new insights into diverse eating patterns in the real world. This review discusses (1) chrononutrition and the importance of understanding eating patterns, (2) the myCircadianClock app, (3) validation of the mCC app, (4) clinical trials to assess the timing of energy intake, and (5) strengths and limitations of the mCC app.

Chrononutrition in Cardiometabolic Health

Article

Full-text available

Jan 2022

In recent years, a healthy balanced diet together with weight reduction has risen to the forefront of minimizing the impact of cardiovascular disease. There is evidence that metabolic processes present circadian rhythmicity. Moreover, the timing of food consumption exerts a powerful influence on circadian rhythms. In this context, the subject of chrononutrition, described as the alignment of timing of food intake to the rhythms imposed by the circadian clock, has attracted considerable interest for possible beneficial effects on cardiovascular health. Current human studies suggest that chrononutrition-based dietary interventions could reduce the risk for cardiovascular disease by improving weight control, hypertension, dyslipidemia, and diabetes. However, meta-analysis of randomized control trials in this topic present varying and somehow conflicting results. Even the traditional association of breakfast skipping with adverse cardiovascular outcomes is nowadays controversial. Therefore, long-term and fairly consistent studies on the effect of chrononutrition on cardiovascular outcomes are needed. The purpose of this review is to provide concise evidence of the most recent literature involving the effects of chrononutrition and the specific chrononutrition-based dietary interventions, in particular time-restricted eating, on body weight and other cardiovascular disease risk factors.

A Low-Glucose Eating Pattern Improves Biomarkers of Postmenopausal Breast Cancer Risk: An Exploratory Secondary Analysis of a Randomized Feasibility Trial

Article

Full-text available

Dec 2021

Postmenopausal breast cancer is the most common obesity-related cancer death among women in the U.S. Insulin resistance, which worsens in the setting of obesity, is associated with higher breast cancer incidence and mortality. Maladaptive eating patterns driving insulin resistance represent a key modifiable risk factor for breast cancer. Emerging evidence suggests that time-restricted feeding paradigms (TRF) improve cancer-related metabolic risk factors; however, more flexible approaches could be more feasible and effective. In this exploratory, secondary analysis, we identified participants following a low-glucose eating pattern (LGEP), defined as consuming energy when glucose levels are at or below average fasting levels, as an alternative to TRF. Results show that following an LGEP regimen for at least 40% of reported eating events improves insulin resistance (HOMA-IR) and other cancer-related serum biomarkers. The magnitude of serum biomarkers changes observed here has previously been shown to favorably modulate benign breast tissue in women with overweight and obesity who are at risk for postmenopausal breast cancer. By comparison, the observed effects of LGEP were similar to results from previously published TRF studies in similar populations. These preliminary findings support further testing of LGEP as an alternative to TRF and a postmenopausal breast cancer prevention strategy. However, results should be interpreted with caution, given the exploratory nature of analyses.

Nutritional Neuroscience An International Journal on Nutrition, Diet and Nervous System Impact of Ramadan fasting on disease activity in patients with multiple sclerosis: a multicenter study Impact of Ramadan fasting on disease activity in patients with multiple sclerosis: a multicenter study

Article

Full-text available

Nov 2021

Changes in migraine characteristics over 30 days of Ramadan fasting: A prospective study

Article

Nov 2021

Impact of Ramadan fasting on disease activity in patients with multiple sclerosis: a multicenter study

Article

Full-text available

Nov 2021

Background The safety of Ramadan fasting for Muslim patients suffering from multiple sclerosis (MS) is still a matter of debate. This work aimed to study the clinical course of MS during Ramadan fasting and to clarify the predictors of relapses and symptoms exacerbation. Methods This retrospective study included 153 Muslim patients with MS. Data related to the disease course before Ramadan were obtained from patients' files, whereas data related to the disease activity during Ramadan, were collected from patients over the two months following Ramadan. Results Patients with MS who experienced relapses, exacerbation of symptoms and development of new symptoms during Ramadan had a statistically significant longer disease duration compared to those who did not experience (P < 0.001, <0.001, 0.01 respectively). Also, patients who experienced relapses, exacerbation of symptoms and development of new symptoms during Ramadan had a statistically significant higher expanded disability status scale (EDSS) compared to those who did not experience (P <0.001, <0.001,0.01, respectively). The occurrence of relapses, exacerbation of symptoms and development of new symptoms during Ramadan, were significantly higher in patients who experienced relapses in the preceding year compared to those who did not (P= 0.002, 0.002, 0.01, respectively). Binary logistic regression revealed that each score elevation of EDSS increased the odds of relapse during Ramadan by 1.02 (P-value = 0.04). Also, each month's increase in disease duration increased the odds of relapse during Ramadan by 1.87 (P-value = 0.046). Conclusion High EDSS and long disease duration are independent predictors of relapse during Ramadan.

Time-restricted feeding improves blood glucose and insulin sensitivity in overweight patients with type 2 diabetes: a randomised controlled trial

Article

Full-text available

Oct 2021
NUTR METAB

Background Time-restricted feeding is an emerging dietary intervention that is becoming increasingly popular. There are, however, no randomised clinical trials of time-restricted feeding in overweight patients with type 2 diabetes. Here, we explored the effects of time-restricted feeding on glycaemic regulation and weight changes in overweight patients with type 2 diabetes over 12 weeks. Methods Overweight adults with type 2 diabetes (n = 120) were randomised 1:1 to two diet groups: time-restricted feeding (n = 60) or control (n = 60). Sixty patients participated in a 10-h restricted feeding treatment program (ad libitum feeding from 8:00 to 18:00 h; fasting between 18:00 and 8:00 h) for 12 weeks. Results Haemoglobin A1c and body weight decreased in the time-restricted feeding group (− 1.54% ± 0.19 and − 2.98 ± 0.43 kg, respectively) relative to the control group over 12 weeks ( p < 0.001). Homeostatic model assessment of β-cell function and insulin resistance changed in the time-restricted feeding group (0.73 ± 0.21, p = 0.005; − 0.51 ± 0.08, p = 0.02, respectively) compared with the control group. The medication effect score, SF-12 score, and the levels of triglycerides, total cholesterol and low-density lipoprotein cholesterol were improved in the time-restricted feeding group (− 0.66 ± 0.17, p = 0.006; 5.92 ± 1.38, p < 0.001; − 0.23 ± 0.08 mmol/L, p = 0.03; − 0.32 ± 0.07 mmol/L, p = 0.01; − 0.42 ± 0.13 mmol/L, p = 0.02, respectively) relative to the control group. High-density lipoprotein cholesterol was not significantly different between the two groups. Conclusion These results suggest that 10-h restricted feeding improves blood glucose and insulin sensitivity, results in weight loss, reduces the necessary dosage of hypoglycaemic drugs and enhances quality of life. It can also offer cardiovascular benefits by reducing atherosclerotic lipid levels. Trial registration : This study was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-15006371).

Evaluating the beneficial effects of dietary restrictions: A framework for precision nutrigeroscience

Article

Sep 2021

Dietary restriction (DR) has long been viewed as the most robust nongenetic means to extend lifespan and healthspan. Many aging-associated mechanisms are nutrient responsive, but despite the ubiquitous functions of these pathways, the benefits of DR often vary among individuals and even among tissues within an individual, challenging the aging research field. Furthermore, it is often assumed that lifespan interventions like DR will also extend healthspan, which is thus often ignored in aging studies. In this review, we provide an overview of DR as an intervention and discuss the mechanisms by which it affects lifespan and various healthspan measures. We also review studies that demonstrate exceptions to the standing paradigm of DR being beneficial, thus raising new questions that future studies must address. We detail critical factors for the proposed field of precision nutrigeroscience, which would utilize individualized treatments and predict outcomes using biomarkers based on genotype, sex, tissue, and age.

ANÁLISE DO GERENCIAMENTO TECNOLÓGICO EM SAÚDE NOS CENTROS DE ESPECIALIDADES ODONTOLÓGICAS

Chapter

Full-text available

Sep 2021

ASPECTOS BIOFARMACÊUTICOS E DO CONTROLE DE QUALIDADE DE FORMAS FARMACÊUTICAS SÓLIDAS ORAIS CONTENDO FÁRMACOS ANTI-HIPERTENSIVOS E ANTIDIABÉTICOS

Chapter

Full-text available

Sep 2021

Time-restricted feeding promotes skeletal muscle function in diet- and genetic-induced obesity through shared and unique pathways

Preprint

Full-text available

Aug 2021

Obesity caused by genetic predisposition, a lifestyle of calorie-dense diets and/or circadian disruption can result in complications including metabolic syndrome, cardiovascular disease, and compromised muscle function. By employing time-restricted feeding (TRF), where daily feeding was limited to 12 hours during the day, we observed improved skeletal muscle function compared to ad libitum feeding (ALF). This was observed in both diet-induced obesity (DIO) and genetic-induced obesity (GIO) in a Drosophila melanogaster (fruit fly) model. We evaluated the mechanistic basis of TRF-mediated benefits by utilizing muscle transcriptomic data of indirect flight muscle (IFM) followed by genetic validations, cytological and biochemical evidences. Significant upregulation of glycine N methyltransferase (Gnmt), sarcosine dehydrogenase (Sardh), CG5955 and downregulation of diacylglycerol o-acyltransferase 2 (Dgat2) were commonly induced by TRF intervention under both obese conditions. Moreover, genetic inhibition of Gnmt, Sardh and CG5955 leads to skeletal muscle dysfunction, aberrant lipid accumulation and loss of TRF-mediated benefits. However, skeletal muscle-specific knockdown (KD) of Dgat2 retained muscle function during aging, a result that mimics TRF-mediated benefits. Furthermore, de novo purine biosynthesis appeared to be upregulated specifically in the DIO model under TRF which led to increased ATP levels resulting in improved muscle performance. Additionally, genes associated with AMP kinase (AMPK) signaling, glycogen metabolism, glycolysis, tricarboxylic acid (TCA) cycle and electron transport chain (ETC) signaling were specifically upregulated in GIO model under TRF. TRF mediated benefits in GIO via activation of AMPK, which led to increased ATP levels. Altogether, we identify the shared and distinct pathways in the regulation of muscle function under TRF, which may aid further research and alternative therapeutic avenues that focus on combating comorbidities linked with obesity.

The Impact of Circadian Timing on Energy Balance: An Extension of the Energy Balance Model

Article

Aug 2021

A significant proportion of the population is classified as having overweight or obesity. One framework which has attempted to explain biobehavioral mechanisms influencing the development of overweight and obesity is the energy balance model. According to this model, the body continually attempts to balance energy intake with energy expenditure. When energy intake and energy expenditure become imbalanced, there is an increase in homeostatic and allostatic pressure, generally to either increase energy intake or decrease energy expenditure, so as to restore energy homeostasis.Recent research has indicated that circadian aspects of energy intake and energy expenditure may influence energy balance. This paper provides a narrative review of existing evidence of the role of circadian timing on components of energy balance. Research on the timing of food intake, physical activity, and sleep indicates that unhealthy timing is likely to increase risk of weight gain. Public health guidelines focus on how much individuals eat and sleep, what foods are consumed, and the type and frequency of exercise, but the field of circadian science has begun to demonstrate that when these behaviors occur may also influence overweight and obesity prevention and treatment efforts.

Time-restricted feeding prevents metabolic diseases through the regulation of galanin/GALR1 expression in the hypothalamus of mice

Article

Full-text available

May 2022
EAT WEIGHT DISORD-ST

PurposeTime-restricted feeding (TRF) reverses obesity and insulin resistance, yet the central mechanisms underlying its beneficial effects are not fully understood. Recent studies suggest a critical role of hypothalamic galanin and its receptors in the regulation of energy balance. It is yet unclear whether TRF could regulate the expression of galanin and its receptors in the hypothalamus of mice fed a high-fat diet.Methods To test this effect, we subjected mice to either ad lib or TRF of a high-fat diet for 8 h per day. After 4 weeks, galanin and many neuropeptides associated with the function of metabolism were examined.ResultsThe present findings showed that mice under TRF consume equivalent calories from a high-fat diet as those with ad lib access, yet are protected against obesity and have improved glucose metabolism. Plasma galanin, orexin A, irisin and adropin levels were significantly reversed by TRF regimen. Besides, TRF regimen reversed the progression of metabolic disorders in mice by increasing GLUT4 and PGC-1α expression in skeletal muscles. Moreover, the levels of galanin and GALR1 expression were severely diminished in the hypothalamus of the TRF mice, whereas GALR2 was highly expressed.ConclusionsTRF diminished galanin and GALR1 expression, and increased GALR2 expression in the hypothalamus of mice fed a high-fat diet. The current studies provide additional evidence that TRF is effective in improving HFD-induced hyperglycemia and insulin resistance in mice, and this effect could be associated with TRF-induced changes of the galanin systems in the hypothalamus.Level of evidenceNo level of evidence, animal studies

Beneficial Effects of Early Time-Restricted Feeding on Metabolic Diseases: Importance of Aligning Food Habits with the Circadian Clock

Article

Full-text available

Apr 2021

The importance of metabolic health is a major societal concern due to the increasing prevalence of metabolic diseases such as obesity, diabetes, and various cardiovascular diseases. The circadian clock is clearly implicated in the development of these metabolic diseases. Indeed, it regulates physiological processes by hormone modulation, thus helping the body to perform them at the ideal time of day. Since the industrial revolution, the actions and rhythms of everyday life have been modified and are characterized by changes in sleep pattern, work schedules, and eating habits. These modifications have in turn lead to night shift, social jetlag, late-night eating, and meal skipping, a group of customs that causes circadian rhythm disruption and leads to an increase in metabolic risks. Intermittent fasting, especially the time-restricted eating, proposes a solution: restraining the feeding window from 6 to 10 h per day to match it with the circadian clock. This approach seems to improve metabolic health markers and could be a therapeutic solution to fight against metabolic diseases. This review summarizes the importance of matching life habits with circadian rhythms for metabolic health and assesses the advantages and limits of the application of time-restricted fasting with the objective of treating and preventing metabolic diseases.

OBESITY AND CIRCADIAN RHYTHM DISORDERS IN PATIENTS WITH PSORIASIS

Article

Full-text available

Mar 2021

Psoriasis is one of the most common dermatoses, which according to WHO world statistics affects from 2% to 4% of the world's population. The problem of psoriasis is quite relevant as it is associated with an increase in morbidity, chronic recurrence, an increase in the number of severe and disabling forms of dermatosis. Despite a large number of scientific studies, the aetiology and pathogenesis of this chronic dermatosis is still remaining unclear. Among the factors contributing to the development of psoriasis, psychosomatic disorders have been considered to play a significant role. Disruption of protective and adaptive mechanisms leads to structural and functional disorders at all levels, including the neuroendocrine and immune systems and this is regarded as the pathogenetic basis of psoriasis. Many individuals develop a hyperphagic way of responding to a stressful situation that is manifested by depression, anxiety, chronic stress, sleep disorders and changes in eating behaviour that in turn lead to weight gain and further development of obesity with a number of metabolic disorders and to changes in the circadian rhythm. The recent increase in comorbid psoriasis and obesity leading to severe, atypical, disabling, and treatment-resistant forms of dermatosis significantly impairs the quality of life of patients, reduces the efficiency and social activity of patients with psoriasis, therefore psoriasis is regarded as the social problem as well. Thus, further in-depth study of the relationship and pathogenesis of the comorbidity between psoriasis, obesity and circadian rhythm changes is promising and essential for the development of scientifically sound principles of early prevention and timely correction of comorbidities.

Circadian Rhythms and Time-Restricted Eating in Healthy Aging and Longevity

Chapter

Mar 2023

The circadian clock is a highly specialized biological oscillator that regulates rhythms of metabolic and endocrine pathways critical for the maintenance of homeodynamic state of the body. Circadian rhythms affect nearly all aspects of behavior and physiology such as cardiovascular activity, body temperature, sleep–wake cycle, endocrine regulation, hepatic metabolism, and gastro-intestinal tract physiology. With increasing age, these endogenous rhythms are however dampened, thereby compromising temporal coordination between circadian clock and physiology. Consuming food that is out of sync with these circadian rhythms results in metabolic desynchrony, potentially increasing the risk of chronic lifestyle diseases. Recent studies have provided evidence that age-associated decline in metabolic health can be slowed down by alignment of the daily eating time window (Time-restricted eating—TRE) with the circadian clock. TRE is a nutritional intervention in which food intake is restricted to a 4–12 h time period without compromising on diet quality and quantity. Several preclinical and clinical studies have reported that TRE improves glucose tolerance, cardiometabolic and gut health, increase metabolic flexibility, reduce body weight, blood pressure, and atherogenic lipids. Since the biological clock regulates energy metabolism involving metabolic proteins as the key underlying factors, therefore, it is important to understand the role of circadian regulation over metabolism for maintaining health. Several human pilot studies have reported this regulation as a novel therapeutic/interventional strategy. This chapter will review the available data of experimental animals and human studies on the impact of meal timings and circadian rhythms in promoting healthy aging and longevity.

Lack of Compensation of Energy Intake Explains the Success of Alternate Day Feeding to Produce Weight Loss

Article

Feb 2023
PHYSIOL BEHAV

Background and aims: This study was designed to obtain daily weighed food intake of participants engaged in Alternate Day Feeding (ADF). Prior ADF studies have used self-reported food intake, a method that has received criticism for its limited accuracy. Subjects and methods: Forty-nine university students received academic credit for participating in the study. Following a 10-day baseline period, participants underwent ADF for the next 8 days. Restricted daily intake to ∼ 75% of baseline food intake levels was followed by ad libitum intake on alternate days. Food intake was weighed before and after each meal. Daily body weight was also tracked. Intervention: After the baseline period, participants underwent 8 days of ADF during which they consumed ∼ 75% of baseline energy intake by weight followed by ad libitum intake on alternate days. The trial concluded with 2 additional days of ad libitum feeding, for a total study duration of 10 days. Results: Daily food intake was constant during the baseline period (slope = -0.93 g/d, p = 0.56), and did not differ significantly (995 g ( 95% CI [752, 1198]) from the total consumed on ad libitum ADF days (951 g (95% CI [777, 1227]). Intake on ad libitum days did not show a trend to increase during the intervention. Body weight declined significantly during ADF. Conclusions: ADF produces significant weight loss because food intake does not increase on ad libitum feeding days to compensate for reduced intake on restricted energy days. Data are consistent with prior work that suggests humans do not fully compensate for imposed deficits in energy intake.

Molecular mechanisms underlying the beneficial effects of exercise and dietary interventions in the prevention of cardiometabolic diseases

Article

Dec 2022
J CARDIOVASC MED

Cardiometabolic diseases still represent a major cause of mortality worldwide. In addition to pharmacological approaches, lifestyle interventions can also be adopted for the prevention of these morbid conditions. Lifestyle changes include exercise and dietary restriction protocols, such as calorie restriction and intermittent fasting, which were shown to delay cardiovascular ageing and elicit health-promoting effects in preclinical models of cardiometabolic diseases. Beneficial effects are mediated by the restoration of multiple molecular mechanisms in heart and vessels that are compromised by metabolic stress. Exercise and dietary restriction rescue mitochondrial dysfunction, oxidative stress and inflammation. They also improve autophagy. The result of these effects is a marked improvement of vascular and heart function. In this review, we provide a comprehensive overview of the molecular mechanisms involved in the beneficial effects of exercise and dietary restriction in models of diabetes and obesity. We also discuss clinical studies and gap in animal-to-human translation.

Validation of the Self-Rating of Biological Rhythm Disorder for Adolescents (SBRDA) Scale by Dim Light Melatonin Onset in Healthy Young Adults

Article

Jan 2023

Understanding the biological rhythms that influence young adult health is vital because the combination of biological changes and a circadian phase delay lead to young adults being at high risk of circadian misalignment. We have previously established a self-rating of biological rhythm disorder for adolescents (SBRDA). However, we did not externally validate the SBRDA against objective measures of biological rhythms such as dim light melatonin onset (DLMO)—the gold standard of the endogenous circadian phase. The purpose of this study was to verify the effectiveness of SBRDA in identifying individuals with biological rhythm disorders. Our participants were 42 (47.2%) boys and 47 (52.8%) girls with an average age of 18.5 ± 1.2 years. Saliva samples were collected from 4 h before bed time to 2 h after sleep every 60 min in a dim-light (<50 lx) laboratory environment. Biological rhythm parameters were assessed using questionnaires, including SBRDA, MEQ, and MCTQ. The mean DLMO time (h) was 22.2 ± 1.9. The DLMO correlated significantly with the SBRDA score ( r = 0.33, p < 0.001), MEQ score ( r = -0.24, p < 0.05), and MSFsc ( r = 0.26, p < 0.05). ROC curve analysis showed that SBRDA was of diagnostic value for biological rhythm disorder ( p < 0.05). Our observations demonstrate that SBRDA, which is consistent with MEQ and MCTQ, can be used to reflect endogenous circadian rhythm disorders in young adults. Exposure to dim light may activate melatonin secretion and lead to an earlier peak in young adults with biological rhythm disorder.

Atmosferik Basınç Soğuk Plazmanın Medikal Alanda Kullanılması

Book

Full-text available

Dec 2022

https://iksadyayinevi.com/wp-content/uploads/2022/12/TEMEL-TIP-BILIMLERINDE-MULTIDISIPLINER-BAKIS-1.pdf

Calorie Restriction with or without Time-Restricted Eating in Weight Loss

Article

Jul 2022
NEW ENGL J MED

Different Exposure Metrics of Rotating Night-Shift Work and Serum Lipid Profiles Among Steelworkers: A Cross-Sectional Survey in North China

Article

Jun 2022

Objectives: To examine the association and potential mediators between rotating night shift work and serum lipid profiles in Chinese steelworkers. Methods: Different exposure metrics of night shifts collected through face-to-face personal interviews. Serum lipid profiles were measured using an automatic biochemical analyzer. Generalized linear models and mediation analyses were used to analyze the main associations. Results: Compared with day workers, the total cholesterol level in night shift workers increased in those with 13-20 years of night shifts and in those with ≥4 nights/month average frequency of night shifts. The association between the duration of night shifts and the total cholesterol level was mediated by systolic and diastolic blood pressure and BMI. Conclusions: Rotating night shift work for 13-20 years was associated with an increase in the total cholesterol levels in steelworkers, and blood pressure and BMI may be involved in the causal pathway.

EVENING CHRONOTYPE AS A RISK FACTOR FOR UNHEALTHY BEHAVIOR AND SOCIAL JETLAG

Article

Dec 2021

Рreference for later bedtimes and rise times characterize evening chronotypes. Evening chronotypes suffer from early work start times thereby contradicting their circadian rhythms, as a result, a late wake-up time on free days reflect an attempt to compensate for a sleep debt accumulated on work days. This leads to a misalignment in sleep timing between weekdays and weekends, known as social jetlag (SJL), which is associated with increased health risk. Here we analyze the risks that evening preferences related with SJL bear and their potential impact on health, and also talk about possible correction measures, primarily of a behavioral nature, using literature data from PubMed and Embase database. Evening chronotype can compromise the maintenance of a healthy lifestyle. Evening chronotypes are more prone to bedtime screen use, which can suppress melatonin rise and extend wakefulness activities far into the night, thus dragging sleep and meal timing to later periods. Preference towards later time-of-day is linked with higher intake of total calories and fats, as well as unhealthy dietary habits (breakfast skipping, snacking, longer eating duration). Evening chronotype also has been associated with high caffeinated drinks intake, alcohol consumption and smoking, low physical activities. It has been found that unhealthy behavior might function as the promoting factors to circadian misalignment and greater SJL. Interventions to prevent and control unhealthy behaviors among evening types should be included in preventive measures of SJL.

Association between rotating night shift work and carotid atherosclerosis among Chinese steelworkers: a cross-sectional survey

Article

Feb 2022

This study aimed to examine the association between rotating night shift work and carotid atherosclerosis in Chinese steelworkers. A total of 3582 subjects were included in this study. Different exposure metrics of night shifts, including current shift status, duration of night shifts (years), the cumulative number of night shifts (nights), cumulative length of night shifts (hours) and average frequency of night shifts (nights/month), were used to examine the relationship between night shift work and carotid atherosclerosis, including carotid plaque and carotid plaque scores. The prevalence of carotid plaque was 29.9% in the study population. Compared with day workers, significantly increased odds of carotid plaque were observed among shift workers in each quartile of the duration of night shifts after adjusting for potential confounders, especially in the third and fourth quartiles: odds ratio (OR) = 1.91, 95% confidence interval (CI): 1.46 to 2.49, in the third quartiles; OR = 1.69, 95% CI: 1.30 to 2.20, in the fourth quartiles. Positive associations of different exposure metrics of night shifts (continuous) with the odds of carotid plaque and the carotid plaque score were observed in the restricted cubic spline (RCS) models. No significant association was found in female workers between night shift work and carotid plaque. Rotating night shift work is associated with elevated odds of carotid atherosclerosis in male steelworkers.

Association of prolonged nightly fasting with cardiovascular, renal, inflammation, and nutritional status biomarkers in community-dwelling older adults

Article

Jan 2022
AM J CLIN NUTR

Background: Prolonged fasting, as a dietary strategy, has been linked to metabolic benefits; however, data corresponded to very small samples of young participants in controlled environments, a few cardiovascular risk markers, and for short periods of time. Objectives: To assess the association of habitual prolonged nightly fasting with a wide array of cardiovascular, renal, inflammation, and nutritional status biomarkers among community-dwelling older adults. Methods: Cross-sectional analysis of data from 1047 adults ≥ 65 years from the Seniors Study on Nutrition and Cardiovascular Risk in Spain 2 (Seniors-ENRICA-2) cohort. Habitual diet was assessed through a validated diet history. Fasting time was classified into the following categories: <10, 10 to < 12, and ≥ 12 hours/day, the latter being considered prolonged nightly fasting. Adjusted geometric means of biomarkers concentrations in blood and serum were estimated using linear regression models, by categories of fasting time. Main confounders included overall diet quality, defined as adherence to a Mediterranean diet score, and body mass index. Results: Longer fasting time was associated with: lower concentration of high-density lipoprotein cholesterol (HDL-c) (difference between the longest and shortest fasting category: -2.94 mg/dL; 95% confidence interval: -4.80, -1.09; p-trend: 0.01); higher potassium levels (0.11 mEq/L; 0.03, 0.19; p-trend: 0.01); and lower concentration of chloride (-0.50 mEq/L; -0.91, -0.09; p-trend: 0.03). These results were slightly attenuated after additional adjustment for body mass index. Conclusions: Habitual prolonged nightly fasting did not show beneficial associations with the examined biomarkers. By contrast, some modest detrimental associations were found suggesting that extended periods of time between meals may not be beneficial for older adults. Clinical Trial Registry: ClinicalTrials.gov NCT03541135.

Tuning up an aged clock: Circadian clock regulation in metabolism and aging

Article

Dec 2021

Circadian rhythms provide temporal variation of a broad range of behavioral and physiological functions, which is precisely controlled by the internal molecular gear, the circadian clock. However, circadian clock functions decline concomitantly with aging-dependent functional deterioration, such as metabolic dysfunction. Metabolic deterioration is widely accepted as one of the hallmarks of aging and leads to various types of aging-associated diseases, such as type 2 diabetes, cardiovascular disease, cancer, and Alzheimer's disease. Importantly, recent transcriptomic, epigenomic, proteomic, and metabolomic data indicates that the circadian clock governs daily fluctuation of metabolic activity and in turn is functionally reliant on metabolic and epigenetic modifications. This suggests that the activation of the circadian clock defends organisms from metabolic aging, eventually resulting in systemic healthy aging. This notion is strongly supported by mounting evidence indicating that dietary interventions robustly affect the circadian clock machinery and subsequent clock-controlled metabolic pathways. In the 21st century, the expansion of an aged population is one of the most important health problem worldwide, making a strategy to promote healthy aging critical. In this review, we summarize the latest evidence regarding an intertwined link between aging and the circadian clock, and propose potential anti-aging therapies centered on the circadian clock.

Development and validation of the self-rating of biological rhythm disorder for Chinese adolescents

Article

Oct 2021
CHRONOBIOL INT

Modern lifestyles, and the popularization of artificial light at night, have led to maladjusted social time and internal circadian rhythm, so developing an instrument on biological rhythms is critical. A 36-item self-rated questionnaire assessing biological rhythm disorder in adolescents was developed according to the literature and expert evaluations. Based on a literature review, four dimensions, digital media use, sleep, eating habits, and activity, were determined. After preliminary item analysis, seven unqualified items were eliminated. A total of 1,152 college students and 8,082 middle school students were selected. Two independent sample t-tests, the Pearson correlations, and confirmatory factor analysis, were used to evaluate the reliability and validity of the questionnaire. The final questionnaire consisted of 4 dimensions covering 29 items, and the variance cumulative contribution was 62.65%. Cronbach's α for the total questionnaire was 0.950 and ranged from 0.817 to 0.904 for each dimension. The Pearson correlation coefficients between each item and the total score ranged from 0.360 to 0.755, and the Pearson correlation coefficient between each item and its dimension was between 0.575 and 0.841. Confirmatory factor analysis showed that the indices of CFI, TLI and RMSEA were 0.911, 0.901 and 0.043, respectively, which is a good degree of fit. The self-rating scale is consistent with the evaluation standard of psychometrics and can be used to evaluate the degree of biological rhythm disorder in adolescents.

Circadian regulation of cardiac muscle function and protein degradation

Article

Sep 2021

Seung-Hee Yoo

The circadian clock plays a fundamental role in physiology. In particular, the heart is a target organ where the clock orchestrates various aspects of cardiac function. At the molecular level, the clock machinery governs daily rhythms of gene expression. Such circadian regulation is in tune with the dynamic nature of heart structure and function, and provides the foundation for chronotherapeutic applications in cardiovascular diseases. In comparison, a regulatory role of the clock in cardiac protein degradation is poorly documented. Sarcomere is the structural and functional unit responsible for cardiac muscle contraction, and sarcomere components are closely regulated by protein folding and proteolysis. Emerging evidence supports a role of the circadian clock in governing sarcomere integrity and function. Particularly, recent studies uncovered a circadian regulation of a core sarcomere component TCAP. It is possible that circadian regulation of the cardiac muscle protein turnover is a key regulatory mechanism underlying cardiac remodeling in response to physiological and environmental stimuli. While the detailed regulatory mechanisms and the molecular links to cardiac (patho)physiology remain to be further studied, therapeutic strategies targeting circadian control in the heart may markedly enhance intervention outcomes against cardiovascular disease.

Continuous energy restriction (CER) plus 16/8 time-restricted feeding improve body composition and metabolic parameters in overweight and obese, but no more than CER alone

Article

Full-text available

May 2021

BACKGROUND: Current guidelines recommend continuous energy restriction (CER) and lifestyle change as the basis of obesity treatment. Recently, several intermittent fasting protocols have received considerable interest as an alternative weight loss strategy. OBJECTIVE: This study compared the effects of 8-week CER versus CER along with 16/8 time-restricted feeding (16/8 TRF) on body composition and metabolic markers in excess weight physically active subjects. METHODS: Twenty-four physically active obese or overweight adults, from both genders, were split into two groups: CER plus 16/8 TRF (CER + TRF) and CER. Both groups consumed a 20%energy restriction diet. CER plus 16/8 TRF were asked to consume their meals during an 8-hour open window (12 to 20 pm). We evaluated body composition and metabolic biomarkers before and after the intervention. RESULTS: We observed a reduction in body weight (BW), body mass index (BMI), waist circumference (WC), and fat mass (FM) in both groups. However, a decrease in fat-free mass (FFM) and skeletal muscle mass (SMM) was seen only in the CER. Although fasting glucose did not change, we observed a decrease in fasting insulin and HOMA-IR in both groups. Leptin decrease in both treatments. Cortisol levels increased only in the CER group. CONCLUSIONS: We can conclude that CER + TRF is as effective as CER to promote weight and fat loss, but, CER + TRF seems to be more efficient in maintaining lean body mass.

Impact of Intermittent Fasting on Health and Disease Processes

Article

Full-text available

Oct 2016

Humans in modern societies typically consume food at least three times daily, while laboratory animals are fed ad libitum. Overconsumption of food with such eating patterns often leads to metabolic morbidities (insulin resistance, excessive accumulation of visceral fat, etc.), particularly when associated with a sedentary lifestyle. Because animals, including humans, evolved in environments where food was relatively scarce, they developed numerous adaptations that enabled them to function at a high level, both physically and cognitively, when in a food-deprived/fasted state. Intermittent fasting (IF) encompasses eating patterns in which individuals go extended time periods (e.g., 16–48 hours) with little or no energy intake, with intervening periods of normal food intake, on a recurring basis. We use the term periodic fasting (PF) to refer to IF with periods of fasting or fasting mimicking diets lasting from 2 to as many as 21 or more days. In laboratory rats and mice IF and PF have profound beneficial effects on many different indices of health and, importantly, can counteract disease processes and improve functional outcome in experimental models of a wide range of age-related disorders including diabetes, cardiovascular disease, cancers and neurological disorders such as Alzheimer’s disease Parkinson’s disease and stroke. Studies of IF (e.g., 60% energy restriction on 2 days per week or every other day), PF (e.g., a 5 day diet providing 750–1100 kcal) and time-restricted feeding (TRF; limiting the daily period of food intake to 8 hours or less) in normal and overweight human subjects have demonstrated efficacy for weight loss and improvements in multiple health indicators including insulin resistance and reductions in risk factors for cardiovascular disease. The cellular and molecular mechanisms by which IF improves health and counteracts disease processes involve activation of adaptive cellular stress response signaling pathways that enhance mitochondrial health, DNA repair and autophagy. PF also promotes stem cell-based regeneration as well as long-lasting metabolic effects. Randomized controlled clinical trials of IF versus PF and isoenergetic continuous energy restriction in human subjects will be required to establish the efficacy of IF in improving general health, and preventing and managing major diseases of aging.

The circadian coordination of cell biology

Article

Full-text available

Oct 2016
J CELL BIOL

Circadian clocks are cell-autonomous timing mechanisms that organize cell functions in a 24-h periodicity. In mammals, the main circadian oscillator consists of transcription-translation feedback loops composed of transcriptional regulators, enzymes, and scaffolds that generate and sustain daily oscillations of their own transcript and protein levels. The clock components and their targets impart rhythmic functions to many gene products through transcriptional, posttranscriptional, translational, and posttranslational mechanisms. This, in turn, temporally coordinates many signaling pathways, metabolic activity, organelles' structure and functions, as well as the cell cycle and the tissue-specific functions of differentiated cells. When the functions of these circadian oscillators are disrupted by age, environment, or genetic mutation, the temporal coordination of cellular functions is lost, reducing organismal health and fitness.

Molecular modulators of the circadian clock: lessons from flies and mice

Article

Full-text available

Mar 2017
CELL MOL LIFE SCI

Circadian timekeeping is a ubiquitous mechanism that enables organisms to maintain temporal coordination between internal biological processes and time of the local environment. The molecular basis of circadian rhythms lies in a set of transcription–translation feedback loops (TTFLs) that drives the rhythmic transcription of core clock genes, whose level and phase of expression serve as the marker of circadian time. However, it has become increasingly evident that additional regulatory mechanisms impinge upon the TTFLs to govern the properties and behavior of the circadian clock. Such mechanisms include changes in chromatin architecture, interactions with other transcription factor networks, post-transcriptional control by RNA modifications, alternative splicing and microRNAs, and post-translational regulation of subcellular trafficking and protein degradation. In this review, we will summarize the current knowledge of circadian clock regulation—from transcriptional to post-translational—drawing from literature pertaining to the Drosophila and murine circadian systems.

Sleep Duration and Diabetes Risk: Population Trends and Potential Mechanisms

Article

Full-text available

Sep 2016
Curr Diabetes Rep

Sleep is important for regulating many physiologic functions that relate to metabolism. Because of this, there is substantial evidence to suggest that sleep habits and sleep disorders are related to diabetes risk. In specific, insufficient sleep duration and/or sleep restriction in the laboratory, poor sleep quality, and sleep disorders such as insomnia and sleep apnea have all been associated with diabetes risk. This research spans epidemiologic and laboratory studies. Both physiologic mechanisms such as insulin resistance, decreased leptin, and increased ghrelin and inflammation and behavioral mechanisms such as increased food intake, impaired decision-making, and increased likelihood of other behavioral risk factors such as smoking, sedentary behavior, and alcohol use predispose to both diabetes and obesity, which itself is an important diabetes risk factor. This review describes the evidence linking sleep and diabetes risk at the population and laboratory levels.

Time-restricted feeding reduces adiposity in mice fed a high-fat diet

Article

Full-text available

Feb 2016
NUTR RES

Circadian misalignment increases cardiovascular disease risk factors in humans

Article

Full-text available

Feb 2016

Significance Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease, even after controlling for traditional risk factors. Shift workers frequently undergo circadian misalignment (i.e., misalignment between the endogenous circadian system and 24-h environmental/behavioral cycles). This misalignment has been proposed to explain, in part, why shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. However, the impact of circadian misalignment per se on 24-h blood pressure and inflammatory markers is poorly understood. We show—under highly controlled laboratory conditions—that short-term circadian misalignment increases 24-h blood pressure and inflammatory markers in healthy adults. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk.

Morning and evening peaks of activity rely on different clock neurons of the Drosophila brain

Article

Full-text available

Nov 2004

A brain clock controls daily rhythms of locomotor activity in Drosophila. It relies on several groups of neurons expressing the period gene, including the PDF-positive ventral lateral neurons (LNv) and the PDF-negative dorsal lateral neurons (LNd). In natural day-night conditions, adult flies exhibit morning and evening peaks of activity. The contribution of the different clock neurons to the rest-activity pattern remains unknown. We have used targeted expression of Per to restore the clock function of specific subsets of lateral neurons in arrhythmic per0 mutants. We show that Per expression restricted to the LNv restores the morning activity only, whereas Per in both the LNv and LNd also restores the evening activity. This provides the first neuronal bases for “morning” and “evening” oscillators in the Drosophila brain. In addition, we show that the LNv alone can generate 24h activity rhythms in constant darkness, indicating that the “morning” oscillator is sufficient to drive the circadian system.

Circadian Rhythms, the Molecular Clock, and Skeletal Muscle

Article

Full-text available

Dec 2014

Circadian rhythms are the approximate 24-h biological cycles that function to prepare an organism for daily environmental changes. They are driven by the molecular clock, a transcriptional:translational feedback mechanism that in mammals involves the core clock genes Bmal1, Clock, Per1/2, and Cry1/2. The molecular clock is present in virtually all cells of an organism. The central clock in the suprachiasmatic nucleus (SCN) has been well studied, but the clocks in the peripheral tissues, such as heart and skeletal muscle, have just begun to be investigated. Skeletal muscle is one of the largest organs in the body, comprising approximately 45% of total body mass. More than 2300 genes in skeletal muscle are expressed in a circadian pattern, and these genes participate in a wide range of functions, including myogenesis, transcription, and metabolism. The circadian rhythms of skeletal muscle can be entrained both indirectly through light input to the SCN and directly through time of feeding and activity. It is critical for the skeletal muscle molecular clock not only to be entrained to the environment but also to be in synchrony with rhythms of other tissues. When circadian rhythms are disrupted, the observed effects on skeletal muscle include fiber-type shifts, altered sarcomeric structure, reduced mitochondrial respiration, and impaired muscle function. Furthermore, there are detrimental effects on metabolic health, including impaired glucose tolerance and insulin sensitivity, which skeletal muscle likely contributes to considering it is a key metabolic tissue. These data indicate a critical role for skeletal muscle circadian rhythms for both muscle and systems health. Future research is needed to determine the mechanisms of molecular clock function in skeletal muscle, identify the means by which skeletal muscle entrainment occurs, and provide a stringent comparison of circadian gene expression across the diverse tissue system of skeletal muscle. © 2014 The Author(s).

Time-Restricted Feeding Is a Preventative and Therapeutic Intervention against Diverse Nutritional Challenges

Article

Full-text available

Dec 2014
CELL METAB

Because current therapeutics for obesity are limited and only offer modest improvements, novel interventions are needed. Preventing obesity with time-restricted feeding (TRF; 8-9 hr food access in the active phase) is promising, yet its therapeutic applicability against preexisting obesity, diverse dietary conditions, and less stringent eating patterns is unknown. Here we tested TRF in mice under diverse nutritional challenges. We show that TRF attenuated metabolic diseases arising from a variety of obesogenic diets, and that benefits were proportional to the fasting duration. Furthermore, protective effects were maintained even when TRF was temporarily interrupted by ad libitum access to food during weekends, a regimen particularly relevant to human lifestyle. Finally, TRF stabilized and reversed the progression of metabolic diseases in mice with preexisting obesity and type II diabetes. We establish clinically relevant parameters of TRF for preventing and treating obesity and metabolic disorders, including type II diabetes, hepatic steatosis, and hypercholesterolemia. Copyright © 2014 Elsevier Inc. All rights reserved.

Huntington's Disease Induced Cardiac Amyloidosis Is Reversed by Modulating Protein Folding and Oxidative Stress Pathways in the Drosophila Heart

Article

Full-text available

Dec 2013
PLOS GENET

Amyloid-like inclusions have been associated with Huntington's disease (HD), which is caused by expanded polyglutamine repeats in the Huntingtin protein. HD patients exhibit a high incidence of cardiovascular events, presumably as a result of accumulation of toxic amyloid-like inclusions. We have generated a Drosophila model of cardiac amyloidosis that exhibits accumulation of PolyQ aggregates and oxidative stress in myocardial cells, upon heart-specific expression of Huntingtin protein fragments (Htt-PolyQ) with disease-causing poly-glutamine repeats (PolyQ-46, PolyQ-72, and PolyQ-102). Cardiac expression of GFP-tagged Htt-PolyQs resulted in PolyQ length-dependent functional defects that included increased incidence of arrhythmias and extreme cardiac dilation, accompanied by a significant decrease in contractility. Structural and ultrastructural analysis of the myocardial cells revealed reduced myofibrillar content, myofibrillar disorganization, mitochondrial defects and the presence of PolyQ-GFP positive aggregates. Cardiac-specific expression of disease causing Poly-Q also shortens lifespan of flies dramatically. To further confirm the involvement of oxidative stress or protein unfolding and to understand the mechanism of PolyQ induced cardiomyopathy, we co-expressed expanded PolyQ-72 with the antioxidant superoxide dismutase (SOD) or the myosin chaperone UNC-45. Co-expression of SOD suppressed PolyQ-72 induced mitochondrial defects and partially suppressed aggregation as well as myofibrillar disorganization. However, co-expression of UNC-45 dramatically suppressed PolyQ-72 induced aggregation and partially suppressed myofibrillar disorganization. Moreover, co-expression of both UNC-45 and SOD more efficiently suppressed GFP-positive aggregates, myofibrillar disorganization and physiological cardiac defects induced by PolyQ-72 than did either treatment alone. Our results demonstrate that mutant-PolyQ induces aggregates, disrupts the sarcomeric organization of contractile proteins, leads to mitochondrial dysfunction and increases oxidative stress in cardiomyocytes leading to abnormal cardiac function. We conclude that modulation of both protein unfolding and oxidative stress pathways in the Drosophila heart model can ameliorate the detrimental PolyQ effects, thus providing unique insights into the genetic mechanisms underlying amyloid-induced cardiac failure in HD patients.

A Drosophila Model of High Sugar Diet-Induced Cardiomyopathy

Article

Full-text available

Jan 2013
PLOS GENET

Diets high in carbohydrates have long been linked to progressive heart dysfunction, yet the mechanisms by which chronic high sugar leads to heart failure remain poorly understood. Here we combine diet, genetics, and physiology to establish an adult Drosophila melanogaster model of chronic high sugar-induced heart disease. We demonstrate deterioration of heart function accompanied by fibrosis-like collagen accumulation, insulin signaling defects, and fat accumulation. The result was a shorter life span that was more severe in the presence of reduced insulin and P38 signaling. We provide evidence of a role for hexosamine flux, a metabolic pathway accessed by glucose. Increased hexosamine flux led to heart function defects and structural damage; conversely, cardiac-specific reduction of pathway activity prevented sugar-induced heart dysfunction. Our data establish Drosophila as a useful system for exploring specific aspects of diet-induced heart dysfunction and emphasize enzymes within the hexosamine biosynthetic pathway as candidate therapeutic targets.

Transcriptional Architecture and Chromatin Landscape of the Core Circadian Clock in Mammals

Article

Full-text available

Aug 2012
SCIENCE

The mammalian circadian clock involves a transcriptional feed back loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression, and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases: a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Only 22% of messenger RNA (mRNA) cycling genes are driven by de novo transcription, suggesting that both transcriptional and posttranscriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling.

Unexpected features of Drosophila circadian behavioural rhythms under natural conditions

Article

Full-text available

Apr 2012
NATURE

Circadian clocks have evolved to synchronize physiology, metabolism and behaviour to the 24-h geophysical cycles of the Earth. Drosophila melanogaster's rhythmic locomotor behaviour provides the main phenotype for the identification of higher eukaryotic clock genes. Under laboratory light-dark cycles, flies show enhanced activity before lights on and off signals, and these anticipatory responses have defined the neuronal sites of the corresponding morning (M) and evening (E) oscillators. However, the natural environment provides much richer cycling environmental stimuli than the laboratory, so we sought to examine fly locomotor rhythms in the wild. Here we show that several key laboratory-based assumptions about circadian behaviour are not supported by natural observations. These include the anticipation of light transitions, the midday 'siesta', the fly's crepuscular activity, its nocturnal behaviour under moonlight, and the dominance of light stimuli over temperature. We also observe a third major locomotor component in addition to M and E, which we term 'A' (afternoon). Furthermore, we show that these natural rhythm phenotypes can be observed in the laboratory by using realistic temperature and light cycle simulations. Our results suggest that a comprehensive re-examination of circadian behaviour and its molecular readouts under simulated natural conditions will provide a more authentic interpretation of the adaptive significance of this important rhythmic phenotype. Such studies should also help to clarify the underlying molecular and neuroanatomical substrates of the clock under natural protocols.

Circadian rhythms of locomotor activity in Drosophila

Article

Full-text available

Oct 2003

Drosophila is by far the most advanced model to understand the complex biochemical interactions upon which circadian clocks rely. Most of the genes that have been characterized so far were isolated through genetic screens using the locomotor activity rhythms of the adults as a circadian output. In addition, new techniques are available to deregulate gene expression in specific cells, allowing to analyze the growing number of developmental genes that also play a role as clock genes. However, one of the major challenges in circadian biology remains to properly interpret complex behavioral data and use them to fuel molecular models. This review tries to describe the problems that clockwatchers have to face when using Drosophila activity rhythms to understand the multiple facets of circadian function.

Circadian rhythms govern cardiac repolarization and arrhythmogenesis

Article

Full-text available

Mar 2012
NATURE

Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada's syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, krüppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis.

A Circadian Rhythm Orchestrated By Histone Deacetylase 3 Controls Hepatic Lipid Metabolism

Article

Full-text available

Mar 2011
SCIENCE

Disruption of the circadian clock exacerbates metabolic diseases, including obesity and diabetes. We show that histone deacetylase 3 (HDAC3) recruitment to the genome displays a circadian rhythm in mouse liver. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Although amounts of HDAC3 are constant, its genomic recruitment in liver corresponds to the expression pattern of the circadian nuclear receptor Rev-erbα. Rev-erbα colocalizes with HDAC3 near genes regulating lipid metabolism, and deletion of HDAC3 or Rev-erbα in mouse liver causes hepatic steatosis. Thus, genomic recruitment of HDAC3 by Rev-erbα directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis.

Insulin resistance and circadian rhythm of cardiac autonomic modulation

Article

Full-text available

Dec 2010
CARDIOVASC DIABETOL

Background Insulin resistance (IR) has been associated with cardiovascular diseases (CVD). Heart rate variability (HRV), an index of cardiac autonomic modulation (CAM), is also associated with CVD mortality and CVD morbidity. Currently, there are limited data about the impairment of IR on the circadian pattern of CAM. Therefore, we conducted this investigation to exam the association between IR and the circadian oscillations of CAM in a community-dwelling middle-aged sample. Method Homeostasis models of IR (HOMA-IR), insulin, and glucose were used to assess IR. CAM was measured by HRV analysis from a 24-hour electrocardiogram. Two stage modeling was used in the analysis. In stage one, for each individual we fit a cosine periodic model based on the 48 segments of HRV data. We obtained three individual-level cosine parameters that quantity the circadian pattern: mean (M), measures the overall average of a HRV index; amplitude (Â), measures the amplitude of the oscillation of a HRV index; and acrophase time (θ), measures the timing of the highest oscillation. At the second stage, we used a random-effects-meta-analysis to summarize the effects of IR variables on the three circadian parameters of HRV indices obtained in stage one of the analysis. Results In persons without type diabetes, the multivariate adjusted β (SE) of log HOMA-IR and M variable for HRV were -0.251 (0.093), -0.245 (0.078), -0.19 (0.06), -4.89 (1.76), -3.35 (1.31), and 2.14 (0.995), for log HF, log LF, log VLF, SDNN, RMSSD and HR, respectively (all P < 0.05). None of the IR variables were significantly associated with Â or θ of the HRV indices. However, in eight type 2 diabetics, the magnitude of effect due to higher HOMA-IR on M, Â, and θ are much larger. Conclusion Elevated IR, among non-diabetics significantly impairs the overall mean levels of CAM. However, the Â or θ of CAM were not significantly affected by IR, suggesting that the circadian mechanisms of CAM are not impaired. However, among persons with type 2 diabetes, a group clinically has more severe form of IR, the adverse effects of increased IR on all three HRV circadian parameters are much larger.

Sleep Duration as a Risk Factor for Cardiovascular Disease- a Review of the Recent Literature

Article

Full-text available

Feb 2010
Curr Cardiol Rev

Sleep loss is a common condition in developed countries, with evidence showing that people in Western countries are sleeping on average only 6.8 hour (hr) per night, 1.5 hr less than a century ago. Although the effects of sleep deprivation on our organs have been obscure, recent epidemiological studies have revealed relationships between sleep deprivation and hypertension (HT), coronary heart disease (CHD), and diabetes mellitus (DM). This review article summarizes the literature on these relationships. Because sleep deprivation increases sympathetic nervous system activity, this increased activity serves as a common pathophysiology for HT and DM. Adequate sleep duration may be important for preventing cardiovascular diseases in modern society.

Circadian Rhythms and Metabolic Syndrome From Experimental Genetics to Human Disease

Article

Full-text available

Feb 2010
CIRC RES

The incidence of the metabolic syndrome represents a spectrum of disorders that continue to increase across the industrialized world. Both genetic and environmental factors contribute to metabolic syndrome and recent evidence has emerged to suggest that alterations in circadian systems and sleep participate in the pathogenesis of the disease. In this review, we highlight studies at the intersection of clinical medicine and experimental genetics that pinpoint how perturbations of the internal clock system, and sleep, constitute risk factors for disorders including obesity, diabetes mellitus, cardiovascular disease, thrombosis and even inflammation. An exciting aspect of the field has been the integration of behavioral and physiological approaches, and the emerging insight into both neural and peripheral tissues in disease pathogenesis. Consideration of the cell and molecular links between disorders of circadian rhythms and sleep with metabolic syndrome has begun to open new opportunities for mechanism-based therapeutics.

Potential Therapeutic Benefits of Strategies Directed to Mitochondria

Article

Full-text available

Dec 2009
ANTIOXID REDOX SIGN

The mitochondrion is the most important organelle in determining continued cell survival and cell death. Mitochondrial dysfunction leads to many human maladies, including cardiovascular diseases, neurodegenerative disease, and cancer. These mitochondria-related pathologies range from early infancy to senescence. The central premise of this review is that if mitochondrial abnormalities contribute to the pathological state, alleviating the mitochondrial dysfunction would contribute to attenuating the severity or progression of the disease. Therefore, this review will examine the role of mitochondria in the etiology and progression of several diseases and explore potential therapeutic benefits of targeting mitochondria in mitigating the disease processes. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate and manipulate mitochondrial function and genomics for therapeutic benefit. These approaches to treat mitochondrial dysfunction rationally could lead to selective protection of cells in different tissues and various disease states. However, most of these approaches are in their infancy.

Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression

Article

Full-text available

Nov 2009
P NATL ACAD SCI USA

In mammals, the circadian oscillator generates approximately 24-h rhythms in feeding behavior, even under constant environmental conditions. Livers of mice held under constant darkness exhibit circadian rhythm in abundance in up to 15% of expressed transcripts. Therefore, oscillations in hepatic transcripts could be driven by rhythmic food intake or sustained by the hepatic circadian oscillator, or a combination of both. To address this question, we used distinct feeding and fasting paradigms on wild-type (WT) and circadian clock-deficient mice. We monitored temporal patterns of feeding and hepatic transcription. Both food availability and the temporal pattern of feeding determined the repertoire, phase, and amplitude of the circadian transcriptome in WT liver. In the absence of feeding, only a small subset of transcripts continued to express circadian patterns. Conversely, temporally restricted feeding restored rhythmic transcription of hundreds of genes in oscillator-deficient mouse liver. Our findings show that both temporal pattern of food intake and the circadian clock drive rhythmic transcription, thereby highlighting temporal regulation of hepatic transcription as an emergent property of the circadian system.

Myosin II Folding Is Mediated by a Molecular Chaperonin

Article

Full-text available

Oct 1999

The folding pathway of the heavy meromyosin subfragment (HMM) of a skeletal muscle myosin has been investigated byin vitro synthesis of the myosin heavy and light chains in a coupled transcription and translation assay. Analysis of the nascent translation products for folding intermediates has identified a major intermediate that contains all three myosin subunits in a complex with the eukaryotic cytosolic chaperonin. Partially folded HMM is released from this complex in an ATP-dependent manner. However, biochemical and functional assays reveal incomplete folding of the myosin motor domain. Dimerization of myosin heavy chains and association of heavy and light chains are accomplished early in the folding pathway. To test for other factors necessary for the complete folding of myosin, a cytoplasmic extract was prepared from myotubes produced by a mouse myogenic cell line. This extract dramatically enhanced the folding of HMM, suggesting a role for muscle-specific factors in the folding pathway. We conclude that the molecular assembly of myosin is mediated by the eukaryotic cytosolic chaperonin with folding of the motor domain as the slow step in the pathway.

Circadian physiology of metabolism

Article

Nov 2016

Satchidananda Panda

A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.

Circadian time signatures of fitness and disease

Article

Nov 2016

Biological clocks are autonomous anticipatory oscillators that play a critical role in the organization and information processing from genome to whole organisms. Transformative advances into the clock system have opened insight into fundamental mechanisms through which clocks program energy transfer from sunlight into organic matter and potential energy, in addition to cell development and genotoxic stress response. The identification of clocks in nearly every single cell of the body raises questions as to how this gives rise to rhythmic physiology in multicellular organisms and how environmental signals entrain clocks to geophysical time. Here, we consider advances in understanding how regulatory networks emergent in clocks give rise to cell type–specific functions within tissues to affect homeostasis.

Sleep Duration and Quality: Impact on Lifestyle Behaviors and Cardiometabolic Health: A Scientific Statement From the American Heart Association

Article

Sep 2016
CIRCULATION

Sleep is increasingly recognized as an important lifestyle contributor to health. However, this has not always been the case, and an increasing number of Americans choose to curtail sleep in favor of other social, leisure, or work-related activities. This has resulted in a decline in average sleep duration over time. Sleep duration, mostly short sleep, and sleep disorders have emerged as being related to adverse cardiometabolic risk, including obesity, hypertension, type 2 diabetes mellitus, and cardiovascular disease. Here, we review the evidence relating sleep duration and sleep disorders to cardiometabolic risk and call for health organizations to include evidence-based sleep recommendations in their guidelines for optimal health.

Restricting feeding to the active phase in middle-aged mice attenuates adverse metabolic effects of a high-fat diet

Article