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Nutrition and Exercise Interventions to Improve Body Composition for Persons with Overweight or Obesity Near Retirement Age: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.
Eglseer, D, Traxler, M, Embacher, S, Reiter, L, Schoufour, JD, Weijs, PJM, Voortman, T, Boirie, Y, Cruz-Jentoft, A, Bauer, S
Advances in nutrition (Bethesda, Md.). 2023;14(3):516-538
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Obesity is characterised by excessive fat accumulation that often occurs during the process of aging. Aging is accompanied not only by a gradual increase in body fat stores but also a decrease in muscle mass, muscle function, and water retention. The aim of this study was to assess which nutrition and exercise interventions are most effective for improving the body composition (fat mass and muscle mass), body mass index, and waist circumference in persons with overweight or obesity near retirement age (55 to 70 years of age). This study was a systematic review and network meta-analysis (NMA) of randomised controlled trials of sixty-six studies. Results of the NMA showed that the most effective strategy to improve body composition, i.e., losing fat without increasing risk of sarcopenia in persons with obesity around retirement age, was combining energy restriction with resistance training or with mixed exercise (resistance combined with aerobic exercise) and/or high-protein intake. In fact, without training, an energy-restricted diet with or without added protein helped individuals lose fat mass but also tended to result in losses of muscle mass. Authors conclude that an energy-restricted diet alone probably contributes to the development of sarcopenic obesity in persons of retirement age. Thus, to simultaneously lose weight and maintain muscle mass, authors recommend a combination of energy restriction and resistance training.
Abstract
The retirement phase is an opportunity to integrate healthy (nutrition/exercise) habits into daily life. We conducted this systematic review to assess which nutrition and exercise interventions most effectively improve body composition (fat/muscle mass), body mass index (BMI), and waist circumference (WC) in persons with obesity/overweight near retirement age (ages 55-70 y). We conducted a systematic review and network meta-analysis (NMA) of randomized controlled trials, searching 4 databases from their inception up to July 12, 2022. The NMA was based on a random effects model, pooled mean differences, standardized mean differences, their 95% confidence intervals, and correlations with multi-arm studies. Subgroup and sensitivity analyses were also conducted. Ninety-two studies were included, 66 of which with 4957 participants could be used for the NMA. Identified interventions were clustered into 12 groups: no intervention, energy restriction (i.e., 500-1000 kcal), energy restriction plus high-protein intake (1.1-1.7 g/kg/body weight), intermittent fasting, mixed exercise (aerobic and resistance), resistance training, aerobic training, high protein plus resistance training, energy restriction plus high protein plus exercise, energy restriction plus resistance training, energy restriction plus aerobic training, and energy restriction plus mixed exercise. Intervention durations ranged from 8 wk to 6 mo. Body fat was reduced with energy restriction plus any exercise or plus high-protein intake. Energy restriction alone was less effective and tended to decrease muscle mass. Muscle mass was only significantly increased with mixed exercise. All other interventions including exercise effectively preserved muscle mass. A BMI and/or WC decrease was achieved with all interventions except aerobic training/resistance training alone or resistance training plus high protein. Overall, the most effective strategy for nearly all outcomes was combining energy restriction with resistance training or mixed exercise and high protein. Health care professionals involved in the management of persons with obesity need to be aware that an energy-restricted diet alone may contribute to sarcopenic obesity in persons near retirement age. This network meta-analysis is registered at https://www.crd.york.ac.uk/prospero/ as CRD42021276465.
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The effects of time-restricted eating on sleep, cognitive decline, and Alzheimer's disease.
Ezzati, A, Pak, VM
Experimental gerontology. 2023;171:112033
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The ageing population is expected to double, with one in four people being over 65 years in Western countries by 2050. As a consequence, the presentation of age-related disorders like Alzheimer's disease (AD) and mild cognitive impairment (MCI) is likely to increase. MCI, a pre-stage of dementia, is considered reversible. However, there are no known cures for AD so far. Hence interventions such as lifestyle modifications that can delay the onset and progression of the disease are of great interest. Previous research demonstrated that calorie restriction (CR) and time-restricted eating (TRE) have beneficial effects on brain function. The authors of this article sought to summarize the current evidence of such eating patterns, as well as their underlying mechanisms and potential benefits concerning MCI and AD. The review also looked at sleep - as sleep disturbances are a risk factor and are associated with both conditions - and the effects of sleep on cognitive decline and neuroinflammatory markers. TRE presents itself as a promising intervention as it can restore the integrity of the blood-brain barrier and support healthy brain function whilst reducing oxidative stress and inflammation. Furthermore, it can be leveraged for weight and glucose management. Preliminary results also indicate a positive impact on sleep, with adequate sleep benefiting cognitive health. As this is a relatively new field, there is still much more to be understood about the underlying mechanisms, with the optimal time window for fasting needing to be determined. The authors advocate for more research on how TRE and sleep relates to neurodegenerative disease.
Expert Review
Conflicts of interest:
None
Take Home Message:
- To highlight the potential benefits of time-restricted eating (TRE) as a potential preventative approach to delay the onset and progression of neurodegenerative disease such as AD
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
- The authors highlight Alzheimer's disease (AD) is the most prevalent neurodegenerative disease affecting over 50 million aging people worldwide. While no cure is known for AD, this review proposes lifestyle interventions such as time-restricted eating (TRE) as a potential approach to delay the onset and progression of a neurodegenerative disease and could hint at autophagic mechanisms
- TRE involves strategically limiting the eating window to 8- to 12-h with fasting—drinking only water and calorie-free coffee/tea—for 12 to 16 h within a 24-h cycle.
Objectives
- To investigate the effects of TRE on sleep and cognitive decline in healthy individuals
Results
- Nine RCTs with varied length between one and sixteen weeks were examined
- A 5-week randomised controlled trial (RCT) showed no significant change in sleep quality between early TRE (fasting between 6 a.m.–3 p.m.), mid-day TRE (11 a.m.–8 p. m.) and control (ad lib intake) in 82 healthy subjects without obesity but the sleep quality improvement was greater in early TRE group (PSQI:Δ=−1.08±1.78vs.Δ=−0.22±2.19andΔ=−0.36±1.73, respectively).
- Sleep quality using the myCircadianClock app reported significant improvement in sleep quality (23 %) following a 12-week single arm intervention of 10-h TRE.
- Following a 16-week TRE intervention sleep duration was reported to be improved from a subjective score of 6 at base line to 8 after 36 weeks in eight overweight and obese subjects; however, the study used a subjective self-assessment survey for measuring sleep duration.
- The Pittsburgh Sleep Quality Index (PSQI) was carried out to assess sleep quality and disturbances in six trials but no trial reported significant improvement in sleep quality using the PSQI survey with TRE
Conclusion
- Authors highlight TRE as promising for its potential to reduce the markers of aging and neurodegenerative disease.
Clinical practice applications:
- To inform practitioners of the potential benefits of TRE that involves limiting the eating window to 8- to 12-h with fasting—drinking only water and calorie-free coffee/tea—for 12 to 16 h within a 24-h cycle.
- TRE may improve regulation of circadian rhythm and autophagy through aligning food intake with circadian rhythm, which coordinates metabolism and physiological functions including glucose, insulin sensitivity, lipid levels, energy expenditure, inflammation, sleep and cognitive function.
- TRE activates a metabolic switch which occurs 12–36 h after fasting is initiated and free fatty acids are released into the blood.
- TRE improved sleep quality and sleep duration, where a longer fasting period in TRE approach (≥12 h fasting) was associated with significantly higher sleep duration.
Considerations for future research:
- The potential benefits of TRE in neurodegenerative diseases such as AD should be further investigated clinically.
- The optimal time to initiate fasting needs to be identified in future trials.
- The potential benefits of TRE in neurodegenerative diseases such as AD in the context of sleep should be further investigated.
Abstract
According to the United Nations, by 2050, one in six individuals will be over age 65 globally, and one in four people would be aged 65 and older in western countries. The unprecedented growth of the aging population is associated with increased age-related disorders like Alzheimer's disease (AD) and Mild cognitive impairment (MCI). To date, no cure is known for AD, thus lifestyle interventions including calorie restriction (CR) and time-restricted eating (TRE) are proposed as potential approach to delay the onset and progression of the disease. Sleep disturbances are common in people with MCI and AD. Moreover, accumulating data indicates that pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8 and IL-10 increase in individuals with AD and MCI versus healthy subjects. Thus, the purpose of the present review is to describe the potential effects of TRE on sleep, cognition decline, and neuroinflammatory markers in humans. Preliminary evidence suggests that TRE may produce neuroprotective effects on cognition and reduce neuroinflammatory markers related to AD in humans. To date, no studies investigated the effects of TRE on sleep disturbances and patients with AD. Thereby, the impact of TRE on cognition in individuals with cognitive decline and AD needs to be investigated further in randomized controlled trials (RCTs).
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Effect of Intermittent Fasting Diet on Glucose and Lipid Metabolism and Insulin Resistance in Patients with Impaired Glucose and Lipid Metabolism: A Systematic Review and Meta-Analysis.
Yuan, X, Wang, J, Yang, S, Gao, M, Cao, L, Li, X, Hong, D, Tian, S, Sun, C
International journal of endocrinology. 2022;2022:6999907
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The prevalence of obesity and metabolic syndrome may increase the risk of cardiovascular disease (CVD), diabetes, and neurological conditions. The imbalance in glucose and lipid metabolism and hypertension characterises the development of these chronic diseases. Intermittent fasting (IF) has been considered an effective dietary strategy for reducing the risk of obesity, insulin resistance, dyslipidaemia, diabetes, and CVD. This systematic review and meta-analysis include ten randomised controlled trials to evaluate the effects of IF intervention on glucose and lipid metabolism in people with metabolic syndrome. IF intervention regulated glucose metabolism by improving fasting blood glucose, glycosylated haemoglobin, insulin, and insulin resistance. IF intervention also positively impacted the body mass index and waist circumference. The total cholesterol, low-density lipoprotein levels, and triglyceride levels also improved, followed by the IF, showing the impact on lipid metabolism. Further robust studies are required due to heterogeneity between the included studies in type of IF, duration, the health status of participants, ethnicity, and outcome measurements. However, healthcare professionals can use the results of this systematic review and meta-analysis to understand the therapeutic effect of IF intervention on glycolipid metabolism in people with metabolic syndrome.
Expert Review
Conflicts of interest:
None
Take Home Message:
- IF does not require calorie restriction which may result in greater compliance
- IF does not restrict macronutrients such as CHO and fats, so may avoid the exclusion of key nutrients e.g. healthy fats and wholegrains.
- IF may have fewer adverse effects on daily routines and quality of life, which may mean adherence is easier.
- Improved glucose and lipid metabolism may prevent the development of chronic health conditions such as T2D, CVD and cancer.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Management of glucose and lipid metabolism can be achieved through weight reduction using dietary interventions such as very low calorie or CHO diets, which may be effective but difficult to sustain long term. An alternative approach for weight management, improved insulin resistance and subsequent prevention of comorbitities e.g. Type 2 Diabetes (T2D), Cardiovascular Disease (CVD) and cancer, is Intermittent Fasting (IF). such as time restricted or periodic fasting.
This study summarises the effects of IF dietary interventions lasting less than three months in overweight and obese women with Metabolic Syndrome, defined as the presence of any metabolic dysfunction including obesity, hyperglycaemia, dyslipidaemia or hypertension.
The meta-anlaysis was carried out following PRISMA guidelines. A literature search in PubMed and Medline using the keywords obesity/overweight, IF diet, metabolic syndrome, RCT’s and humans resulted in 10 studies with 12 types of intervention for analysis. The following outcomes were evaluated: glucose and lipid metabolism, insulin resistance, weight loss and blood pressure.
Results were analysed in R software using mean differences and 95% confidence intervals, and either random or fixed effects depending on the Cochrane’s Q and I(2) statistics. Funnel plots were inspected for potential bias and Egger’s regression tests for publication bias.
There were significant differences before and after the interventions for all glucose and lipid metabolism markers as well as body weight and systolic blood pressure :
Glucose metabolism:
- Fasting glucose reduced by 0.15mmol/L
- Insulin plasma reduced by 13.25uUI
- HbA1c reduced by 0.08%
- HOMA-IR (insulin resistance index) reduced by 0.31 on average
Lipid metabolism:
- Total cholesterol reduced by 0.32mmol/L
- LDL reduced by 0.22mmol/L
- Triglyceride reduced by 0.04mmol/L
Weight loss:
- Body weight reduced by 1.87kg
- BMI reduced by 0.8kg/m2
- Waist circumference reduced by 2.08cm
Blood pressure:
- Systolic reduced by 2.58mmHg
- Diastolic reduced by 3.12mmHg
Despite limitations of the meta-analysis, this study demonstrates IF has therapeutic effects on those with disordered lipid and glucose metabolism, and may prove to be an effective and sustainable approach.
Clinical practice applications:
- IF may be an effective alternative to restricted calorie or CHO diets for weight management with the associated benefits of glucose and lipid metabolism.
- IF has been shown to have therapeutic effects on individuals with impaired glucose and lipid metabolism.
- IF may be considered as a sustainable lifestyle choice rather than a ‘weight loss’ programme such as a very low calorie diet, which can result in poor quality of life and subsequent reduced adherence.
- Since it may take time for impaired glucose and lipid metabolism to progress to more serious disease states, establishing IF as an early intervention, may be considered as a prudent form of preventative medicine.
- IF has shown to have other health benefits such as reduced blood pressure and may be considered as adjuvant therapy.
Considerations for future research:
- Compares the effects of IF on different ethnicities, sex and age categories
- Evaluates the effect of IF on other disease states e.g. cancer, auto-immune conditions
- Assesses the response of other biomarkers e.g. inflammatory cytokines
- Compares different types and durations of IF on health biomarkers (eg periodic, time restricted)
Abstract
The question of whether or not intermittent fasting diets improve the clinical indicators of glycolipid metabolism remains unclear. This study systematically reviewed the relevant clinical trials to evaluate the effects of intermittent fasting diet on glucose and lipid metabolism and insulin sensitivity in patients with metabolic syndrome. To evaluate the effect of intermittent fasting diet intervention on patients with disorders of glucose and lipid metabolism, random-effect or fixed-effect meta-analysis models were used to calculate the average difference before and after intermittent fasting diet intervention and the corresponding 95% confidence intervals (CIs). After intermittent fasting diet intervention, in terms of glucose metabolism, fasting blood glucose reduced by 0.15 mmol/L (95% CI: -0.23; -0.06), glycosylated hemoglobin reduced by 0.08 (95% CIs: -0.25; -0.10), insulin plasma levels reduced by 13.25 uUI (95% CIs: -16.69; -9.82), and HOMA-IR decreased by 0.31 on an average (95% CIs: -0.44; -0.19). In addition, BMI decreased by 0.8 kg/m2 (95% CIs: -1.32; -0.28), body weight reduced by 1.87 kg (95% CIs: -2.67; -1.07), and the waist circumference decreased by 2.08 cm (95% CIs: -3.06; -1.10). Analysis of lipid metabolism showed that intermittent fasting diet intervention effectively reduced the total cholesterol level by 0.32 mmol/L (95% CIs: -0.60; -0.05), low-density lipoprotein level by 0.22 mmol/L (95% CIs: -0.37; -0.07), and triglyceride level by 0.04 mmol/L (95% CIs: -0.15; -0.07). Intermittent fasting diets have certain therapeutic effects on blood glucose and lipids in patients with metabolic syndrome and significantly improve insulin resistance. It may be considered as an auxiliary treatment to prevent the occurrence and development of chronic diseases.
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Comparison of the Effects of Intermittent Energy Restriction and Continuous Energy Restriction among Adults with Overweight or Obesity: An Overview of Systematic Reviews and Meta-Analyses.
Wang, J, Wang, F, Chen, H, Liu, L, Zhang, S, Luo, W, Wang, G, Hu, X
Nutrients. 2022;14(11)
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Obesity is the leading cause of cardiovascular disease, diabetes, hypertension, hyperlipidaemia, and some forms of cancer. 38% of people worldwide are overweight, and 20% are obese. To combat obesity and associated comorbidities, calorie restriction (CR) is found to be a cost-effective non-pharmacological intervention. Intermittent energy restriction (IER) and continuous energy restriction (CER) are two forms of CR characterised by notable calorie restriction and normal energy intake phases. Forms of IER included in this research are the 5:2 diet, alternate-day fasting (ADF), and time-restricted feeding (TRF). For weight loss, CER limits calorie intake by 15-40%. A total of eleven randomised controlled studies were included in this systematic review and meta-analysis to compare the effectiveness of IER protocols with CER in reducing weight, BMI and waist circumferences in overweight or obese individuals. Improvements in anthropometric parameters were not different between IER and CER. A long-term robust study is necessary to evaluate the effects of IER and CER on improving anthropometric and metabolic parameters due to the limitations and heterogeneity of current research evidence. Nevertheless, healthcare professionals can use the results of this study to understand the role of IER and CER in weight loss and their clinical relevance for improving overall health and lifespan.
Abstract
There is considerable heterogeneity across the evidence regarding the effects of intermittent energy restriction and continuous energy restriction among adults with overweight or obesity which presents difficulties for healthcare decision-makers and individuals. This overview of systematic reviews aimed to evaluate and synthesize the existing evidence regarding the comparison of the two interventions. We conducted a search strategy in eight databases from the databases' inception to December 2021. The quality of 12 systematic reviews was assessed with A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE). One review was rated as high quality, 1 as moderate, 4 as low, and 6 as critically low. A meta-analysis of the original studies was conducted for comparison of primary intermittent energy restriction protocols with continuous energy restriction. Intermittent energy restriction did not seem to be more effective in weight loss compared with continuous energy restriction. The advantages of intermittent energy restriction in reducing BMI and waist circumference and improvement of body composition were not determined due to insufficient evidence. The evidence quality of systematic reviews and original trials remains to be improved in future studies.
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Effect of Intermittent Fasting on Reproductive Hormone Levels in Females and Males: A Review of Human Trials.
Cienfuegos, S, Corapi, S, Gabel, K, Ezpeleta, M, Kalam, F, Lin, S, Pavlou, V, Varady, KA
Nutrients. 2022;14(11)
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Intermittent fasting is a term for three different diet regimes. Alternate day fasting involves a feast day where individuals can eat what they want followed by a water only day. The 5:2 diet involves 5 feast days and 2 fast days per week. Time-restricted eating (TRE) involves a short eating window of a specific number of hours per day. Although these are all popular diet regimes for weight loss, animal studies have highlighted concerns with regards to reproductive health. This review paper aimed to summarise the human research on the effects of intermittent fasting on reproductive hormone levels in both men and women. It was found that overall, there were very few studies, however evidence was found on the effect of intermittent fasting on some of the sex hormones. For women, moving calorie intake to earlier in the day may be of benefit to oestrogen, sex hormone binding globulin, and androgen levels in those with polycystic ovary syndrome (PCOS). In addition, a fasting diet may be of benefit to androgen and SHBG levels in women with PCOS. However even though weight loss may be achieved with intermittent fasting, this is insufficient to improve the gonadotrophins. Intermittent fasting was found to be safe in women who were breastfeeding, with no significant change to milk production. In men, TRE was found to negatively affect testosterone levels, but had no effect on SHBG. The effect of intermittent fasting on sex hormones may involve changes in the gut microbiome and circadian rhythms as a direct result of intermittent fasting. It was concluded that the sex hormone levels of women with PCOS may benefit from intermittent fasting, however in men it may be detrimental to sex hormone production. This study could be used by healthcare professionals to understand that recommending an intermittent fasting diet may be of benefit to hormone levels and fertility in women with PCOS, however this may not be the case for men.
Abstract
Intermittent fasting is a popular diet for weight loss, but concerns have been raised regarding the effects of fasting on the reproductive health of women and men. Accordingly, we conducted this literature review to clarify the effects of fasting on reproductive hormone levels in humans. Our results suggest that intermittent fasting decreases androgen markers (i.e., testosterone and the free androgen index (FAI)) while increasing sex hormone-binding globulin (SHBG) levels in premenopausal females with obesity. This effect was more likely to occur when food consumption was confined to earlier in the day (eating all food before 4 pm). In contrast, fasting did not have any effect on estrogen, gonadotropins, or prolactin levels in women. As for men, intermittent fasting reduced testosterone levels in lean, physically active, young males, but it did not affect SHBG concentrations. Interestingly, muscle mass and muscular strength were not negatively affected by these reductions in testosterone. In interpreting these findings, it is important to note that very few studies have been conducted on this topic. Thus, it is difficult to draw solid conclusions at present. From the limited data presented here, it is possible that intermittent fasting may decrease androgen markers in both genders. If this is the case, these results would have varied health implications. On the one hand, fasting may prove to be a valuable tool for treating hyperandrogenism in females with polycystic ovarian syndrome (PCOS) by improving menstruation and fertility. On the other hand, fasting may be shown to decrease androgens among males, which could negatively affect metabolic health and libido. More research is warranted to confirm these preliminary findings.
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Intermittent Fasting in Cardiovascular Disorders-An Overview.
Malinowski, B, Zalewska, K, Węsierska, A, Sokołowska, MM, Socha, M, Liczner, G, Pawlak-Osińska, K, Wiciński, M
Nutrients. 2019;11(3)
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Intermittent fasting (IF) is an eating pattern that cycles between periods of fasting and eating. IF has gained popularity in recent years with people wanting to lose weight, and it may have many long-term health benefits. In this review, the authors looked at human and animal studies using variations of IF including time restricted eating (TRE), where eating is confined within a specific window during the day (for example 8 hours eating and 16 hours fasting), and alternate day fasting (ADF), where a day of eating normally is alternated with a day of either fasting entirely, or significant calorie restriction. The authors found that IF is related to many beneficial effects on the cardiovascular system, involving atherosclerosis progression, benefits for diabetes mellitus type 2 such as improved glucose metabolism and insulin sensitivity, lowering of blood pressure, and other cardiovascular risk factors (such as lipid profile and inflammation). It is currently unclear whether the benefits of IF are solely due to weight loss or other mechanisms. The success of every type of diet depends on compliance, and IF seems to be as easy or easier to follow than more traditional diets for many people. Fasting is not recommended for people with hormonal imbalances, pregnant and breastfeeding women, and diabetics. People with eating disorders and underweight people are also not recommended to use the intermittent fasting diet. In recent years, the IF diet and its varieties have become increasingly popular. This diet not only serves to reduce body weight but seems to have other long-term health benefits. However, individuals’ current health and situation should be considered before commencing the IF diet.
Abstract
Intermittent fasting is a form of time restricted eating (typically 16 h fasting and 8 h eating), which has gained popularity in recent years and shows promise as a possible new paradigm in the approach to weight loss and the reduction of inflammation, and has many potential long term health benefits. In this review, the authors will incorporate many aspects of fasting, mainly focusing on its effects on the cardiovascular system, involving atherosclerosis progression, benefits for diabetes mellitus type 2, lowering of blood pressure, and exploring other cardiovascular risk factors (such as lipid profile and inflammation).
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Autophagy and intermittent fasting: the connection for cancer therapy?
Antunes, F, Erustes, AG, Costa, AJ, Nascimento, AC, Bincoletto, C, Ureshino, RP, Pereira, GJS, Smaili, SS
Clinics (Sao Paulo, Brazil). 2018;73(suppl 1):e814s
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Autophagy is a cellular mechanism that removes unnecessary or dysfunctional components and is being studied intensively with regards to chronic disease, including cancer. Dietary restriction, as in intermittent fasting, is thought to activate autophagy. The authors review the literature and possible mechanisms for autophagy in cancer, noting that autophagy can both suppress and support cancer development and growth. It appears that fasting in combination with cytotoxic drugs elicits differential responses in normal and cancer cells, whereby normal cells prioritise maintenance pathways and inactivate growth factor signalling when nutrients are absent, whilst cancer cells, do not inhibit stress resistance pathways, thus becoming vulnerable to cytotoxic treatment Preclinical studies on calorie restriction or intermittent fasting in combination with chemo- and/or radiotherapy have found beneficial effects in animal and in vitro studies. There are a number of clinical human trials underway, but only two completed pilot trials, which showed promising results with reducing side effects and increasing efficacy of the chemotherapeutic drugs through intermittent fasting.
Abstract
Cancer is a leading cause of death worldwide, and its incidence is continually increasing. Although anticancer therapy has improved significantly, it still has limited efficacy for tumor eradication and is highly toxic to healthy cells. Thus, novel therapeutic strategies to improve chemotherapy, radiotherapy and targeted therapy are an important goal in cancer research. Macroautophagy (herein referred to as autophagy) is a conserved lysosomal degradation pathway for the intracellular recycling of macromolecules and clearance of damaged organelles and misfolded proteins to ensure cellular homeostasis. Dysfunctional autophagy contributes to many diseases, including cancer. Autophagy can suppress or promote tumors depending on the developmental stage and tumor type, and modulating autophagy for cancer treatment is an interesting therapeutic approach currently under intense investigation. Nutritional restriction is a promising protocol to modulate autophagy and enhance the efficacy of anticancer therapies while protecting normal cells. Here, the description and role of autophagy in tumorigenesis will be summarized. Moreover, the possibility of using fasting as an adjuvant therapy for cancer treatment, as well as the molecular mechanisms underlying this approach, will be presented.
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Calories, carbohydrates, and cancer therapy with radiation: exploiting the five R's through dietary manipulation.
Klement, RJ, Champ, CE
Cancer metastasis reviews. 2014;33(1):217-29
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Radiation therapy is standard care for cancer patients alongside surgery and chemotherapy. However, there are still some cancers which seem to withstand this treatment. This study looks at whether calorie reduction (CR) and carbohydrate restriction can have any impact on treatment outcomes. The reason for exploring this idea comes from data showing a high level of ‘glycolysis’ (a need for sugar) in cancer cells. Calorie reduction is defined as 30-50% less calories per day achieved either by intermittent fasting or a fixed calorie regime. Carbohydrate restriction is defined as a ketogenic diet (KD); a diet which removes carbohydrate foods and sugars and focuses on high fat foods and limited protein. Both nutritional protocols have been shown to have similar metabolic effects of reducing blood sugar levels and insulin activity, and thus reducing the ability of cancer cells to communicate. The 5R principle of radiotherapy tries to exploit the differences between cancer cells and healthy tissue. The 5Rs are Repair to DNA damage, Repopulation of the tumour, Redistribution of cells, Reoxygenation of the tumour area and Radio resistance in cells which do not respond to treatment. The concern with restricting calories and carbohydrates is triggering detrimental weight loss in cancer patients, although some fat loss may be beneficial in overweight patients with hormonal cancers. Intermittent fasting seems to fit well with typical radiation treatment schedules over 2-3-month periods. Trials of ketogenic diets on healthy volunteers have shown it encourages muscle mass which is a strong predictor of survival in cancer patients. Of the two, a carbohydrate-restricted, ketogenic diet appears the most viable adjunct to radiation therapy.
Abstract
Aggressive tumors typically demonstrate a high glycolytic rate, which results in resistance to radiation therapy and cancer progression via several molecular and physiologic mechanisms. Intriguingly, many of these mechanisms utilize the same molecular pathways that are altered through calorie and/or carbohydrate restriction. Furthermore, poorer prognosis in cancer patients who display a glycolytic phenotype characterized by metabolic alterations, such as obesity and diabetes, is now well established, providing another link between metabolic pathways and cancer progression. We review the possible roles for calorie restriction (CR) and very low carbohydrate ketogenic diets (KDs) in modulating the five R's of radiotherapy to improve the therapeutic window between tumor control and normal tissue complication probability. Important mechanisms we discuss include (1) improved DNA repair in normal, but not tumor cells; (2) inhibition of tumor cell repopulation through modulation of the PI3K-Akt-mTORC1 pathway downstream of insulin and IGF1; (3) redistribution of normal cells into more radioresistant phases of the cell cycle; (4) normalization of the tumor vasculature by targeting hypoxia-inducible factor-1α downstream of the PI3K-Akt-mTOR pathway; (5) increasing the intrinsic radioresistance of normal cells through ketone bodies but decreasing that of tumor cells by targeting glycolysis. These mechanisms are discussed in the framework of animal and human studies, taking into account the commonalities and differences between CR and KDs. We conclude that CR and KDs may act synergistically with radiation therapy for the treatment of cancer patients and provide some guidelines for implementing these dietary interventions into clinical practice.