Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.

Dietary Restrictions and Nutrition in the Prevention and Treatment of Cardiovascular Disease.

Cardiovascular disease (CVD) is the leading cause of death in many developed countries and remains one of the major diseases strongly affected by the diet. Nutrition can affect CVD directly by contributing to the accumulation of vascular plaques and also indirectly by regulating the rate of aging. This review summarizes research on nutrition and CVD incidence based on a multipillar system that includes basic research focused on aging, epidemiological studies, clinical studies, and studies of centenarians. The relevant research linking nutrition and CVD with focus on macronutrients and aging will be highlighted. We will review some of the most relevant studies on nutrition and CVD treatment, also focusing on interventions known to delay aging. We will discuss both everyday dietary compositions, as well as intermittent and periodic fasting interventions with the potential to prevent and treat CVD.

Periodic and Intermittent Fasting in Diabetes and Cardiovascular Disease.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is one of the leading causes of death globally. Nutrition plays a central role in CVD risk by affecting aging, adiposity, glycemia, blood pressure, cholesterol, inflammation, and other risk factors and can affect CVD risk not only based on calorie intake and dietary composition but also the timing and range of meals. This review evaluates the effects of fasting, fasting-mimicking diets, and time-restricted eating on the reduction of CVD risk factors and provides initial data on their potential to serve as CVD prevention and treatment therapies. RECENT FINDINGS: Intermittent fasting (IF), time-restricted eating (TRE), prolonged fasting (PF), and fasting-mimicking diets (FMD) show promise in the reduction of CVD risk factors. Results on IF, TRE, PF, and FMD on CVD risk factors are significant and often independent of weight loss, yet long-term studies on their effect on CVD are still lacking. Coupling periodic and prolonged, or intermittent and more frequent cycles of fasting or fasting-mimicking diets, designed to maximize compliance and minimize side effects, has the potential to play a central role in the prevention and treatment of CVD and metabolic syndrome.

Correction: Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy.

[This corrects the article DOI: 10.1371/journal.pbio.2001951.].

Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy.

Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexamethasone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such toxicity can be reversed by reducing circulating glucose levels by fasting or insulin. Furthermore, glucose injections alone reversed the fasting-dependent protection against DXR in mice, indicating that elevated glucose mediates, at least in part, the sensitizing effects of rapamycin and dexamethasone. In yeast, glucose activates protein kinase A (PKA) to accelerate aging by inhibiting transcription factors Msn2/4. Here, we show that fasting or glucose restriction (GR) regulate PKA and AMP-activated protein kinase (AMPK) to protect against DXR in part by activating the mammalian Msn2/4 ortholog early growth response protein 1 (EGR1). Increased expression of the EGR1-regulated cardioprotective peptides atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in heart tissue may also contribute to DXR resistance. Our findings suggest the existence of a glucose-PKA pathway that inactivates conserved zinc finger stress-resistance transcription factors to sensitize cells to toxins conserved from yeast to mammals. Our findings also describe a toxic role for drugs widely used in cancer treatment that promote hyperglycemia and identify dietary interventions that reverse these effects.

Personalized Nutrition: Translating the Science of NutriGenomics Into Practice: Proceedings From the 2018 American College of Nutrition Meeting.

Adverse reactions to foods and adverse drug reactions are inherent in product defects, medication errors, and differences in individual drug exposure. Pharmacogenetics is the study of genetic causes of individual variations in drug response and pharmacogenomics more broadly involves genome-wide analysis of the genetic determinants of drug efficacy and toxicity. The similarity of nutritional genomics and pharmacogenomics stems from the innate goal to identify genetic variants associated with metabolism and disease. Thus, nutrigenomics can be thought of as encompassing gene-diet interactions involving diverse compounds that are present in even the simplest foods. The advances in the knowledge base of the complex interactions among genotype, diet, lifestyle, and environment is the cornerstone that continues to elicit changes in current medical practice to ultimately yield personalized nutrition recommendations for health and risk assessment. This information could be used to understand how foods and dietary supplements uniquely affect the health of individuals and, hence, wellness. The individual's gut microbiota is not only paramount but pivotal in embracing the multiple-functional relationships with complex metabolic mechanisms involved in maintaining cellular homeostasis. The genetic revolution has ushered in an exciting era, one in which many new opportunities are expected for nutrition professionals with expertise in nutritional genomics. The American College of Nutrition's conference focused on "Personalized Nutrition: Translating the Science of NutriGenomics Into Practice" was designed to help to provide the education needed for the professional engagement of providers in the personalized medicine era.

Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice.

Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin (HN) is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. The present study aimed to test the hypothesis that chronic supplementation of exogenous HN in middle-aged mice could prevent and reverse cardiac fibrosis and apoptosis in the aging heart. Female C57BL/6N mice at 18 mo of age received 14-mo intraperitoneal injections of vehicle (old group; n = 6) or HN analog (HNG; 4 mg/kg 2 times/wk, old + HNG group, n = 8) and were euthanized at 32 mo of age. C57BL/6N female mice (young group, n = 5) at 5 mo of age were used as young controls. HNG treatment significantly increased the ratio of cardiomyocytes to fibroblasts in aging hearts, as shown by the percentage of each cell type in randomly chosen fields after immunofluorescence staining. Furthermore, the increased collagen deposition in aged hearts was significantly reduced after HNG treatment, as indicated by picrosirius red staining. HNG treatment also reduced in aging mice cardiac fibroblast proliferation (5'-bromo-2-deoxyuridine staining) and attenuated transforming growth factor-ß1, fibroblast growth factor-2, and matrix metalloproteinase-2 expression (immunohistochemistry or real-time PCR). Myocardial apoptosis was inhibited in HNG-treated aged mice (TUNEL staining). To decipher the pathway involved in the attenuation of the myocardial fibrosis by HNG, Western blot analysis was done and showed that HNG upregulated the Akt/glycogen synthase kinase -3ß pathway in aged mice. Exogenous HNG treatment attenuated myocardial fibrosis and apoptosis in aged mice. The results of the present study suggest a role for the mitochondria-derived peptide HN in the cardioprotection associated with aging. NEW & NOTEWORTHY Cardiac fibrosis is a biological process that increases with age and contributes to myocardial dysfunction. Humanin is an endogenous mitochondria-derived peptide that has cytoprotective effects and reduces oxidative stress. Here, we demonstrate, for the first time, that exogenous humanin treatment attenuated myocardial fibrosis and apoptosis in aging mice. We also detected upregulated Akt/glycogen synthase kinase-3ß pathway in humanin analog-treated mice, which might be the mechanism involved in the cardioprotective effect of humanin analog in aging mice.

Safety and feasibility of fasting in combination with platinum-based chemotherapy.

BACKGROUND: Short-term starvation prior to chemotherapy administration protects mice against toxicity. We undertook dose-escalation of fasting prior to platinum-based chemotherapy to determine safety and feasibility in cancer patients. METHODS: 3 cohorts fasted before chemotherapy for 24, 48 and 72 h (divided as 48 pre-chemo and 24 post-chemo) and recorded all calories consumed. Feasibility was defined as ≥ 3/6 subjects in each cohort consuming ≤ 200 kcal per 24 h during the fast period without excess toxicity. Oxidative stress was evaluated in leukocytes using the COMET assay. Insulin, glucose, ketones, insulin-like growth factor-1 (IGF-1) and IGF binding proteins (IGFBPs) were measured as biomarkers of the fasting state. RESULTS: The median age of our 20 subjects was 61, and 85 % were women. Feasibility criteria were met. Fasting-related toxicities were limited to ≤ grade 2, most commonly fatigue, headache, and dizziness. The COMET assay indicated reduced DNA damage in leukocytes from subjects who fasted for ≥48 h (p = 0.08). There was a non-significant trend toward less grade 3 or 4 neutropenia in the 48 and 72 h cohorts compared to 24 h cohort (p = 0.17). IGF-1 levels decreased by 30, 33 and 8 % in the 24, 48 and 72 h fasting cohorts respectively after the first fasting period. CONCLUSION: Fasting for 72 h around chemotherapy administration is safe and feasible for cancer patients. Biomarkers such as IGF-1 may facilitate assessment of differences in chemotherapy toxicity in subgroups achieving the physiologic fasting state. An onging randomized trial is studying the effect of 72 h of fasting. TRIAL REGISTRATION: NCT00936364 , registered propectively on July 9, 2009.

Fasting and Caloric Restriction in Cancer Prevention and Treatment.

Cancer is the second leading cause of death in the USA and among the leading major diseases in the world. It is anticipated to continue to increase because of the growth of the aging population and prevalence of risk factors such as obesity, smoking, and/or poor dietary habits. Cancer treatment has remained relatively similar during the past 30 years with chemotherapy and/or radiotherapy in combination with surgery remaining the standard therapies although novel therapies are slowly replacing or complementing the standard ones. According to the American Cancer Society, the dietary recommendation for cancer patients receiving chemotherapy is to increase calorie and protein intake. In addition, there are no clear guidelines on the type of nutrition that could have a major impact on cancer incidence. Yet, various forms of reduced caloric intake such as calorie restriction (CR) or fasting demonstrate a wide range of beneficial effects able to help prevent malignancies and increase the efficacy of cancer therapies. Whereas chronic CR provides both beneficial and detrimental effects as well as major compliance challenges, periodic fasting (PF), fasting-mimicking diets (FMDs), and dietary restriction (DR) without a reduction in calories are emerging as interventions with the potential to be widely used to prevent and treat cancer. Here, we review preclinical and preliminary clinical studies on dietary restriction and fasting and their role in inducing cellular protection and chemotherapy resistance.

Exploring juventology: unlocking the secrets of youthspan and longevity programs.

In recent decades, the study of biological aging has evolved from simplistic theories like the free radical theory to more complex and nuanced perspectives. In particular, the identification of evolutionary conserved genes and signaling pathways that can modulate both lifespan but also healthspan has resulted in the expanding understanding of the link between nutrients, signal transduction proteins, and aging along with substantial support for the existence of multiple "longevity programs," which are activated based on the availability of nutrients. Periodic fasting and other dietary restrictions can promote entry into a longevity program characterized by cellular protection and optimized function, and the activation of regenerative processes that lead to rejuvenation. This review discusses the idea of juventology, a novel field proposing the existence of longevity programs that can maintain organisms in a highly functional state for extended periods of time. Drawing upon research on Saccharomyces cerevisiae and other model organisms, the review explores the distinctiveness of juventology from traditional aging-centered views. The focus on the "age of youth" challenges conventional thinking and opens new avenues for understanding and extending the period of peak functionality in organisms. Thus, a "juventology"-based strategy can complement the traditional gerontology approach by focusing not on aging but on the longevity program affecting the life history period in which mortality is very low and organisms remain youthful, healthy, and fully functional.

Fasting-mimicking diet causes hepatic and blood markers changes indicating reduced biological age and disease risk.

In mice, periodic cycles of a fasting mimicking diet (FMD) protect normal cells while killing damaged cells including cancer and autoimmune cells, reduce inflammation, promote multi-system regeneration, and extend longevity. Here, we performed secondary and exploratory analysis of blood samples from a randomized clinical trial (NCT02158897) and show that 3 FMD cycles in adult study participants are associated with reduced insulin resistance and other pre-diabetes markers, lower hepatic fat (as determined by magnetic resonance imaging) and increased lymphoid to myeloid ratio: an indicator of immune system age. Based on a validated measure of biological age predictive of morbidity and mortality, 3 FMD cycles were associated with a decrease of 2.5 years in median biological age, independent of weight loss. Nearly identical findings resulted from  a second clinical study (NCT04150159). Together these results provide initial support for beneficial effects of the FMD on multiple cardiometabolic risk factors and biomarkers of biological age.

Breakfast keeps hunger in check.

Many studies associate skipping breakfast with increased overall and disease-specific mortality. In this issue, studies by Ruddick-Collins et al. and Vujovic et al. may begin to explain these findings by showing that those who either skip breakfast or shift high calorie intake from morning to evening display increased hunger. Of note, skipping breakfast also resulted in lower energy expenditure.

The Effects of Dietary Interventions on Brain Aging and Neurological Diseases.

Dietary interventions can ameliorate age-related neurological decline. Decades of research of in vitro studies, animal models, and clinical trials support their ability and efficacy to improve behavioral outcomes by inducing biochemical and physiological changes that lead to a more resilient brain. Dietary interventions including calorie restriction, alternate day fasting, time restricted feeding, and fasting mimicking diets not only improve normal brain aging but also slow down, or even reverse, the progression of neurological diseases. In this review, we focus on the effects of intermittent and periodic fasting on improving phenotypic outcomes, such as cognitive and motor-coordination decline, in the normal aging brain through an increase in neurogenesis and synaptic plasticity, and decrease in neuroinflammation, mitochondrial dysfunction, and oxidative stress. We summarize the results of various dietary interventions in animal models of age-related neurological diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, and Multiple Sclerosis and discuss the results of clinical trials that explore the feasibility of dietary interventions in the prevention and treatment of these diseases.

Fasting and fasting-mimicking diets for chemotherapy augmentation.

The increasingly older population in most developed countries will likely experience aging-related chronic diseases such as diabetes, metabolic syndrome, heart and lung diseases, osteoporosis, arthritis, dementia, and/or cancer. Genetic and environmental factors, but also lifestyle choices including physical activity and dietary habits, play essential roles in disease onset and progression. Sixty-five percent of Americans diagnosed with cancer now survive more than 5 years, making the need for informed lifestyle choices particularly important to successfully complete their treatment, increase the recovery from the cytotoxic therapy options, and improve cancer-free survival. This review will discuss the findings on the use of prolonged fasting, as well as fasting-mimicking diets to augment cancer treatment. Preclinical studies in rodents strongly support the implementation of these dietary interventions and a small number of clinical trials begin to provide encouraging results for cancer patients and cancer survivors.

Time-Restricted Eating, Intermittent Fasting, and Fasting-Mimicking Diets in Weight Loss.

PURPOSE OF REVIEW: This article reviews the current literature on dietary interventions, including time-restricted eating (TRE), intermittent fasting (IF), and fasting-mimicking diets (FMD) and their effects on weight loss. RECENT FINDINGS: Dietary interventions, primarily known for their potential health benefits, are attracting considerable interest also for their effects on weight loss. The literature suggests that many popular diets can induce weight loss but only a limited number of studies actually demonstrate long-term weight loss efficacy. Here we present an update on the latest studies on some of the most popular dietary interventions able to trigger the physiology of fasting and highlight their impact on weight loss in overweight or obese individuals.

Fasting-mimicking diet prevents high-fat diet effect on cardiometabolic risk and lifespan.

Diet-induced obesity is a major risk factor for metabolic syndrome, diabetes and cardiovascular disease. Here, we show that a 5-d fasting-mimicking diet (FMD), administered every 4 weeks for a period of 2 years, ameliorates the detrimental changes caused by consumption of a high-fat, high-calorie diet (HFCD) in female mice. We demonstrate that monthly FMD cycles inhibit HFCD-mediated obesity by reducing the accumulation of visceral and subcutaneous fat without causing loss of lean body mass. FMD cycles increase cardiac vascularity and function and resistance to cardiotoxins, prevent HFCD-dependent hyperglycaemia, hypercholesterolaemia and hyperleptinaemia and ameliorate impaired glucose and insulin tolerance. The effect of monthly FMD cycles on gene expression associated with mitochondrial metabolism and biogenesis in adipocytes and the sustained ketogenesis in HFCD-fed mice indicate a role for fat cell reprogramming in obesity prevention. These effects of an FMD on adiposity and cardiac ageing could explain the protection from HFCD-dependent early mortality.

Diet composition influences the metabolic benefits of short cycles of very low caloric intake.

Diet composition, calories, and fasting times contribute to the maintenance of health. However, the impact of very low-calorie intake (VLCI) achieved with either standard laboratory chow (SD) or a plant-based fasting mimicking diet (FMD) is not fully understood. Here, using middle-aged male mice we show that 5 months of short 4:10 VLCI cycles lead to decreases in both fat and lean mass, accompanied by improved physical performance and glucoregulation, and greater metabolic flexibility independent of diet composition. A long-lasting metabolomic reprograming in serum and liver is observed in mice on VLCI cycles with SD, but not FMD. Further, when challenged with an obesogenic diet, cycles of VLCI do not prevent diet-induced obesity nor do they elicit a long-lasting metabolic memory, despite achieving modest metabolic flexibility. Our results highlight the importance of diet composition in mediating the metabolic benefits of short cycles of VLCI.

Assessing Insulin and Glucose Tolerance in the Aging Mouse.

Basic preclinical research on the pathophysiology of aging-related and/or metabolic diseases, including type 2 diabetes, largely relies on animal models. Mice, the most commonly used species to study the biological processes that regulate aging and its associated functional decline, have helped researchers to identify pathways, mechanisms, and genes that regulate aging-related diseases and aging itself and thus are intervention targets. Changes in energy metabolism are a central component of the biological processes that undergo significant alterations with age. For example, the prevalence of type 2 diabetes and impaired glucose tolerance increases with aging. Not surprisingly, the characterization of these changes for metabolic phenotyping is commonly found in laboratories around the world. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) do not require surgery, are relatively easy to perform, and, most importantly, are minimally invasive and are thus the preferred method to evaluate glucose homeostasis in the aging animal. Both assays measure blood glucose following the bolus injection of either glucose (for GTT) or insulin (for ITT). Although they are standard procedures, the interpretation of both assays is strongly influenced by laboratory practices and variable experimental conditions. Here, we aim to provide simple guidelines that can be useful to standardize GTT and ITT in the aging mouse.

Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers.

Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. Here we show that vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1 and ferritin in KRAS-mutant cancer cells, consequently increasing reactive iron, oxygen species, and cell death; an effect further potentiated by chemotherapy. In support of a potential role of ferritin in colorectal cancer progression, an analysis of The Cancer Genome Atlas Database indicates that KRAS mutated colorectal cancer patients with low intratumor ferritin mRNA levels display longer 3- and 5-year overall survival. Collectively, our data indicate that the combination of a fasting-mimicking diet and vitamin C represents a promising low toxicity intervention to be tested in randomized clinical trials against colorectal cancer and possibly other KRAS mutated tumors.