Nutritional influences on epigenetics and age-related disease

Nutritional epigenetics has emerged as a novel mechanism underlying gene-diet interactions, further elucidating the modulatory role of nutrition in aging and age-related disease development. Epigenetics is defined as a heritable modification to the DNA that regulates chromosome architecture and modulates gene expression without changes in the underlying bp sequence, ultimately determining phenotype from genotype. DNA methylation and post-translational histone modifications are classical levels of epigenetic regulation. Epigenetic phenomena are critical from embryonic development through the aging process, with aberrations in epigenetic patterns emerging as aetiological mechanisms in many age-related diseases such as cancer, CVD and neurodegenerative disorders. Nutrients can act as the source of epigenetic modifications and can regulate the placement of these modifications. Nutrients involved in one-carbon metabolism, namely folate, vitamin B12, vitamin B6, riboflavin, methionine, choline and betaine, are involved in DNA methylation by regulating levels of the universal methyl donor S-adenosylmethionine and methyltransferase inhibitor S-adenosylhomocysteine. Other nutrients and bioactive food components such as retinoic acid, resveratrol, curcumin, sulforaphane and tea polyphenols can modulate epigenetic patterns by altering the levels of S-adenosylmethionine and S-adenosylhomocysteine or directing the enzymes that catalyse DNA methylation and histone modifications. Aging and age-related diseases are associated with profound changes in epigenetic patterns, though it is not yet known whether these changes are programmatic or stochastic in nature. Future work in this field seeks to characterise the epigenetic pattern of healthy aging to ultimately identify nutritional measures to achieve this pattern.     

Nutritional Epigenomics: A Portal to Disease Prevention

Epigenetics can be defined as inheritable and reversible phenomena that affect gene expression without altering the underlying base pair sequence. Epigenomics is the study of genome-wide epigenetic modifications. Because gene expression changes are critical in both normal development and disease progression, epigenetics is widely applicable to many aspects of biological research. The influences of nutrients and bioactive food components on epigenetic phenomena such as DNA methylation and various types of histone modifications have been extensively investigated. Because an individual’s epigenetic patterns are established during early gestation and are changed and personalized by environmental factors during our lifetime, epigenetic mechanisms are quite important in the development of transgenerational and adult obesity as well as in the development of diabetes mellitus. Aging and cancer demonstrate profound genome-wide DNA methylation changes, suggesting that nutrition may affect the aging process and cancer development through epigenetic mechanisms.     

Dietary factors and epigenetic regulation for prostate cancer prevention

The role of epigenetic alterations in various human chronic diseases has gained increasing attention and has resulted in a paradigm shift in our understanding of disease susceptibility. In the field of cancer research, e.g., genetic abnormalities/mutations historically were viewed as primary underlying causes; however, epigenetic mechanisms that alter gene expression without affecting DNA sequence are now recognized as being of equal or greater importance for oncogenesis. Methylation of DNA, modification of histones, and interfering microRNA (miRNA) collectively represent a cadre of epigenetic elements dysregulated in cancer. Targeting the epigenome with compounds that modulate DNA methylation, histone marks, and miRNA profiles represents an evolving strategy for cancer chemoprevention, and these approaches are starting to show promise in human clinical trials. Essential micronutrients such as folate, vitamin B-12, selenium, and zinc as well as the dietary phytochemicals sulforaphane, tea polyphenols, curcumin, and allyl sulfur compounds are among a growing list of agents that affect epigenetic events as novel mechanisms of chemoprevention. To illustrate these concepts, the current review highlights the interactions among nutrients, epigenetics, and prostate cancer susceptibility. In particular, we focus on epigenetic dysregulation and the impact of specific nutrients and food components on DNA methylation and histone modifications that can alter gene expression and influence prostate cancer progression.     

Nutritional Status Impacts Epigenetic Regulation in Early Embryo Development: A Scoping Review

With the increasing maternal age and the use of assisted reproductive technology in various countries worldwide, the influence of epigenetic modification on embryonic development is increasingly notable and prominent. Epigenetic modification disorders caused by various nutritional imbalance would cause embryonic development abnormalities and even have an indelible impact on health in adulthood. In this scoping review, we summarize the main epigenetic modifications in mammals and the synergies among different epigenetic modifications, especially DNA methylation, histone acetylation, and histone methylation. We performed an in-depth analysis of the regulation of various epigenetic modifications on mammals from zygote formation to cleavage stage and blastocyst stage, and reviewed the modifications of key sites and their potential molecular mechanisms. In addition, we discuss the effects of nutrition (protein, lipids, and one-carbon metabolism) on epigenetic modification in embryos and emphasize the importance of various nutrients in embryonic development and epigenetics during pregnancy. Failures in epigenetic regulation have been implicated in mammalian and human early embryo loss and disease. With the use of reproductive technologies, it is becoming even more important to establish developmentally competent embryos. Therefore, it is essential to evaluate the extent to which embryos are sensitive to these epigenetic modifications and nutrition status. Understanding the epigenetic regulation of early embryo development will help us make better use of reproductive technologies and nutrition regulation to improve reproductive health in mammals.     

Epigenetics: A New Link Between Nutrition and Cancer

Emerging studies suggest that dietary components can affect gene expression through epigenetic mechanisms. Epigenetic modifications are heritable and potentially reversible changes in gene expression that do not require changes in the DNA sequence. The main mechanisms of epigenetic control in mammals are DNA methylation, histone modifications, and RNA silencing. The potential reversibility of epigenetic changes suggests that they could be modulated by nutrition and bioactive food compounds. Thus, epigenetic modifications could mediate environmental signals and provide a link between susceptibility genes and environmental factors in the etiology of cancer. Elucidating the impact of nutrition on epigenetic mechanisms may serve as a tool to predict an individuals’ susceptibility to cancer, provide dietary recommendations, or provide therapeutic applications of natural compounds against cancer. The optimal duration and the dose necessary for a chemopreventive effect require further studies. There is limited information about tissue specificity and temporal aspects of dietary treatments. Species differences need to be considered when interpreting results from various models. Importantly, molecular mechanisms of bioactive dietary components should be investigated in greater detail in human intervention studies. Although some of these issues remain controversial, this review mainly focuses on promising data that support the developing field of Nutritional Epigenetics.     

饮食限制延缓衰老的表观遗传学机制

目的 近年来兴起的表观遗传学被认为在饮食影响健康、延缓衰老中发挥重要的作用。本文旨在从表观遗传学视角分析饮食限制延缓衰老的机制,为临床上抗衰老及其防治相关疾病提供理论参考。方法 系统综述了表观遗传学与衰老的关系,及饮食限制延缓衰老的表观遗传调控方式。结果 饮食限制通过DNA甲基化、组蛋白修饰、非编码RNA调控和染色质重塑等表观遗传修饰调节基因表达,进而影响衰老及其相关疾病的发生发展。结论 饮食限制是一种有效的可操作的环境因素,可通过调节表观遗传修饰进而延缓衰老,保持健康。     

Early Life Nutrition,Epigenetics and Programming of Later Life Disease

The global pandemic of obesity and type 2 diabetes is often causally linked to marked changes in diet and lifestyle; namely marked increases in dietary intakes of high energy diets and concomitant reductions in physical activity levels. However, less attention has been paid to the role of developmental plasticity and alterations in phenotypic outcomes resulting from altered environmental conditions during the early life period. Human and experimental animal studies have highlighted the link between alterations in the early life environment and increased risk of obesity and metabolic disorders in later life. This link is conceptualised as the developmental programming hypothesis whereby environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the health and well-being of the offspring. In particular, the nutritional environment in which the fetus or infant develops influences the risk of metabolic disorders in offspring. The late onset of such diseases in response to earlier transient experiences has led to the suggestion that developmental programming may have an epigenetic component, as epigenetic marks such as DNA methylation or histone tail modifications could provide a persistent memory of earlier nutritional states. Moreover, evidence exists, at least from animal models, that such epigenetic programming should be viewed as a transgenerational phenomenon. However, the mechanisms by which early environmental insults can have long-term effects on offspring are relatively unclear. Thus far, these mechanisms include permanent structural changes to the organ caused by suboptimal levels of an important factor during a critical developmental period, changes in gene expression caused by epigenetic modifications (including DNA methylation, histone modification, and microRNA) and permanent changes in cellular ageing. A better understanding of the epigenetic basis of developmental programming and how these effects may be transmitted across generations is essential for the implementation of initiatives aimed at curbing the current obesity and diabetes crisis.     

Considering Maternal Dietary Modulators for Epigenetic Regulation and Programming of the Fetal Epigenome

Fetal life is characterized by a tremendous plasticity and ability to respond to various environmental and lifestyle factors, including maternal nutrition. Identification of the role of dietary factors that can modulate and reshape the cellular epigenome during development, including methyl group donors (e.g., folate, choline) and bioactive compounds (e.g., polyphenols) is of great importance; however, there is insufficient knowledge of a particular effect of each type of modulator and/or their combination on fetal life. To enhance the quality and safety of food products for proper fetal health and disease prevention in later life, a better understanding of the underlying mechanisms of dietary epigenetic modulators during the critical prenatal period is necessary. This review focuses on the influence of maternal dietary components on DNA methylation, histone modification, and microRNAs, and summarizes current knowledge of the effect and importance of dietary components on epigenetic mechanisms that control the proper expression of genetic information. Evidence reveals that some components in the maternal diet can directly or indirectly affect epigenetic mechanisms. Understanding the underlying mechanisms of how early-life nutritional environment affects the epigenome during development is of great importance for the successful prevention of adult chronic diseases through optimal maternal nutrition.     

Targeting DNA Methylation in the Adult Brain through Diet

Metabolism and nutrition have a significant role in epigenetic modifications such as DNA methylation, which can influence gene expression. Recently, it has been suggested that bioactive nutrients and gut microbiota can alter DNA methylation in the central nervous system (CNS) through the gut–brain axis, playing a crucial role in modulating CNS functions and, finally, behavior. Here, we will focus on the effect of metabolic signals in shaping brain DNA methylation during adulthood. We will provide an overview of potential interactions among diet, gastrointestinal microbiome and epigenetic alterations on brain methylation and behavior. In addition, the impact of different diet challenges on cytosine methylation dynamics in the adult brain will be discussed. Finally, we will explore new ways to modulate DNA hydroxymethylation, which is particularly abundant in neural tissue, through diet.     

Epigenetics and maternal nutrition: nature v. nurture

Under- and over-nutrition during pregnancy has been linked to the later development of diseases such as diabetes and obesity. Epigenetic modifications may be one mechanism by which exposure to an altered intrauterine milieu or metabolic perturbation may influence the phenotype of the organism much later in life. Epigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene expression from one generation of cells to the next. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodelling and histone modifications play key roles in adipogenesis and the development of obesity. Epigenetic modifications affecting processes important to glucose regulation and insulin secretion have been described in the pancreatic β-cells and muscle of the intrauterine growth-retarded offspring, characteristics essential to the pathophysiology of type-2 diabetes. Epigenetic regulation of gene expression contributes to both adipocyte determination and differentiation in in vitro models. The contributions of histone acetylation, histone methylation and DNA methylation to the process of adipogenesis in vivo remain to be evaluated.     

Nutrition and epigenetics: An emerging field

Epigenetics refers to heritable changes to gene expression encoded not by differences in the genetic sequence but by other chemical modifications to chromatin, such as methylation of the DNA backbone, or acetylation and methylation of the histone core. The total set of such epigenetic marks can be referred to as the epigenome, but unlike the genome, epigenetic marks differ between tissues and are modified by metabolic conditions and environmental exposures throughout life. In humans and animal models, key metabolic pathways, such as those of energy metabolism and obesity, are believed to be partly regulated by epigenetic mechanisms and to be subject to metabolic and nutritional modification in utero and throughout life. There is growing interest in the possibility that extremes of energy or micronutrient availability may modulate the epigenome and hence modify the development and disease susceptibility of individuals. Particular interest is evident for methyl donors, including folic acid, which might directly modify DNA methylation in humans.     

The Interaction between Epigenetics,Nutrition and the Development of Cancer

Unlike the genome, the epigenome can be modified and hence some epigenetic risk markers have the potential to be reversed. Such modifications take place by means of drugs, diet or environmental exposures. It is widely accepted that epigenetic modifications take place during early embryonic and primordial cell development, but it is also important that we gain an understanding of the potential for such changes later in life. These “later life” epigenetic modifications in response to dietary intervention are the focus of this paper. The epigenetic modifications investigated include DNA methylation, histone modifications and the influence of microRNAs. The epigenotype could be used not only to predict susceptibility to certain cancers but also to assess the effectiveness of dietary modifications to reduce such risk. The influence of diet or dietary components on epigenetic modifications and the impact on cancer initiation or progression has been assessed herein.     

环境表观遗传学研究进展

在许多复杂疾病如肿瘤、心血管系统疾病等的发生发展过程中,遗传学机制和环境因素均发挥着重要的作用。遗传学的核心研究内容集中在基因突变、基因重组等基因序列的改变,而目前的研究发现除基因序列外,还存在着其他一些因素影响着基因的表达。表观遗传学即是研究除基因序列改变之外,基因功能的可逆的、可遗传的改变,主要有DNA甲基化、组蛋白乙酰化、微小RNA等。随着环境医学研究的不断深入,表观遗传的重要作用得以凸显,表观遗传的改变不仅可以解释某些疾病的发病机制,而且还可以作为疾病早期诊断和预防的标志。环境中化学因素、物理因素、生物因素和精神心理以及其他因素的表观遗传学改变已被证实与疾病密切相关,因此了解环境中各种因素的表观遗传效应十分必要。     

Epigenetic Effects of Human Breast Milk

A current aim of nutrigenetics is to personalize nutritional practices according to genetic variations that influence the way of digestion and metabolism of nutrients introduced with the diet. Nutritional epigenetics concerns knowledge about the effects of nutrients on gene expression. Nutrition in early life or in critical periods of development, may have a role in modulating gene expression, and, therefore, have later effects on health. Human breast milk is well-known for its ability in preventing several acute and chronic diseases. Indeed, breastfed children may have lower risk of neonatal necrotizing enterocolitis, infectious diseases, and also of non-communicable diseases, such as obesity and related-disorders. Beneficial effects of human breast milk on health may be associated in part with its peculiar components, possible also via epigenetic processes. This paper discusses about presumed epigenetic effects of human breast milk and components. While evidence suggests that a direct relationship may exist of some components of human breast milk with epigenetic changes, the mechanisms involved are still unclear. Studies have to be conducted to clarify the actual role of human breast milk on genetic expression, in particular when linked to the risk of non-communicable diseases, to potentially benefit the infant’s health and his later life.     

Use of exfoliated cells from target tissues to predict responses to bioactive food components

A host of bioactive food components have been proposed to promote health and reduce the risk of disease states. It is clear that not all individuals respond identically to these essential and nonessential food components. Genetic polymorphisms may influence absorption, metabolism and accumulation of bioactive food components, thereby influencing their actions in target tissues. Unfortunately, serum concentrations of bioactive food components may not correlate with tissue concentrations and may therefore under- or overestimate the response in target tissues. Exfoliated cells may be useful to assess the actions of nutrients in specific tissues. Although not extensively examined, evidence already suggests the usefulness of these cells in predicting changes in gene expression, DNA methylation, DNA damage, protein expression and accumulation of dietary components. Although there are limitations on the collection of exfoliated cells, the inaccessibility of tissues they can represent raises intriguing possibilities for their ability to predict the outcome of nutritional intervention studies.     

Epigenetics in Food Allergy and Immunomodulation

Food allergy (FA) is an increasing problem worldwide and, over recent years, its prevalence is rising in developed countries. Nowadays, the immunological and cellular processes that occur in the allergic reactions are not fully understood, which hampers the development of in vitro diagnostic tools and further treatment options. Moreover, allergic diseases could be reinforced by environmental exposure and genetic modifications. Gene expression can be controlled by different epigenetic mechanisms like DNA methylation, histone modifications, and microRNAs. In addition, several environmental factors such as dietary components (vitamin D, butyrate, folic acid) are able to regulate this epigenetic mechanism. All these factors produce modifications in immune genes that could alter the development and function of immune cells, and therefore the etiology of the disease. Furthermore, these epigenetic mechanisms have also an influence on immunomodulation, which could explain sustained responsiveness or unresponsiveness during immunotherapy due to epigenetic modifications in key genes that induce tolerance in several FA. Thus, in this review we focus on the different epigenetic mechanisms that occur in FA and on the influence of several dietary components in these gene modifications.     

Epigenetic regulation during mammalian oogenesis

The advent of the epigenetic era has sparked a new frontier in molecular research and the understanding of how development can be regulated beyond direct alterations of the genome. Thus far, the focal point of epigenetic regulation during development has been chromatin modifications that control differential gene expression by DNA methylation and histone alterations. But what of events that alter gene expression without direct influence on the DNA itself? The present review focuses on epigenetic pathways regulating development from oogenesis to organogenesis and back that do not involve methylation of cytosine in DNA. We discuss target components of epigenetic modification such as organelle development, compartmentalisation of maternal factors and molecular mediators in the oocyte and how these factors acting during oogenesis impact on later development. Epigenetic regulation of development, be it via cytosine methylation or not, has wide-ranging effects on the subsequent success of a pregnancy and the intrinsic health of offspring. Perturbations in epigenetic regulation have been clearly associated with disease states in adult offspring, including Type II diabetes, hypertension, cancers and infertility. A clear understanding of all epigenetic mechanisms is paramount when considering the increased use of assisted reproductive techniques and the risks associated with their use.