Epigenetic

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Table Content:1. Mechanism of Epigenetic2. History of Epigenetic3. Factors affecting Epigenetics4. How does Epigenetics work?5. Illness related to Epigenetics6. Challenges in Epigenetic7. Present and Future of anti-aging epigenetic diet8. Epigenetic between nutrition and longevity9. Drug side effects10. The future of Epigenetics

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Epigenetics means “above” or “on top of “genetics. It refers to external modification to DNA that turn genes “on” or “off”. These modification do not change the DNA sequence, but instead, they affect how cells “read” genes. It also refers to heritable changes in gene expression (active versus inactive genes) that does not involve changes to the underlying DNA sequence, but a change in phenotype without a change in genotype. Epigenetic change is a regular and natural occurrence but can also be influenced by several factors including age, environment or lifestyle and disease state.

Mechanisms of epigeneticsEpigenetic changes alter the physical structure of DNA. One

example of epigenetic changes is DNA methylation. It’s the addition of a methyl group or a ‘chemical cap’ to part of DNA molecule, which prevents certain genes from being expressed. Another example is histone modification. Histones are proteins that DNA wrap around. (Without histones, DNA would be too long to fit inside cells). If histones squeeze DNA tightly, the DNA cannot be ‘read’ by the cell. Modification that relax the histones can make the DNA accessible to proteins ‘read’ genes. Epigenetics is the reason why a skin cell looks different from a brain cell or a muscle cell. All three cells contain the same DNA, but their genes are expressed differently (turned “on” or “off”), which creates the different cell types.

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Histone modificationHistones are highly basic proteins whose function is to organize

DNA within the nucleus. As mentioned above, in the nucleus, DNA is tightly packaged into chromatin, a DNA protein complex that consists of DNA in a double helix, histone proteins, and many associated regulatory proteins. Modification of histones is a crucial mechanism for epigenetic tagging of the genome.25,51 Histone modification can occur as a consequence of DNA methylation, or can be mediated by mechanisms that are independent of DNA methylation and controlled by intracellular signaling. The basic unit of chromatin is the nucleosome, which is composed of an octomer of histone proteins around which wrapped like a rope on a windless (DNA double helix)

Epigenetic essentially affects how genes are bead by cells, and subsequently how they produce proteins. Here are few important points about epigenetics• Epigenetics Controls Genes.

- Certain circumstances in life can cause genes to be silenced or expressed over time. In other words, they can be turned off (becoming dormant) or turned on (becoming active).

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• Epigenetics Is Everywhere.

- What you eat, where you live, who you interact with, when you sleep, how you exercise, even aging – all of these can eventually cause chemical modifications around the genes that will turn those genes on or off over time. Additionally, in certain diseases such as cancer or Alzheimer’s, various genes will be switched into the opposite state, away from the healthy state

• Epigenetics Makes Us Unique.

- Even though we are all human, why do some of us have blonde hair or darker skin? Why do some of us hate the taste of mushrooms or eggplants? Why are some of us more sociable than others? The different combinations of genes that are turned on or off is what makes each one of us unique. Furthermore, there have been indications that some epigenetic changes can be inherited.

• Epigenetics Is Reversible.

- With 20,000+ genes, what will be the result of the different combinations of genes being turned on or off? The possible arrangements are enormous! But if we could map every single cause and effect of the different combinations, and if we could reverse the gene’s state to keep the good while eliminating the bad, then we could theoretically cure cancer, slow aging, stop obesity, and so much more.

There are few mechanisms involved in epigenetic alteration, yet the most common is DNA methylation. Understanding of epigenetic mechanism is vital for the prevention of certain diseases as well as to determine the type of food that we should choose to in order to preserve our gene exhaustion. “Dr. Thenmaaran, MBBS, MSc (Molecular Medicine)”.

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“Epigenetics defines the set of distinct and heritable molecular mechanisms able to influence gene expression without altering the primary genetic sequence. When normal epigenetic pathway function is disrupted, disease may result.” Dr.Lau Cher Rene, Medical Practitioner, Malaysia

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History of Epigenetics

Conrad H.W Ernst Hadorn The term epigenetics, which was coined by Conrad

H. Waddington in 1942, was derived from the Greek word “epigenetics” which originally described the influence of genetic processes on development. Conrad H. Waddington and Ernst Hadorn, started the study of epigenetics. During the 1990s there became a renewed interest in genetic assimilation. This lead to elucidation of the molecular basis of Conrad Waddington’s observations in which environmental stress caused genetic assimilation of certain phenotypic characteristics in Drosophila fruit flies. Since then, researcher efforts have been focused on unraveling the epigenetic mechanisms related to these types of changes. Currently, DNA methylation is one of the most broadly studied and well-characterized epigenetic modification dating back to studies done by Griffith and Mahler in 1969 which suggested that DNA methylation may be important in long term memory function.

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Epigenetic InheritanceIt may be possible to pass down epigenetic changes to future generations if the changes occur in sperm or egg cells. Most epigenetic changes that occur in sperm and egg cells get erased when the two combine to form a fertilized egg, in a process called “reprogramming”. This reprogramming allows the cells of the fetus to “start from scratch” and make their own epigenetic changes. But scientists think some of the epigenetic changes in parents, the sperm and egg cells may avoid the reprogramming process, and make it through to the next generation. If this partially true. Things like the food that a person eats before conceive could affect their future child.

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The Challenges of Proving epigenetic inheritance is not always straightforward. To provide a watertight case for epigenetic inheritance, researchers must:

• Rule out the possibility of genetic changes in organisms with larg-er genomes, a single mutation can hide like a needle in a haystack.• Show that the epigenetic effect can pass through enough generations to rule out the possibility of direct exposure.

Epigenetic inheritance adds another dimension to the modern picture of evolution. The genome changes slowly, through the processes of random mutation and natural selection. It takes many generations for a genetic trait to become common in a population. The epigenome, on the other hand, can change rapidly in response to signals from the environment. And epigenetic changes can happen in many individuals at once. Through epigenetic inheritance, some of the experiences of the parents may pass to future generations. At the same time, the epigenome remains flexible as environmental conditions continue to change. Epigenetic inheritance may allow an organism to continually adjust its gene expression to fit its environment - without changing its DNA code.

The term epigenetics was coined by Conrad H.Waddington by an experiment with fruit flies called Drosophilia. He started to investigate the epigenetic changes and discovered human being also carries an epigenetic changes. This discovery is really amazing and contributes in the advancement of science and technology. “ Dr. Thenmaaran, MBBS,MSc (molecular medicine)”.

“Food that a person eats before conceive could affect their future child. This shows that epigenetic are related to our daily food. Selection on the right food is crucial for everyone especially for pregnant woman.” Dr.Lau Cher Rene, Medical Practitioner, Malaysia

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Norwegian University of Science and Technology researchers Ingerid Arbo and Hans-Richard Brattbakk have fed slightly about overweight people have different diets, and studied the effect of this on gene expression. Gene

expression refers to the process where information from a gene’s DNA sequence is translated into a substance, like a protein, that is used in a cell’s structure or function. “We have found that a diet with 65% carbohydrates, which often is what the average Norwegian eats in some meals, causes a number of classes of genes to work overtime,” says Berit Johansen, a professor of biology at NTNU.

Researcher Johansen said “Both low-carb and high-carb diets are wrong,” “But a low-carb diet is closer to the right diet. A healthy diet shouldn’t be made up of more than one-third carbohydrates (up to 40 per cent of calories) in each meal, otherwise we stimulate our genes to initiate the activity that creates inflammation in the body.” He also supervises the project’s doctoral students and has conducted research on gene expression since the 1990s, saying that ‘This affects not only the genes that cause inflammation in the body, which was what we originally wanted to study, but also genes associated with development of cardiovascular disease, some cancers, dementia, and type 2 diabetes, all the major lifestyle-related diseases.’

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What are the factor affects epigeneticsFood

You might think that stress merely affects your mood temporarily or gives you a brief headache. But the truth is that chronic stress can affect your health on a much deeper level.

For proof that stress can affect your genes, in 2013 study published in Proceedings of the National Academy of Sciences. The report found that exposure to chronic stress specifically stress that sets off a person’s fight to fight response, which affects the sympathetic nervous system by changed the way genes are activated in immune cells. Basically, excessive amounts of stress over time got the cells fired up to fight off an infection that didn’t really exist, which led to the cells fired up to fight off an infection that didn’t really exist. The problem is that inflammation raises the risk for all sort of serious health conditions, such as heart disease, obesity, diabetes and many more. The researchers found this negative cycle to be true in both the cells of mice and the cells of humans.

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Stress

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Drug

The presence of drugs or chemicals in an organism’s environment can also influence gene expression in the organism. Cyclops fish are a dramatic example of the way in which an environmental chemical can affect development. In 1907,

researcher C. R. Stockard created cyclopean fish embryos by placing fertilized Fundulus heteroclitus eggs in 100 mL of seawater mixed with approximately 6 g of magnesium chloride. Normally, F. heteroclitus embryos feature two eyes; however, in this experiment, half of the eggs placed in the magnesium chloride mixture gave rise to one-eyed embryos (Stockard, 1907).

Environmental pollution

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The development and expression of traits also depends on the external and internal environment. The frequency with which a certain trait is expressed in a population is called penetrance, and the extent to which a phenotype is expressed in an individual is called expressivity. Exhaust from cars and trucks is a significant source of outdoor air pollution. When we breathe in high levels of the particles present in exhaust, these particles can irritate the lungs and cause breathing disorders. Once in the bloodstream, fine particles (2.5 micrometers in diameter or less) may lead to inflammation throughout the body. Outdoor air pollution has been associated with heart attacks, strokes, and cancers.

Not much is known about how fine particles affect the body on a molecular level. However, breathing in fine particles has been associated with epigenetic changes that may increase the risk of disease. Epigenetic changes are alterations in the way genes are switched on and off without a change in the DNA sequence. The type of epigenetic change associated with air pollution is DNA methylation, the attachment of methyl groups to DNA.

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How lifestyle can influence Epigenetic changes from one generation to next generation.

The field of epigenetics is quickly growing and with the understanding that both the environment and individual lifestyle can also direct interact with the genome to influence epigenetic change. These changes may be reflected at various stages throughout a person’s life and even next generation. For example, human epidemiological studies have provided evidence that prenatal and early postnatal environmental factors influence the adult risk of developing various chronic diseases and behavioral disorders. Studies have shown that children born during the period of the Dutch famine from 1944-1945 have increased rates of coronary heart disease and obesity after maternal exposure to famine during early pregnancy compared to those not exposed to famine.

The root cause of epigenetic alteration is the factors that involved in gene modification which comprises of diet intake, stress, alcohol consumption, smoking, drugs and also environmental pollution. These are the main factors that change the epigenetic and lead to disease progression. Hence, we must learn, aware and minimize those factors in our life. “Dr. Thenmaaran, MBBS,MSc (molecular medicine)”.

“Now we know that epigenetics leads to most health issue. What causes epigenetic changes? Food, Water, Stress, Drugs and Environmental pollution. Therefore, lifestyle modification improves epigenetic alteration and epigenetic inheritance can be avoided to pass on to our next generation.” Dr.Lau Cher Rene, Medical Practitioner, Malaysia

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How does epigenetic works

An epigenome consists of a record of the chemical changes to the DNA and histone proteins of an organism, these changes can be passed down to an organism’s offspring. Changes to the epigenome can result in changes to the structure of chromatin and changes to the function of the genome. The epigenome is a multitude of chemical compounds that can tell the genome what to do. The human genome is the complete assembly of DNA (deoxyribonucleic acid) about 3 billion base pairs that makes each individual unique.

DNA holds the instructions for building the proteins that carry out a variety of functions in a cell. The epigenome is made up of chemical compounds and proteins that can attach to DNA and direct such actions as turning genes on or off, controlling the production of proteins in particular cells.

When epigenomic compounds attach to DNA and modify its function, they are said to have “marked” the genome. These marks do not change the sequence of the DNA. Rather, they change the way cells use the DNA’s instructions. The marks are sometimes passed on from cell to cell as cells divide. They also can be passed down from one generation to the next. Epigenetic tags act as a kind of cellular memory. A cell’s epigenetic profile as a collection of tag that tell genes whether to be on or off. It is the sum of the signals that received during lifetime.

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The changing Epigenome informs Gene Expression

As a fertilized egg develop into a baby, dozens of signals received over days, weeks, and months cause incremental changes in gene expression patterns. Epigenetic tags record the cell’s experiences on the DNA, helping to stabilize gene expression. Each signal shuts down some genes and activates others as it nudges a cell towards its final fate. Different experiences cause the epigenetic profiles of each cell type to grow increasingly different over time. In the end, hundreds of cell types form, each with a distinct identify and a specialized function. Even in differentiated cells, signals fine-tune cell function through changes in gene expression. A flexible epigenome allows us to adjust to changes in the world around us, and to learn from our experiences.

The epigenome changes in response to signals. Signals come from inside the cell, from neighboring cells, or from the outside world (environment).

In early development, most signals come from within cells or from neighboring cell. Mom’s nutrition is also important at this stage. The food she bring into her body forms the building blocks for shaping the growing fetus and its development epigenome. Other types of signals, such as stress hormones. It also can travel from mom to fetus.

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After birth as life continues, A wider variety of environmental factors start to play a role in shaping the epigenome. Social interactions, physical activity, diet and other inputs generate sig-nals that travel from cell to cell throughout the body. As in early development, signals from within the body continue to be important for many processes, including physical growth and learning. Hormonal signals trigger big changes at puberty. Even into old age, cells continue to listen for signals. Environmental signals trigger changes in the epigenome, allowing cells to respond dynamically to the outside world. Internal signals direct activities that are necessary for body maintenance, such as replenishing blood cells and skin and repairing damages tissues and organs. During the old age processes, just like during embryonic development, the cell’s experiences are transferred to the epigenome, where they sut down and activate specific sets of genes.

Epigenetic works by switching on and off the gene depending on the factors that inducing the gene. Once, the particular gene involved in alteration, the protein formation for the cell function will be inhibited. “ Dr. Thenmaaran, MBBS, MSc(molecular medicine).”

“Epigenetics is essentially additional information layered on top of the sequence of letters (strings of molecules called A, C, G, and T) that makes up DNA. Any outside stimulus that can be detected by the body has the potential to cause epigenetic modifications.” Dr.Lau Cher Rene, Medical Practitioner, Malaysia

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Illness related to epigeneticsI. Alzheimer’s Disease

Alzheimer’s disease (AD) and bipolar disorder (BD) are progressive neuropsychiatric illnesses with overlapping symptoms and neuropathology, including brain atrophy, cognitive impairment, emotional disturbances, neuro inflammation, excitotoxicity and upregulated brain arachidonic acid (AA) metabolism Common behavioral disturbances in AD, aside from memory loss, are apathy, depression, agitation and general withdrawal. Apathy is the most prevalent disturbance, affecting about 70% of AD patients; depression ranks second, occurring in about 54% of patients; and agitation ranks third, appearing in about 50% of patients. Progressive neuro structural changes have been reported in adolescent and adult patients with BD, associated with cognitive impairment. Although genome-wide studies have identified a number of potential risk alleles for BD and late-onset AD, the contribution of each is small and explains only a fraction of the known heritability. High throughput genetic analysis confirms that neuropsychiatric disorders are very complex and involve many small interdependent genetic abnormalities that are influenced by polygenic inheritance, epigenetic interactions and pleiotropy. Several studies have implicated epigenetic mecha-nisms in these illnesses.In this study, we examined brain epigenetic changes in AD and BD.

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II. Cancer

The first human disease to be linked to epigenetics was cancer, in 1983. Researchers found that diseased tissue from patients with colorectal cancer had less DNA methylation than normal tissue from the same patients (Feinberg & Vogelstein, 1983). Because methylat-ed genes are typically turned off, loss of DNA methylation can cause abnormally high gene activation by altering the arrangement of chro-matin. On the other hand, too much methylation can undo the work of protective tumor suppressor genes.

III. Cardiovascular disease

Heart disease is often attributed to genetic predisposition, but epigenetic marks that vary between cell types and respond to endogenous and exogenous stimuli likely share culpability DNA methylation is critical for the development of atherosclerosis and cardiovascular disease; recently hyper methylation has been shown in differentially methylated genomic regions of patients suffering with coronoary artery disease (CAD). DNA methyltransferases (DNMTs) exhibit hypo methylation in mice, an observation associated with increased expression of inflammatory mediators. DNA hypermethylation has been observed in the estrogen receptor genes ESR1 and ESR2 of vascular smooth muscle which contributes to atherosclerosis.

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Autoimmune Diseases

Autoimmune diseases are a complex group of diseases that do not have the same epidemiology, pathology or symptoms but do have a common origin. All autoimmune diseases share immunogenetic mechanisms mediated in part by several genes. Many studies over the years have shown that these diseases are caused by alterations in many loci and genes in human genome. However, until recent years, epigenetic studies have focused on autoimmune diseases. Therefore, it is important to underline the fact that autoimmune diseases may be generated by several alterations in the same epigenetic mechanism. Also, it is essential to understand that epigenetics is not the only mechanism that may cause autoinnunity. In fact, there are intrinsic and extrinsic components (mutation and environmental factors) that predispose to autoimmunity.

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I. Rheumatoid arthritis (RA)

We have recently undertaken the study of Rheumatoid Arthritis (RA) as a model for testing our approach to epigenetic epidemiology. RA is a chronic systemic autoimmune disease, and also a complex genetic disease. It affects up to 1% of the population and is twice as frequent in women as in men. The concordance rate for monozygotic twins is only 15%, suggesting a strong epigenetic component, i.e., not explained by DNA sequence. Traditional genetic studies such as genome-wide association can explain only approximately 20% of the cause of the disease.

To address Rheumatoid Arthritis from a genetic and epigenetic basis, we examined 354 cases and 337 controls that had already been genetically tested as part of the EIRA study in Sweden. We used the Illumina Infinium Human Methylation Bead Chip array, to which we had contributed design elements from our earlier work. This study was performed by Yun Liu, a genetics postdoctoral fellow, Dani Fallin noted above, and Martin Aryee, a faculty biostatistician. The study was performed jointly and equally with a Swedish team led by Tomas Ekstrom, Lars Klareskog, and Leonid Padyukov at the Karolinska Institute. This work was recently published in Nature Biotechnology and its findings are summarized here.

II. Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, with mechanisms that remain to be elucidated. Previous studies have proposed that genes and environment arerequired for lupus to develop. It has been found that epigenetics have a significant influence on SLE. The present review will concentrate on epigenetic in SLE. There are a number of studies reporting that autoreactive T cells and B cells with SLE have evidence of altered patterns of DNA methylation.

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III. Type 1 Diabetes (T1D)

T1D is a T-cell-mediated autoimmune disease that develops in genetically susceptible individuals and affects their endocrine pancreas. There are some mechanisms by which epigenetics may play an important role in T1D by modulating lymphocyte maturation and cytokine gene expression and by differentiation of subtype T helper cells ruled by epigenetic controls. In this autoimmune disease, in contrast to SLE and RA, there is a global hypermethylation activity caused by altered metabolism of homocysteine.

Glucose and insulin levels are determinants of methylation. They alter homocysteine metabolism by increasing cell homocysteine production through its inhibition of trans-sulfuration. When there is an increase in the levels of homocysteine, methionine in cells will be catalyzed by DNMTs in S-adenosylmethionine. This will enhance DNMT activity that will subsequently lead to increased global DNA methylation. Also, an increase in maternal homocysteine during pregnancy as a result of a low protein diet can produce an altered methionine metabolism that will cause a decrease in islet mass and vascularity in the fetus with a subsequent glucose intolerance in adult life.

IV. Multiple sclerosis (MS)

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized with autoimmune response against myelin proteins and progressive axonal loss. The heterogeneity of the clinical course and low concordance rates in monozygotic twins have indicated the involvement of complex heritable and environmental factors in MS pathogenesis. MS is more often transmitted to the next generation by mothers than fathers suggesting an epigenetic influence. One of the possible reasons of this parent-of-origin effect might

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be the human leukocyte antigen, which is the major risk factor for MS and regulated by epigenetic mechanisms such as DNA methylation and histone deacetylation. Moreover, major environmental risk factors for MS, vitamin D deficiency, smoking and Ebstein-Barr virus are all known to exert epigenetic changes. In the last few decades, compelling evidence implicating the role of epigenetics in MS has accumulated. Increased or decreased acetylation, methylation and citrullination of genes regulating the expression of inflammation and myelination factors appear to be particularly involved in the epigenetics of MS. Although much less is known about epigenetic factors causing neurodegeneration, epigenetic mechanisms regulating axonal loss, apoptosis and mitochondrial dysfunction.

For every disease, the epigenetic change plays an important role in gene expression which mediating inflammatory pathway and results in cell or tissue damage. For example, most of the infectious agent like bacteria or virus can alter the gene expression and lead to some other manifestations. “ Dr. Thenmaaran, MBBS, MSc (molecular medicine).”

“DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. A growing number of human diseases have been found to be associated with aberrant DNA methylation. The vitamin folate is a key source of the one carbon group used to methylate DNA. Therefore, increase folate intake may reduce this epigenetic modification.” Dr.Lau Cher Rene, Medical Practitioner, Malaysia

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Challenges in epigeneticsThere are many challenges in studying epigenetics. Unlike

genome-wide association studies that can be conducted from easily obtained blood or skin samples. Epigenetic modifications are cell-specific. “For genetics, if you think of the DNA, it does not matter if you take the DNA from fibroblasts, skin, blood, whatever organ. Resercher Casoccia said “We have the same genetic mutation regardless”. But in epigenetics, it’s completely different. A liver cell would be different from a blood cell or a brain cell.” Additionally, monitoring epigenetic changes in the human brain is also challenging. Samples can only be obtained postmortem, according to Casaccia. The conundrum there is obvious: “How do you know if what you are studying in a postmortem brain is what really happens in life?” she said. It’s easier to monitor epigenetic changes in immune cells circulating in the blood. But even that is challenging because of the frequency of different cell types. “There are high frequencies of CD4-positive cells or CD19-positive cells that can be readily isolated from peripheral blood, but rarer forms are too infrequent to readily characterize and study.

Epigenetic changesEpigenetic modifications are reversible, heritable changes that

alter chromatin compaction and gene expression without changing the sequence of the nucleotides and include DNA methylation, posttranslational histone modification and noncoding RNA-mediated silencing pathways. Unlike the genome, the epigenetic profile varies from one cell to another in the same cell, between health and diseases status. DNA methylation, the most extensively studied epigenetic modification, involves the covalent addition of a methyl group. This methyl group protrudes into the major groove of the double-stranded DNA and can recuit protein complexes that alter chromatin compaction or displace transcription factors and silence the genomic region involved.

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Experiment with epigenetics

Dr. Lard Olov Brygren conducted an experiment where he collected data from kid born in 1905 who grew up in Norbotten, Sweden. Its small farming village, Brygren collected data on these kids, ther children and grandchildren to see what affect this eating pattern would have on them. Bygren found that kids who had extreme eating habits had kids and grandchildren who lived shorter lives. These kids died an average of 32 years before children who had not experienced this diet. A separate experiment where 14,024 pregnant women from the same area were recruited by ALSPC (Avon Longitudinal Study of Parents and Children). Found that specific environement conditions in pregnancy and during infancy affect children, Example peanut allergies, High anxiety during pregnancy and baby easily gets asthma and children kept extremely clean lead to higher risk of eczema. The experiment also found 166 fathers in the study had started smoking before age of 11 (right before the body goes through puberty), the sperm may could have been affected by epigenomes, changed by the early smoking. Sons of 166 fathers on average had a higher BMI than other children.

Epigenetic and aging

According to the dictionary, aging means “to grow old”; but more in keeping with the aim of this chapter, we will center our discussion on aging as “the time-dependent functional decline that affects most living organisms” Of the nine hallmarks of aging that these authors propose, this review will deal with that of epigenetic alterations, the other eight being: genomic instability, telomere attrition, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Taken together, these events enable the identification and categorization of the cellular and molecular events leading to an aging phenotype.

First of all, and continuing with definitions, we will use epigenetic regulation to refer to the biological mechanisms in which DNA, RNA, and proteins are chemically or structurally modified, without changing their primary sequence. These epigenetic modifications play critical roles in the regulation of numerous cellular processes, including gene expression, DNA replication, and recombination. Epigenetic regulatory mechanisms include, among others, DNA methylation and hydroxymethylation, histone modification, chromatin remodeling, RNA methylation, and regulation by small and long non-coding RNAs. While epigenetic modifications can be very stable, and passed on to multiple generations in some cases, they can also change dynamically in response to specific cellular conditions or environmental stimuli. When epigenetic mechanisms are misregulated, the result can be detrimental to health and they are therefore, emerging as important diagnostic and/or prognostic biomarkers in many fields of medicine.

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Present and future of anti-aging epigenetic diets.

Dietary factors play a role in normal biological processes and are involved in the regulation of pathological progression over a lifetime. Epigenetic changes are pivotal in the establishment of developmental patterns in the early life stages, but they appear also to the both triggers and consequences of the phenotypic alteration that characterize ageing. In the past decades a great effort has been placed in order to identify the epigenetic landscapes of ageing and age-related diseases and to interpret them in the framework of ageing theories. From the studies a complex scenario emerges, in which a general relaxation in the mechanisms controlling epigenetic modification coexists with systemic changes, suggesting that in epigenetic program originating during development contributes at least in part to the ageing process. Given their tissue specificity, epigenetic modifications could be also able to provide consistent hints regarding the ‘mosaic of ageing’ theory, which states that different tissues or organs age at different rates and differently contribute to the ageing of the whole organism. In addition, the identification of age-related epigenetic changes has two practical consequences. On one side, epigenetic signatures have emerged as potential biomarkers of biological age. On other side, the malleability of epigenetic modification has prompted the search for interventions that acting on epigenetic regulators, could delay or even revert the aged phenotype.

A growing number of studies suggest nutrition as one of most promising anti-ageing interventions. Indeed, specific diet components have proved to directly regulate the activity of enzymes that catalyze epigenetic modification and diet habits can alter the establishment and maintenance of epigenetic patterns by modifying the intracellular metabolic state or the cellular microenvironment itself.

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Figure 1: Age-associated changes in DNA methylation patterns. The figure reports the methylation pattern of 3 genomic loci, indicated as A, B and C, in 4 cells from the same tissue in a young (left) and in an old (right) subject. In each DNA molecule, a CpG site can be unmethylated (white circle) or methylated (black circle); for clarity, the methylation profile of only one of the two homologous chromosomes is reported. In the bottom of the figure, the DNA methylation levels measured by current approaches are reported. Note that, as the current methods to analyze DNA methylation do not have single-cell resolution, they provide an estimate of the mean methylation level of each site in the cellular population. Repetitive elements (locus A) tend to become unmethylated during ageing, leading to a decrease in the global DNA methylation levels of the genome. The CpG islands at the promoter of some genes (locus B) are

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hypermethylated in elderly respect to young subjects as a consequence of an ‘‘aging program’’ or of age-associated environmental cues. Finally, the maintenance of the methylation patterns at some genomic loci (locus C) is impaired in the elderly, leading to increased cell-to-cell heterogeneity in DNA methylation profiles. As a consequence,the methylation levels measured by current approaches tends towards 50%.

Epigenetic machanisms in anti-aging nutritional interventions.

Diet is a key environmental factor that has profound effects on human development and health. Chronic exposure to certain dietary patterns, such as unbalanced energy or deficiencies in essential nutrients, creates metabolic stress. This type of stress is closely related to the incidence and progression of various chronic, non-communicable diseases and aging. Metabolic stress affects the regulation of gene expression, resulting in cellular and physiological changes, but it rarely causes acute and deleterious damage, such as mutations to the genome.

Nutrigenomics is an emerging science that aims to understand how dietary components and metabolites affect gene expression and interact with the genome. It provides a mechanistic link between dietary factors and the genomic response. It is important to understand gene-nutrient interactions to learn how to regulate metabolic processes that contribute to age-related disease risk factors, such as obesity, cardiovascular disease, and inflammation. Intriguingly, dietary and nutritional effects can be passed on to the next generation. The effects of nutrition on the body are also mediated by epigenetic mechanisms. Epigenetic mechanisms can mediate between nutrient availability and phenotype throughout life; however, little is known about how nutrition plays a role in longevity and aging via

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epigenetic mechanisms. The aim of this review is to summarize the growing evidence that numerous dietary factors, such as calorierestriction and polyphenols, can modify epigenetic marks influencing longevity and aging.

Epigenetic between nutrition and longevityMetabolism is important in aging because energy

regulation changes during the aging process. Metabolic challenges are related to age-related chronic diseases. Aging-associated changes in epigenetic modifications and epigenetic enzymatic activity have mainly been shown to influence metabolic pathways for insulin signaling, in which a cascade of phosphorylation occurs with inactivation of transport of FOXO (forkhead box O) transcription factors to the nucleus and inhibition of anti-aging genes. These metabolism-associated epigenetic modulations in cellular signaling pathways are mediated by nutrient availability or bioactive compounds.

Longevity-related epigenetic changes in response to nutrient availability and calorie restriction

Calorie restriction has been shown to extend life span and delay the incidence of age-related chronic diseases. In primate studies, calorie restriction was shown to modulate longevity positively. A study of monkeys at the Wisconsin National Primate Research Center reported that moderate calorie restriction improved both overall mortality and age-related mortality, and it reduced the incidence of cancer, cardiovascular disease, and diabetes. Consistent with these findings, clinical research has shown beneficial effects of calorie restriction on age-related phenomena. Calorie restriction reduced the risk factors for atherosclerosis, including lipid parameters and blood pressure and it improved two types of aging biomarkers, fasting insulin levels and core body temperature.

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Dietary modification highly related to epigenetic changes, I would rather say that food is the best medicine to preserve the genomic stability. This is because, packed, canned or preserved food contains chemicals that can change your gene expression. On top of that, deep fried food or the food that is overcooked may contain carcinogens that can induce the growth of tumor cells. “ Dr. Thenmaaran, MBBS, MSc (molecular medicine).”

“Perhaps most fundamentally, there is a gradual reduction of DNA repair with aging. Our DNA is constantly under threat from a variety of environmental factors, most notoriously, radiation. Random errors during cell division are also important. When we are young, the repair of damaged DNA is robust; as we age, not so much. The process of DNA repair is under epigenetic control and this epigenetic repair gradually wanes with age.” Dr.Lau Cher Rene, Medical Practitioner, Malaysia

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Evidence and Proof based on research

Epigenetics has the potential to be very useful in animal breeding, as it may provide information relating to the heritability

of complex traits and diseases. In turn this would serve to improve breeding and the genetics of livestock. Indeed, livestock genetics is currently benefiting from massive amounts of genomic information (e.g. arrays that genotype more than 500K SNPs along the bovine genome) that are being incorporated into the prediction of genetic advantage, providing higher accuracyand leading to important changes in the animal breeding industry. However, it is now clear that in addition to DNA sequence information, epigenetic information also determines the overall phenotype.

Recent technological advances in the field of epigenomics in-clude genome-wide next-generation sequencing, dynamic imaging of genomic loci, quantitative proteomics and computational analyses. Together, these have facilitated fine detail-mapping of DNA methylation and its derivatives captured histone modifications in single cells, and they have significantly contributed to chromatin accessibility studies, such as chromosome conformation capture (3C) technologies. These are important advances as they are beginning to allow us to understand higher-order regulation of gene expression and how it is linked to cellular plasticity and diversity.

Nevertheless, a significant upcoming challenge in livestock breeding is to track epigenetic information that changes from one generation to another. However, it has been known for some time that a significant proportion of the phenotypic variance is explained by paternally imprinted loci where one allele’s expression differs from the other because expression depends on the parent from whom it was inherited. Nowadays, the current genetic improvement scheme in

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livestock assumes that the expression of desirable traits is dependent of parental origin . These traits show a complex inheritance, which is the result of multiple combined genetic and environmental factors. According to animal breeding theory, most of the traits are affected by a large number of genes but each individual gene contributes only very little to the overall phenotypic variance of the trait. Importantly, individual gene effects, or more precisely effects of chromosomal regions, are detectable in quantitative traits . Some of these, referred to as quantitative trait loci (QTLs), show parent-of-origin-specific effects and comprise imprinted loci This asymmetric allelic expression is established via epigenetic mechanisms during development of germ cells into sperm or egg. An imprint-ed gene is in effect heterozygotic, making it more vulnerable to negative mutational effects that are often connected to disease. Hence, a single mutation can have dramatic phenotypic consequences .

Until recently it was thought that dosage compensation does not occur in birds. However, we now know that many Z-linked genes in chicken are indeed dosage-compensated . The process does not involve sex chromosome inactivation typical of mammals but rather some unknown mechanism . In poultry, it has been suggested that QTLs for economically important traits, such as egg weight, age at first egg, feed intake, egg quality and body weight with parent-of-origin-specific expression, could be the result of genomic imprinting, which is often assumed to be unique to mammals. However, differentially methylated alleles in the chicken genome have yet to be identified experimentally. Furthermore, genes such as Igf2 that are imprinted in mammals are all expressed in birds.

In parthenogenesis, growth and development of embryos occur without fertilization. Consequently, expression of imprinted genes is severely affected. Developmental studies of parthenogenesis in sheep fetus identified effects on growth and subsequently death and the

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unbalanced expression of imprinted genes is thought to be involved in these severe effects. Many imprinted human and mouse genes are also imprinted in sheep. Moreover, many imprinted genes have been detected across numerous species including cow, sheep, dog, pig, rabbit, chicken, opossum, lab opossum, human, mouse, rat and wallaby .The current number of confirmed imprinted genes in livestock (cow, sheep, dog, pig, chicken,) is about 60 (26.3 %), and most of them are found in pig and cow. Importantly, there is an increasing interest in the role of certain imprinted genes, such as IGF2, in livestock because it is thought to play a role in the variation of complex production traits, such as muscle mass and fat deposition in pigs as well as meat and milk production in beef and dairy cattle.

In 2003 biologist Ming Zhu Fang and her colleagues at Rutgers University published a paper in the journal Cancer Research on the epigenetic effects of green tea. In animal studies, green tea prevented the growth of cancers in several organs. Fang found that epigallocatechin-3-gallate (EGCG), the major polyphenol from green tea, can prevent deleterious methylation dimmer switches from landing on (and shutting down) certain cancer-fighting genes. The researchers described the study as the first to demonstrate that a consumer product can inhibit DNA methylation. Fang and her colleagues have since gone on to show that genistein and other compounds in soy show similar epigenetic effects.

Research centers in Japan, Europe, and the United States have all begun individual pilot studies to assess the difficulty of such a project. The early signs are encouraging. In June, the European Human Epigenome Project released its data on epigenetic patterns of three human chromosomes. A recent flurry of conferences have forwarded the idea of creating an intenational epigenome project that could centralize the data, set goals for different groups, and standardize the technology for decoding epigenetic patterns.

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Until recently, the idea that your environment might change your heredity without changing a gene sequence was scientific heresy. Everyday influences—the weights Dad lifts to make himself muscle-bound, the diet regimen Mom follows to lose pounds—don’t produce stronger or slimmer progeny, because those changes don’t affect the germ cells involved in making children. Even after the principles of epigenetics came to light, it was believed that methylation marks and other epigenetic changes to a parent’s DNA were lost during the process of cell division that generates eggs and sperm and that only the gene sequence remained. In effect, it was thought, germ cells wiped the slate clean for the next generation.

That turns out not to be the case. In 1999 biologist Emma Whitelaw, now at the Queensland Institute of Medical Research in Australia, demonstrated that epigenetic marks could be passed from one generation of mammals to the next. (The phenomenon had already been demonstrated in plants and yeast.) Like Jirtle and Waterland in 2003, Whitelaw focused on the agouti gene in mice, but the implications of her experiment span the animal kingdoms.

“It changes the way we think about information transfer across generations,” Whitelaw says. “The mind-set at the moment is that the information we inherit from our parents is in the form of DNA. Our experiment demonstrates that it’s more than just DNA you inherit. In a sense that’s obvious, because what we inherit from our parents are chromosomes, and chromosomes are only 50 percent DNA. The other 50 percent is made up of protein molecules, and these proteins carry the epigenetic marks and information.”

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What are the Epigenetic Marks and What do they do?

There are two basic molecular epigenetic mechanisms that are widely studied at present – regulation of chromatin structure through histone post-translational modifications, and covalent modification of DNA principally through DNA methylation. These two mechanisms will be discussed in the next sections of this chapter. Other epigenetic molecular mechanisms such as regulation of gene expression through non-coding RNAs, and recombination of non-genic DNA, are also known to exist and will be briefly discussed. Finally, for the last part of this chapter we will highlight a number of emerging functional roles for epigenetic mechanisms in the nervous system as an introduction to the rest of this book.

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Essential nutrients on human studies

The nutrients known as essentials for human beings are proteins, carbohydrate, fats and oils, minerals, vitamins and water. Most essential nutrients are needed only in a small quantities,and are stored and reused by the body. As a result, unlike absence of air or water for human, absence of essential nutrients usually leads only gradually to the development of a deficiency disease.

Human nutrition refers to the provision of essential nutrients necessary to support human life and health. Generally, people can survive up to 40 days without food, a period largely depending on the amount of water consumed, stored body fat, muscle mass and genetic factors.

Poor nutrition is a chronic problem often linked to poverty, poor nutrition understanding and practices, and deficient sanitation and food security. Malnutrition and its consequences are immense

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contributors to deaths and disabilities worldwide. Promoting good nutrition helps children grow, promotes human development and eradication of poverty.

The human body contains chemical compounds, such as water, carbohydrates (sugar, starch, and fiber), amino acids (in proteins), fatty acids (in lipids), and nucleic acids (DNA and RNA). These compounds consist of elements such as carbon, hydrogen, oxygen, nitrogen, phosphorus, calcium, iron, zinc, magnesium, manganese, and so on. All the chemical compounds and elements contained in the human body occur in various forms and combinations such as hormones, vitamins, phospholipids and hydroxyapatite. These compounds may be found in the human body as well as in the various types of organisms that humans consume.

Any study done to determine nutritional status must take into account the state of the body before and after experiments, as well as the chemical composition of the whole diet and of all the materials excreted and eliminated from the body (including urine and feces). Comparing food to waste material can help determine the specific compounds and elements absorbed and metabolized by the body. [medical citation needed] The effects of nutrients may only be discernible over an extended period of time, during which all food and waste must be analyzed. The number of variables involved in such experiments is high, making nutritional studies time-consuming and expensive, which explains why the science of human nutrition is still slowly evolving.

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Various type of Nutrients

The seven major classes of nutrients are carbohydrates, fats, fiber, minerals, proteins, vitamins, and water. These nutrient classes are categorized as either macronutrients or micronutrients (needed in smaller quantities). The macronutrients are carbohydrates, fats, fiber, proteins, and water. The micronutrients are minerals and vitamins.

The macronutrients (excluding fiber and water) provide structural material (amino acids from which proteins are built, and lipids from which cell membranes and some signaling molecules are built), and energy. Some of the structural material can be used to generate energy internally, and in either case it is measured in Joules or kilocalories (often called “Calories” and written with a capital ‘C’ to distinguish them from little ‘c’ calories). Carbohydrates and proteins provide 17 kJ approximately (4 kcal) of energy per gram, while fats provide 37 kJ (9 kcal) per gram though the net energy from either depends on such factors as absorption and digestive effort, which vary substantially from instance to instance.

Vitamins, minerals, fiber, and water do not provide energy, but are required for other reasons. A third class of dietary material, fiber (i.e., nondigestible material such as cellulose), seems also to be required, for both mechanical and biochemical reasons, though the exact reasons remain unclear. For all age groups, males need to consume higher amounts of macronutrients than females. In general, intakes increase with age until the second or third decade of life.

Molecules of carbohydrates and fats consist of carbon, hydrogen, and oxygen atoms. Carbohydrates range from simple monosaccharides (glucose, fructose, galactose) to complex polysaccharides (starch). Fats are triglycerides, made of assorted fatty acid monomers bound to a glycerol backbone. Some fatty acids, but not all, are essential in the diet: they cannot be synthesized in the body. Protein molecules

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contain nitrogen atoms in addition to carbon, oxygen, and hydrogen.[citation needed] The fundamental components of protein are nitrogen-containing amino acids, some of which are essential in the sense that humans cannot make them internally. Some of the amino acids are convertible (with the expenditure of energy) to glucose and can be used for energy production just as ordinary glucose. By breaking down existing protein, some glucose can be produced internally; the remaining amino acids are discarded, primarily as urea in urine. This occurs naturally when atrophy takes place, or during periods of starvation.

CarbohydratesCarbohydrates may be classified as monosaccharides,

disaccharides or polysaccharides depending on the number of monomer (sugar) units they contain. They are a diverse group of substances, with a range of chemical, physical and physiological properties. They make up a large part of foods such as rice, noodles, bread, and other grain-based products, but they are not an essential nutrient, meaning a human does not need to eat carbohydrates.

Monosaccharides contain one sugar unit, disaccharides two, and polysaccharides three or more. Monosaccharides include glucose, fructose and galactose. Disaccharides include sucrose, lactose, and maltose; purified sucrose, for instance, is used as table sugar. Polysaccharides, which include starch and glycogen, are often referred to as ‘complex’ carbohydrates because they are typically long multiple-branched chains of sugar units. The difference is that complex carbohydrates take longer to digest and absorb since their sugar units must be separated from the chain before absorption. The spike in blood glucose levels after ingestion of simple sugars is thought to be related to some of the heart and vascular diseases, which have become more common in recent times. Simple sugars form a greater part of modern diets than in the past, perhaps leading to more cardiovascular disease. The degree of causation is still not clear.

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Simple carbohydrates are absorbed quickly, and therefore raise blood-sugar levels more rapidly than other nutrients. However, the most important plant carbohydrate nutrient, starch, varies in its absorption. Gelatinized starch (starch heated for a few minutes in the presence of water) is far more digestible than plain starch, and starch which has been divided into fine particles is also more absorbable during digestion. The increased effort and decreased availability reduces the available energy from starchy foods substantially and can be seen experimentally in rats and anecdotally in humans. Additionally, up to a third of dietary starch may be unavailable due to mechanical or chemical difficulty.

FatA molecule of dietary fat typically consists of several fatty

acids (containing long chains of carbon and hydrogen atoms), bonded to a glycerol. They are typically found as triglycerides (three fatty acids attached to one glycerol backbone). Fats may be classified as saturated or unsaturated depending on the detailed structure of the fatty acids involved, [citation needed] Saturated fats have all of the carbon atoms in their fatty acid chains bonded to hydrogen atoms, whereas unsaturated fats have some of these carbon atoms double-bonded, so their molecules have relatively fewer hydrogen atoms than a saturated fatty acid of the same length. Unsaturated fats may be further classified as monounsaturated (one double-bond) or polyunsaturated (many double-bonds). Furthermore, depending on the location of the double-bond in the fatty acid chain, unsaturated fatty acids are classified as omega-3 or omega-6 fatty acids. Trans fats are a type of unsaturated fat with trans-isomer bonds; these are rare in nature and in foods from natural sources; they are typically created in an industrial process called (partial) hydrogenation.

Many studies have shown that consumption of unsaturated fats, particularly monounsaturated fats, is associated with better health in humans. Saturated fats, typically from animal sources, are next in order

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of preference, while trans fats are associated with a variety of disease and should be avoided. Saturated and some trans fats are typically solid at room temperature (such as butter or lard), while unsaturated fats are typically liquids (such as olive oil or flaxseed oil). Trans fats are very rare in nature, but have properties useful in the food processing industry, such as rancidity resistance.

Most fatty acids are not essential, meaning the body can produce them as needed, generally from other fatty acids and always by expending energy to do so. However, in humans, at least two fatty acids are essential and must be included in the diet. An appropriate balance of essential fatty acids – omega-3 and omega-6 fatty acids.

Vitamin AThis essential vitamin plays an important role in general growth

and development, including proper vision, healthy teeth, glowing skin, strong bones and more. Vitamin A also protects the body from different types of infections and promotes the health and growth of cells and tissues in the body. Vitamin A comes in two forms – retinoids and carotenoids. Some foods rich in vitamin A are carrots, sweet potatoes, cantaloupe, pumpkin, spinach, eggs, watermelon, kale, papaya, peaches, apricots, tomatoes, dried beans, lentils, red peppers, guava, broccoli, liver, milk and fortified cereals.

Vitamin CThis water-soluble vitamin is an antioxidant that helps protect

cells from free-radical damage, lowers the risk of different types of cancer, regenerates your vitamin E supply, and improves iron absorption. It also keeps the gums healthy, aids in healing wounds, boosts the immune system, and keeps infections at bay. Your body can’t store vitamin C or make it, so you need to consume some every day. Some foods rich in vitamin C are red peppers, kiwi, oranges, strawberries, cantaloupe, broccoli, guava, grapefruit, Brussels sprouts, parsley, lemon juice, papaya, cauliflower, kale and mustard greens.

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Vitamin EVitamin E is the collective name of eight fat-soluble compounds

with distinctive antioxidant activities. This particular vitamin protects the skin from harmful ultraviolet light, prevents cell damage from free radicals, improves communication between cells, and protects against prostate cancer and Alzheimer’s disease. Some foods rich in vitamin E are spinach, chard, turnip greens, mustard greens, cayenne pepper, almonds, sunflower seeds, wheat germ, asparagus, bell peppers, whole grain cereals and safflower oil.

Folic Acid (Vitamin B9)Folic acid, also known as folate, is a form of the water-soluble

vitamin B9. Folic acid supports red blood cell production to prevent anemia, prevents homocysteine buildup in your blood, and helps the nerves function properly. It also prevents osteoporosis-related bone fractures and dementias, including Alzheimer’s disease. The body cannot store folic acid, so it is highly essential to consume it every day to maintain an adequate amount in your system. Some good food sources of folic acid are romaine lettuce, spinach, asparagus, turnip greens, mustard greens, parsley, collard greens, broccoli, cauliflower, beets, lentils, asparagus, cabbage, egg yolks and lettuce.

Iron Iron helps make red blood cells, which carry oxygen around

the body. It is also necessary to support proper metabolism for muscles and other active organs. A lack of iron in the body can lead to iron-deficiency anemia that can result in fatigue, weakness, and irritability. Some iron-rich foods are oysters, red meats, chicken liver, soybeans, fortified cereal, pumpkin seeds, beans, lentils, spinach, nuts, dried apricots, brown rice, watercress, kale, Swiss chard, thyme, asparagus, cumin, turmeric, tofu, blackstrap molasses, collard greens, leeks, oregano, black pepper, basil and turnips. Also increasing the amount of vitamin C in your diet will help your body absorb iron more effectively.

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FiberDietary fiber is a carbohydrate, specifically a polysaccharide,

which is incompletely absorbed in humans and in some animals. Like all carbohydrates, when it is metabolized, it can produce four Calories (kilocalories) of energy per gram, but in most circumstances, it accounts for less than that because of its limited absorption and digestibility. The two subcategories are insoluble and soluble fiber. Insoluble dietary fiber consists mainly of cellulose, a large carbohydrate polymer that is indigestible by humans, because humans do not have the required enzymes to break it down, and the human digestive system does not harbor enough of the types of microbes that can do so. Soluble dietary fiber comprises a variety of oligosaccharides, waxes, esters, resistant starches, and other carbohydrates that dissolve or gelatinize in water. Many of these soluble fibers can be fermented or partially fermented by microbes in the human digestive system to produce short-chain fatty acids which are absorbed and therefore introduce some caloric content.

Whole grains, beans and other legumes, fruits (especially plums, prunes, and figs), and vegetables are good sources of dietary fiber. Fiber is important to digestive health and is thought to reduce the risk of colon cancer, [citation needed] For mechanical reasons, fiber can help in alleviating both constipation and diarrhea.

ProteinProteins are the basis of many animal body structures

(e.g. muscles, skin, and hair) and form the enzymes which catalyse chemical reactions throughout the body. Each protein molecule is composed of amino acids which contain nitrogen and sometimes sulphur (these components are responsible for the distinctive smell of burning protein, such as the keratin in hair). The body requires amino acids to produce new proteins (protein retention) and to replace damaged proteins (maintenance). Amino acids are soluble in the

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digestive juices within the small intestine, where they are absorbed into the blood. Once absorbed, they cannot be stored in the body, so they are either metabolized as required or excreted in the urine.

MineralsDietary minerals are the chemical elements required by living

organisms, other than the four elements carbon, hydrogen, nitrogen, and oxygen that are present in nearly all organic molecules. The term “mineral” is archaic, since the intent is to describe simply the less common elements in the diet. Some are heavier than the four just mentioned – including several metals, which often occur as ions in the body. Some dietitians recommend that these be supplied from foods in which they occur naturally, or at least as complex compounds, or sometimes even from natural inorganic sources (such as calcium carbonate from ground oyster shells). Some are absorbed much more readily in the ionic forms found in such sources. On the other hand, minerals are often artificially added to the diet as supplements; the most famous is likely iodine in iodized salt which prevents goiter.

VitaminsAs with the minerals discussed above, some vitamins are

recognized as essential nutrients, necessary in the diet for good health. (Vitamin D is the exception: it can alternatively be synthesized in the skin, in the presence of UVB radiation.) Certain vitamin-like compounds that are recommended in the diet, such as carnitine, are thought useful for survival and health, but these are not “essential” dietary nutrients because the human body has some capacity to produce them from other compounds. Moreover, thousands of different phytochemicals have recently been discovered in food (particularly in fresh vegetables), which may have desirable properties including antioxidant activity experimental demonstration has been suggestive but inconclusive. Other essential nutrients not classed as vitamins include essential amino acids, essential fatty acids, and the minerals discussed in the preceding section.

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Vitamin deficiencies may result in disease conditions: goiter, scurvy, osteoporosis, impaired immune system, disorders of cell metabolism, certain forms of cancer, symptoms of premature aging, and poor psychological health (including eating disorders), among many others.

Drugs side effects.Some of the drugs described in “Epigenetic side-effects of common pharmaceuticals, A potential new field in medicine and pharmacology” as having adverse effects through an epigenetic mechanism are: • Synthetic estrogens • Combined oral contraceptive pills• Fluoroquinolone antibiotics• Beta-blockers• Statins• Cox-2 inhibitors• Neuroleptics• SSRIs• Ritalin• Adderall• Chemotherapeutics • General anesthetics

Examples of drug for which there is clinical or experimental evidence for epigenetic effects as a direct effect on DNA methylation or histone acetylation, or indirect effect on transcription factor activation or receptor expression. List below is drugs which have been documented to cause persistent side-effects, but for which an epigenetic etiology for such affects has yet to be known.

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Pharmaceutical drug Known or postulated epigenetic effects or clinical consequences.

Hydralazine dan procainamide

Inhibit DNA methyltransferase, drug-induced SLE, autoimmunity.

Methotrexate Alters methionine synthesis, DNA methylation, drug resistance.

Valproic acid Inhibits Histone deacetylase, altered gene expression, skeletal malformation.

Thalidomide Teratogenic, major malformations, sometimes transgenerational.

Isotretinoin Teratogenic, major malformations, hyperlipidemia, ocular problems, alopecia, psychiatric disturbances.

Neuroleptics Tardive dyskinesia, hyperglycemia, diabetes, congnitive dysfunction.

Methyphenidate Altered gene expression, synaptic plasticity, behavioral changes.

SSRIs and antidepressants Altered chromatin architecture, gene expression, behavior, infertility.

Chemotherapeutics Genotoxic, secondary cencers, “Chemo brain”

General anesthetics1 Cognitive dysfunction, Alzheimer’s and Parkinson disease.

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Pharmaceutical drug Known or postulated epigenetic effects or clinical consequences.

Contraceptives Cancer, osteoporosis, weight gain, sexual dysfunction

Chloroquine antibiotics Psychiatric illnesses, cardiac arrhythmias, dysglycemia, tendon ruptures.

Beta-blockers Hyperglycemia, diabetes, insomnia, depression

Statins Myalgia, muscle cramps, muscle and liver damage, gastrointestinal issues.

Cox-2 inhibitors Persistently increased cardiovascular mortality risk.

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Retinoic acid (RA)

Retinoic acid mediates many of the functions of vitamin A, which regulates gene expression by activating intracellular Retinoic Acid receptors. The functions of vitamin A are essential for immunological function, reproduction and embryonic development as shown by the impaired growth, susceptibility to infection and birth defects observed in populations receiving suboptimal vitamin A in their diet. It is now known that RA can influence gene expression and protein production in many ways. Genes can respond to Retinoic Acid through a ‘‘direct” pathway; while others respond through ‘‘indirect” mechanisms. More than 500 genes have been put forward as regulatory targets. Isotretinoin’s exact mechanism of action is unknown, but it is known that, like Retinoic Acid, it alters DNA transcription. It has also recently been shown to alter DNA methylation patterns, although it is not yet known if these are direct or indirect effects. In any case, the gene expression changes cause decreased size and output of sebaceous glands, making the cells that are sloughed off less sticky, and therefore less able to form comedones. Isotretinoin noticeably reduces the production of sebum and shrinks the sebaceous glands, and stabilizes keratinization, preventing comedones from forming. Adverse drug reactions associated with isotretinoin include dryness of skin, lips and mucous membranes, infection of the cuticles, cheilitis, skin fragility and peeling, nose bleeds, dry eyes, conjunctivitis and other ocular problems, hyperlipidaemia, raised liver enzymes, alopecia, myalgia or arthralgia, headaches and intracranial hypertension, depression, psychosis, and other psychiatric disorders . The following adverse effects have been reported to persist, even after discontinuing therapy, suggesting persistent (or perhaps slowly-reversing) gene expression changes and epigenetic effects: alopecia , arthralgias , ocular abnormalities, inflammatory bowel disease, keloids, osteopenia , hyperlipidemia, erectile dysfunction, and psychiatric disturbances.

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Isotretinoin is postulated to have complex effectson the brain and central nervous system. One study utilizingpositron emission tomography (PET) showed functional brain imaging changes in treated patients.

Beta-blockersBeta-blockers (b-blockers) are a class of drugs used to treat

hypertension and manage cardiac arrhythmias and cardioprotection after myocardial infarction. Side-effects associated with their use include: bronchospasm, dyspnea, bradycardia, hypotension, heart failure, heart block, various psychiatric disorders, sexual dysfunction, and alteration of lipid and glucose metabolism. The latter is particularly troublesome since recent studies have revealed that beta-blockers, especially when used in combination with diuretics, increase a patient’s risk of developing diabetes. Since diabetes is now considered to be a disease with a potentially large epigenetic component, and as previously mentioned, transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia, it is tempting to speculate that beta-blockers may accelerate the development of diabetes by an epigenetic mechanism.

StatinsThe statins (or HMG-CoA reductase inhibitors) are a class of

hypolipidemic drugs used to lower cholesterol levels in people with or at risk of cardiovascular disease. They lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-imiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver stimulates the production of LDL receptors, presumably by an epigenetic mechanism, resulting

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in an increased clearance of low-density lipoprotein (LDL) from the bloodstream and a decrease in blood cholesterol levels . Many patients on statin therapy suffer from myalgias, muscle cramps, and sometimes gastrointestinal or other symptoms . Liver enzyme derangements and multiple other side-effects may also occur. The precise mechanism of muscle injury and other side effects is unknown, but it is known that statins cause extensive alterations in gene expression in target organs. Decreased expression of the atrogin-1 gene by an epigenetic mechanism, is believed to be responsible for promoting muscle fiber damage. It has also been proposed that mitochondrial impairment by statins leads to a mitochondrial calcium leak that directly interferes with the regulation of sarcoplasmic reticulum calcium cycling, without excluding a direct effect of statin on the sarcoplasmic reticulum. Both mitochondrial and calcium impairments may account for the apoptotic process, oxidative stress, and muscle remodeling and degeneration.

Cox-2 inhibitorsA Cox-2 selective inhibitor is a form of Non-steroidal

anti-inflammatory drug (NSAID) that directly targets Cox-2, an enzyme responsible for inflammation and pain. Selectivity for Cox-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib (Vioxx), rofecoxib and other members of this drug class. Cox-2-selectivity does not seem to affect other adverse-effects of NSAIDs, and epidemiological studies have shown that there is an increased risk of heart attack, thrombosis and stroke by a relative increase in thromboxane. Interestingly, there is some data suggesting that even after patients stop taking Vioxx, they still have a 74% higher stroke/heart attack risk. What this means is the relative risk of a cardiovascular event with Vioxx even after the drug is stopped, is very similar to the risk while taking the drug. A persistent epigenetic effect on cardiovascular tissues is one possibility, since Cox-2 inhibitors have been shown to cause extensive gene expression changes.

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Chloroquine and fluoroquinolone antibiotics The quinolones are a family of broad-spectrum antibiotics. They

inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Eukaryotic cells do not contain DNA gyrase or topoisomerase IV, so it has been assumed that quinolones and fluoroquinolones have no effect on human cells, but they have been shown to inhibit eukaryotic DNA polymerase alpha and beta, and terminal deoxynucleotidyl transferase, affect cell cycle progression and function of lymphocytes in vitro, and cause other genotoxic effects. These agents have been associated with a diverse array of side-effects including hypoglycemia, hyperglycemia, dysglycemia, QTc prolongation, torsades des pointes, seizures, phototoxicity, tendon rupture, and pseudomembranous colitis. Cases of persistent neuropathy resulting in paresthesias, hypoaesthesias, dysesthesias, and weakness are quite common. Even more common are ruptures of the shoulder, hand, Achilles, or other tendons that require surgical repair or result in prolonged disability. Interestingly, extensive changes in gene expression were found in articular cartilage of rats receiving the quinolone antibacterial agent ofloxacin, suggesting a potential epigenetic mechanism for the arthropathy caused by these agents. It has also been documented that the incidence of hepatic and dysrhythmic cardiovascular events following use of fluoroquinolones is increased compared to controls, suggesting the possibility of persistent gene expression changes in the liver and heart.

Synthetic estrogens and the Combined Oral Contraceptive Pill (COCP)

The Combined Oral Contraceptive Pill (COCP) is a combination of an estrogen and a progestin, taken by mouth to inhibit normal female fertility. Estrogen and progestin are both sex steroids, hormones that interact with receptors. Their effects are mediat-ed by genomic mechanisms through nuclear receptors as well as by

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nongenomic mechanisms through membrane-associated receptors and signaling cascades. Fetal and neonatal exposure to a prototypical synthetic estrogen, diethylstilbestrol (DES), which was used to prevent miscarriages and other pregnancy complications between 1938 and 1971, is known to cause cancer in the male and female reproductive tracts later in life. Many other adverse associations have been identified in DES-exposed women and their offspring, and animal studies have shown effects in the next generation (grandchildren), a clear demonstration of transgenerational epigenetic effects. There is now significant evidence that that DES-induced abnormalities of reproductive organs are associated with altered expression levels of DNA methyltransferases and DNA methylation. Estrogen was also recently shown to cause very rapid epigenetic changes in breast cancer cells, suggesting that steroid hormone mediated epigenetic regulation can affect gene expression immediately and long-term. COCP increases the risk of breast cancer by an average of 44% in pre-menopausal women who took, or were taking, oral contraceptives (OCs) prior to their first pregnancy, according to a comprehensive analysis of international studies conducted between 1980 and 2002. Of the 23 studies examined, 21 showed an increased risk of breast cancer with COCP use prior to a first pregnancy in pre-menopausal women. The study reinforces the 2005 classification of COCP as a Type 1 carcinogen in humans by the International Agency for Cancer Research.

The adverse effect and side effect of the drugs are mainly due to epigenetic changes that caused by the drug itself. I would say all the drugs have side effects, the underlying cause for this phenomena is the drug that interact with the particular gene and results in gene expressed in unusual way. This will pave the unwanted effect from our body system. “ Dr. Thenmaaran, MBBS, MSc (molecular medicine).”

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As knowledge of the epigenome grows, we continue to learn more about how the substances we consume and the social situations we inhabit influence the way our genes are expressed. Scientists are already rethinking the way organisms evolve and how traits are passed on from parent to offspring. But at what point will this knowledge begin to change the way we live? At what point will we be able to take a pill and block or unblock the right combination of genes to improve our quality of life?

While turning off aging and fine-tuning the human genome are pretty awe-inspiring possibilities, epigeneticists are far more interested in discovering ways to treat epigenetic diseases. As some cancers occur due to the deactivation of tumor-suppressing genes, researchers have worked to develop medications that reactivate them. The drug azacitidine, for instance, treats leukemia in this manner. Finding just the right parts of the epigenome to treat, however, can be like finding a needle in a haystack. And once researchers find the areas they want to affect, epigenetic drugs aren’t all that specific. They might succeed in blocking or unblocking the genes they wanted to treat, but also affect other genes, resulting in potentially dangerous side effects.

Stem cells are also of key interest to epigeneticists. By studying the epigenetic changes that determine how cells develop, it may eventually become possible to dictate what tissue type a stem cell will develop into. For more information on the implications of this,

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The future of healthcare is within the range of epigenetic transformation. I could foresee myself that, drugs might not be needed as the science and technology are drastically developing and this will gives a greatest impact in our lives. “ Dr. Thenmaaran, MBBS, MSc (molecular medicine).”

“Epigenetic changes can also be brought about by our environment and exposure to pollutants, diet, and social interactions. And what’s peculiar about epigenetic processes (as opposed to genetic) is that they have the potential to be reversed.” Dr.Lau Cher Rene, Medical Practitioner, Malaysia

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Referrence:

1. Simo-Riudalbas L, Esteller M (2013) Cancer genomics identifies disrupted epigenetic genes. Hum Genet. Oct 9. PMID: 24104525.

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