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 epigenetics: impact of folate deficiency on DNA methylation and colon cancer susceptibility

The inheritance of information based on gene expression levels is known as epigenetics, as opposed to genetics, which refers to information transmitted on the basis of gene sequence. In contrast to genetic changes observed in cancer, epigenetic changes are gradual in onset and are progressive, their effects are dose-dependent and are potentially reversible. These observations present new opportunities in cancer-risk modification and prevention using dietary and lifestyle factors and potential chemopreventive drugs. In this regard, folate, a water-soluble B vitamin, has been a focus of intense interest because of an inverse association between folate status and the risk of several malignancies (in particular, colorectal cancer) and of its potential ability to modulate DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, in chromosomal modifications, and in the development of mutations. Aberrant patterns and dysregulation of DNA methylation are mechanistically related to colorectal carcinogenesis. Folate plays an essential role in one-carbon transfer involving re-methylation of homocysteine to methionine, thereby ensuring the provision of S-adenosylmethionine, the primary methyl group donor for most biological methylation reactions. The portfolio of evidence from animal, human, and in vitro studies suggests that the effects of folate deficiency and supplementation on DNA methylation are gene and site specific, and appear to depend on cell type, target organ, stage of transformation, and the degree and duration of folate depletion.     

A quantitative model of cellular senescence influence on cancer and longevity

Contrary to the paradigm that cancer incidence increases indefinitely with age, significant data now suggest cancer incidence may markedly reduce beyond age 80 years for humans and beyond 800 days for mice, and is not inevitable. We show that increasing cellular senescence with age is a possible cause of this reduction, since senescent cells are removed from the pool of cells that retain proliferative ability necessary for cancer. We further show that animal interventions appearing to alter senescence, p53 mutation and melatonin dosing, support the prediction that increasing senescence rate reduces cancer while reducing lifespan, and vice versa. Studies of environmental agents associated with increased cancer might be re-examined to find if there is an association with longevity increases, which may markedly alter our view of such agents. We also show that if an agent functions by slowing both senescence and carcinogenesis, longevity is increased while reducing cancer. Dietary restriction is the only known intervention that accomplishes this, but there may be others.     

Nutritional effects on neuron numbers

Undernutrition during early life is known to cause deficits and distortions of brain structure although it has remained uncertain whether or not this includes a diminution of the total numbers of neurons. Estimates of numerical density (e.g. number of cells per microscopic field, or number of cells per unit area of section, or number of cells per unit volume of tissue) are extremely difficult to interpret and do not provide estimates of total numbers of cells. However, advances in stereological techniques have made it possible to obtain unbiased estimates of total numbers of cells in well defined biological structures. These methods have been utilised in studies to determine the effects of varying periods of undernutrition during early life on the numbers of neurons in various regions of the rat brain. The regions examined so far have included the cerebellum, the dentate gyrus, the olfactory bulbs and the cerebral cortex. The only region to show, unequivocally, that a period of undernutrition during early life causes a deficit in the number of neurons was the dentate gyrus. These findings are discussed in the context of other morphological and functional deficits present in undernourished animals.     

The influence of (public) health expenditure on longevity

Objectives

We report new evidence on the contribution of health expenditure to increasing life expectancy in OECD countries, differentiating the effects of public and private health expenditures.

Methods

A theoretical model is presented and estimated though a cross-country fixed effects multiple regression analysis for a sample of OECD countries over the period 1980–2000.

Results

Although the effect of aggregate health expenditure is not conclusive, public health expenditure plays a significant role in enhancing longevity. However, its influence diminishes as the size of the public health sector on GDP expands, reaching a maximum around the 8 %.

Conclusions

With the influence of public health expenditure being positive, the ambiguous effect of the aggregate expenditure suggests that the weight of public and private health sectors matters, the second having a lower impact on longevity. This might explain the poor evolution of the life expectancy in countries with a high amount of private resources devoted to health. In such cases, an extension of public services could give rise to a better outcome from the overall health investment.     

限制热能摄入与健康、长寿和肿瘤的控制

热能的摄入过多而引起肥胖,并由此导致一系列的慢性疾病,已成为西方发达国家严重的公共卫生问题和社会问题.在我国,这一问题也变得越来越严重.同样,热能摄入不足,仍是许多不发达国家的主要营养问题.     

Nutritional mechanisms that influence cardiovascular disease

Current evidence suggests that most significant risk factors for heart disease have been identified. Although age, sex, and genetics are important unmodifiable risk factors, most new cases of acute myocardial infarctions today can be predicted by the presence and level of 9 risk (or cardioprotective) factors that can easily be assessed and, most importantly, modified. These risk factors are the same in almost every geographic region and in every racial/ethnic group worldwide and are consistent in men and women. Eight of these 9 risk factors are influenced by diet, and most act by promoting atherogenesis, which is the most important background condition for cardiovascular disease. Dietary interventions mostly affect atherogenesis by modulating, at the cellular level, proinflammatory processes that initiate and perpetuate endothelial dysfunction, plaque formation, and, eventually, plaque rupture. For example, there is now enough evidence, both epidemiologic and clinical, of the beneficial effects of n-3 fatty acids. Either as part of a normal low-fat diet or as supplements, these fatty acids are now recommended to prevent cardiovascular disease. This review will summarize the mechanisms by which diet may influence atherogenesis through the early inception, progression, and clinical emergence of atherosclerosis, with a special focus on n-3 fatty acids.     

Nutritional and environmental effects on reproduction in small ruminants

Animals live in environments that are both complex and continually changing, so they have to respond to short- and long-term variations in a wide range of factors, such as photoperiod, nutrition and sociosexual signals. Before they were domesticated, animals developed reproductive strategies that coped with these changes and often took advantage of them. The physiological processes that implement these strategies have been modified to some extent during several millennia of controlled breeding, but most persist. Thus, many genotypes still exhibit profound responses to external inputs, such as the induction of ovulation by sociosexual signals and the doubling of litter size by a change in nutrition. The complexity in these responses is now becoming clearer. For example, with sociosexual signals, we now need to consider the stimulatory effects of males on females, of females on males and of females on females. Similarly, the impact of nutrition has been extended beyond the control of puberty and the production of gametes to include phenomena such as 'fetal programming', with its potentially profound effects on the life-long performance of the animals. Fortunately, our capacity to research these phenomena has been greatly enhanced by technical improvements in hormone assays, molecular and cellular biology, and real-time ultrasound. This has brought us a better understanding of several of the environmental influences on reproduction, including: the cellular processes within ovarian follicles that mediate the effect of nutrition on ovulation rate; the neuroendocrine pathways through which nutritional inputs affect the brain centres that control appetite and reproduction; and the intracerebral pathways through which sociosexual signals (olfactory and non-olfactory) stimulate the reproductive axis. Importantly, we are now beginning to realise that, as well as considering interactions between environmental inputs and genotype, we need to take into account interactions between the environmental factors themselves, just as the animals do. We still have a long way to go for a complete understanding, but we are nevertheless in a position where we can begin to use this information to develop new management systems for our animals to improve their productivity.     

Nutritional effects on chlordane toxicity in rainbow trout

Summary Rainbow trout were fed the commercial diets Oregon Moist, Glencoe, Silver Cup, or Ewos, and synthetic diets containing 23% or 45% protein. After feeding the diets for 42 days, chlordane was tested against rainbow trout in static toxicity tests. LC50s (96-hr) for chlordane were 8.2, 9.1, 20, 31, 29 and 47 g/1 for the groups fed Oregon Moist, Glencoe, Silver Cup, Ewos diets and synthetic diets that contained 23 and 45% protein, respectively. The LC50 for the group fed the 45% protein diet was statistically (P=0.05) different from the values for all the other groups. Also, the values differed among groups fed commercial diets.     

Nutritional effects of oral contraceptives

In this research we investigate factors associated with nonuse of condoms for sexually active Botswana women. Nationally represented data, drawn from the 2004 Botswana AIDS Impact Survey, were used. A sample of 5,236 women aged 15–49 who have had sexual intercourse was considered for the analysis. Cross-tabulations were used to gain insights into the phenomena to be reinforced with logistic regression. Through logistic regression analysis, we reveal that the relative odds of having had no HIV/AIDS tests, had an older sexual partner, and had sexual intercourse intoxicated under alcohol were significantly less among teenagers and women aged 20–34. It is shown that women with primary education were less likely to have been tested for HIV/AIDS and have had sexual intercourse while intoxicated. Christians were less likely to have had sexual intercourse while intoxicated. Last, women who did not use condoms at last sexual intercourse were significantly more likely to have had sexual intercourse while under the influence of alcohol, had older sexual partners, and believed that people cannot reduce their chances of getting HIV/AIDS by using a condom.     

Sublethal effects of larval methoprene exposure on adult mosquito longevity.

Larvae of Aedes aegypti were exposed to sublethal concentrations of the insect growth regulator, methoprene, and the glycogen content of pupae and surviving adults was compared and effects on adult longevity determined. The glycogen reserves in both male and female Ae. aegypti pupae were significantly reduced as a result of methoprene exposure. The longevity of adult females was also significantly reduced, but exposure affected neither the longevity nor the glycogen content of adult males. Adult sugar feeding increased the amount of glycogen in both treated and control females. The reduced longevity of adult females from larval methoprene treatment appeared not to be directly related to reduced glycogen, but rather reflected neuroendocrine abnormalities induced by this juvenile hormone analogue.     

Nutritional influence on the plasma and urine-free alkaline ribonuclease levels in severe trauma victims

The significance of free alkaline ribonuclease (RNase) activity as a criterion of protein metabolism and nutrition in traumatized man is evaluated in this report. Plasma and urinary levels of RNase were measured in severely injured, hypermetabolic patients and in normal controls. Significant increases in the plasma and urinary RNase levels were seen in these polytrauma victims and they were positively correlated. Plasma RNase levels were also significantly related to blood urea nitrogen and daily urinary nitrogen excretion. Urinary clearance of RNase was increased by 220% in trauma victims, although the creatinine clearance was not affected by trauma. In a subgroup of eight patients who were fed intravenously (1.4 times basal energy expenditure calories and 250-300 mg of N per kilogram per day) for 6 days, the daily excretions of urinary RNase, nitrogen, 3-methylhistidine, creatinine, and catecholamines were measured. There was a significant negative correlation between daily urine RNase and nitrogen balance. A general increase in all the metabolic parameters on the first day of feeding was seen, suggesting a nutritional stress superimposed on the trauma-induced metabolic stress. Excretion of RNase, 3-methylhistidine, and creatinine peaked on the first day of feeding and then decreased. The normal levels could not be reached even after 6 days of adequate nutrition. The results suggest that RNase levels could be used as a biomarker of protein metabolism.     

Nutritional supplementation: effects on child stunting because of diarrhea

Research has shown that the positive effect of nutritional supplementation on child growth in malnourished populations is small relative to the large negative effect of diarrheal disease. To test the hypothesis that the effects of supplementation and diarrhea are synergistic in that supplementation modifies the negative effect of diarrhea on linear growth, length and diarrheal morbidity were compared at 36 mo of age for two cohorts of Colombian children: supplemented from birth and unsupplemented. Among unsupplemented children diarrhea was negatively associated with length. Among supplemented children diarrhea had no effect on length and differed from that of unsupplemented children. Thus, supplementation completely offset the negative effect of diarrheal disease on length. Targeting supplementation programs to the critical period of high diarrheal prevalence among infants and young children should increase the effectiveness of such programs in preventing growth retardation associated with diarrhea.     

Environmental chemical exposures and human epigenetics

Every year more than 13 million deaths worldwide are due to environmental pollutants, and approximately 24% of diseases are caused by environmental exposures that might be averted through preventive measures. Rapidly growing evidence has linked environmental pollutants with epigenetic variations, including changes in DNA methylation, histone modifications and microRNAs. Environ mental chemicals and epigenetic changes All of these mechanisms are likely to play important roles in disease aetiology, and their modifications due to environmental pollutants might provide further understanding of disease aetiology, as well as biomarkers reflecting exposures to environmental pollutants and/or predicting the risk of future disease. We summarize the findings on epigenetic alterations related to environmental chemical exposures, and propose mechanisms of action by means of which the exposures may cause such epigenetic changes. We discuss opportunities, challenges and future directions for future epidemiology research in environmental epigenomics. Future investigations are needed to solve methodological and practical challenges, including uncertainties about stability over time of epigenomic changes induced by the environment, tissue specificity of epigenetic alterations, validation of laboratory methods, and adaptation of bioinformatic and biostatistical methods to high-throughput epigenomics. In addition, there are numerous reports of epigenetic modifications arising following exposure to environmental toxicants, but most have not been directly linked to disease endpoints. To complete our discussion, we also briefly summarize the diseases that have been linked to environmental chemicals-related epigenetic changes.     

肺癌表遗传学研究进展

表遗传学机制在肺癌的形成中占据重要地位,包括DNA的甲基化和组蛋白修饰,肺癌中与癌形成有关基因的失活多与异常甲基化有关,并且组蛋白修饰和甲基化紧密联系着。表遗传学改变多发生在肺癌早期,使得它成为肺癌化学预防的优良指标,了解肺癌表遗传现象的机制及其与传统遗传学的相互作用关系将有利于发现安全、高效的化学预防药物。     

Nutritional effects of salmonellosis in mice.

Mice infected with a standard challenge of Salmonella typhimurium manifest a number of changes associated with endotoxemia. These changes result in profound alterations in the nutritional and metabolic status of the host. Food and water intake approaches levels of total inanition, blood glucose declines more rapidly than in fasted controls, hepatic phosphoenolpyruvate carboxykinase (the enzyme that is rate limiting in gluconeogenesis) shows diminished activity and loss of cortisol inducibility, and hypothermia, rather than hyperthermia, becomes acute. These changes occur at a time when bacteremia is first demonstrable. This occurs on the 3rd day after infection under the conditions employed. Death occurs in most mice within the next 24 to 48 hr. Mice vaccinated with a highly immunogenic ribosomal preparation and subsequently infected with the standard number of organisms did not manifest the above changes. Other work from this laboratory has established that effects of the type described are elicited by bacterial endotoxin as a result of mediating substances released into the blood by cells of the reticuloendothelial system. Presumably these substances appear in blood of infected mice as well.