Epigenetic alterations in aging tooth and the reprogramming potential

Tooth compartments and associated supportive tissues exhibit significant alterations during aging, leading to their impaired functioning. Aging not only affects the structure and function of dental tissue but also reduces its capacity to maintain physiological homeostasis and the healing process. Decreased cementocyte viability; diminished regenerative potential of stem cells residing in the pulp, alveolar bone and periodontal ligament; and impaired osteogenic and odontogenic differentiation capacity of progenitor cells are among the cellular impacts associated with oral aging. Various physiological and pathological phenomena are regulated by the epigenome, and hence, changes in epigenetic markers due to external stimuli have been reported in aging oral tissues and are considered a possible molecular mechanism underlying dental aging. The role of nutri-epigenetics in aging has emerged as an attractive research area. Thus far, various nutrients and bioactive compounds have been identified to have a modulatory effect on the epigenetic machinery, showing a promising response in dental aging. The human microbiota is another key player in aging and can be a target for anti-aging interventions in dental tissue. Considering the reversible characteristics of epigenetic markers and the potential for environmental factors to manipulate the epigenome, to minimize the deteriorative effects of aging, it is important to evaluate the linkage between external stimuli and their effects in terms of age-related epigenetic modifications.     

A systematic review of biological,social and environmental factors associated with epigenetic clock acceleration

Aging involves a diverse set of biological changes accumulating over time that leads to increased risk of morbidity and mortality. Epigenetic clocks are now widely used to quantify biological aging, in order to investigate determinants that modify the rate of aging and to predict age-related outcomes. Numerous biological, social and environmental factors have been investigated for their relationship to epigenetic clock acceleration and deceleration. The aim of this review was to synthesize general trends concerning the associations between human epigenetic clocks and these investigated factors. We conducted a systematic review of all available literature and included 156 publications across 4 resource databases. We compiled a list of all presently existing blood-based epigenetic clocks. Subsequently, we created an extensive dataset of over 1300 study findings in which epigenetic clocks were utilized in blood tissue of human subjects to assess the relationship between these clocks and numeral environmental exposures and human traits. Statistical analysis was possible on 57 such relationships, measured across 4 different epigenetic clocks (Hannum, Horvath, Levine and GrimAge). We found that the Horvath, Hannum, Levine and GrimAge epigenetic clocks tend to agree in direction of effects, but vary in size. Body mass index, HIV infection, and male sex were significantly associated with acceleration of one or more epigenetic clocks. Acceleration of epigenetic clocks was also significantly related to mortality, cardiovascular disease, cancer and diabetes. Our findings provide a graphical and numerical synopsis of the past decade of epigenetic age estimation research and indicate areas where further attention could be focused in the coming years.     

Epigenetic enzymes: A role in aging and prospects for pharmacological targeting

The development of interventions aimed at improving healthspan is one of the priority tasks for the academic and public health authorities. It is also the main objective of a novel branch in biogerontological research, geroscience. According to the geroscience concept, targeting aging is an effective way to combat age-related disorders. Since aging is an exceptionally complex process, system-oriented integrated approaches seem most appropriate for such an interventional strategy. Given the high plasticity and adaptability of the epigenome, epigenome-targeted interventions appear highly promising in geroscience research. Pharmaceuticals targeted at mechanisms involved in epigenetic control of gene activity are actively developed and implemented to prevent and treat various aging-related conditions such as cardiometabolic, neurodegenerative, inflammatory disorders, and cancer. In this review, we describe the roles of epigenetic mechanisms in aging; characterize enzymes contributing to the regulation of epigenetic processes; particularly focus on epigenetic drugs, such as inhibitors of DNA methyltransferases and histone deacetylases that may potentially affect aging-associated diseases and longevity; and discuss possible caveats associated with the use of epigenetic drugs.     

DNA methylation-based age clocks: From age prediction to age reversion

Aging as an irretrievable occurrence throughout the entire life is characterized by a progressive decline in physiological functionality and enhanced disease vulnerability. Numerous studies have demonstrated that epigenetic modifications, particularly DNA methylation (DNAm), correlate with aging and age-related diseases. Several investigations have attempted to predict chronological age using the age-related alterations in the DNAm of certain CpG sites. Here we categorize different studies that tracked the aging process in the DNAm landscape to show how epigenetic age clocks evolved from a chronological age estimator to an indicator of lifespan and healthspan. We also describe the health and disease predictive potential of estimated epigenetic age acceleration regarding different clinical conditions and lifestyle factors. Considering the revealed age-related epigenetic changes, the recent age-reprogramming strategies are discussed which are promising methods for resetting the aging clocks.     

Epigenetic age acceleration is associated with allergy and asthma in children in Project Viva

1. Download : Download high-res image (199KB)
2. Download : Download full-size image

     

CircadiOmic medicine and aging

The earth displays daily, seasonal and annual environmental cycles that have led to evolutionarily adapted ultradian, circadian and infradian rhythmicities in the entire biosphere. All biological organisms must adapt to these cycles that synchronize the function of their circadiome. The objective of this review is to discuss the latest knowledge regarding the role of circadiomics in health and aging. The biological timekeepers are responsive to the environmental cues at microsecond to seasonal time-scales and act with precision of a clock machinery. The robustness of these rhythms is essential to normal daily function of cells, tissues and organs. Mis-alignment of circadian rhythms makes the individual prone to aging, sleep disorders, cancer, diabetes, and neuro-degenerative diseases. Circadian and CircadiOmic medicine are emerging fields that leverage our in-depth understanding of health issues, that arise as a result of disturbances in circadian rhythms, towards establishing better therapeutic approaches in personalized medicine and for geroprotection.     

Epigenetic modifications in spinal ligament aging

Spinal stenosis is a common degenerative spine disorder in the aged population and the spinal ligament aging is a main contributor to this chronic disease. However, the underlying mechanisms of spinal ligament aging remain unclear. Epigenetics is the study of heritable and reversible changes in the function of a gene or genome that occur without any alteration in the primary DNA sequence. Epigenetic alterations have been demonstrated to play crucial roles in age-related diseases and conditions, and they are recently studied as biomarkers and therapeutic targets in the field of cancer research. The main epigenetic modifications, including DNA methylation alteration, histone modifications as well as dysregulated noncoding RNA modulation, have all been implicated in spinal ligament aging diseases. DNA methylation modulates the expression of critical genes including WNT5A, GDNF, ACSM5, miR-497 and miR-195 during spinal ligament degeneration. Histone modifications widely affect gene expression and obvious histone modification abnormalities have been found in spinal ligament aging. MicroRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) exert crucial regulating effects on spinal ligament aging conditions via targeting various osteogenic or fibrogenic differentiation related genes. To our knowledge, there is no systematic review yet to summarize the involvement of epigenetic mechanisms of spinal ligament aging in degenerative spinal diseases. In this study, we systematically discussed the different epigenetic modifications and their potential functions in spinal ligament aging process.     

hTERT表观调控及其与肿瘤相关性研究

hTERT基因编码人端粒酶催化亚基,该亚基以端粒酶RNA为模板反转录形成TTAGGG短串联重复,这些重复序列添加于染色体端粒DNA 3 '端以维护染色体稳定性.hTERT的转录受多种因素的影响,如以DNA甲基化为代表的表观遗传途径和多种转录因子的调控.hTERT表观异常修饰可能与肿瘤发生相关,探讨hTERT启动子甲基化改变有望为细胞衰老、死亡的调控以及肿瘤诊断提供重要的生物学指标.该文就hTERT不同层次的表观遗传调控改变及其与肿瘤的相关性进行概述.     

表遗传学修饰研究方法新进展

表遗传学修饰重新编程通过DNA甲基化和组蛋白乙酰化等多种修饰方式,有序地改变染色质构形、调整基因表达,在哺乳动物的生殖发育等过程中作用重要。近年来随着有关研究深入,各种新技术、新思路不断涌现,研究方法得以不断改进和完善,该文就表遗传学修饰研究方法学的最新进展作一综述。     

The role of epigenetics in aging and age-related diseases

The role of epigenetics in aging and age-related diseases is a key issue in molecular physiology and medicine because certain epigenetic factors are thought to mediate, at least in part, the relationship between the genome and the environment. An active role for epigenetics in aging must meet two prior conditions: there must be specific epigenetic changes during aging and they must be functionally associated with the aged phenotype. Assuming that specific epigenetic modifications can have a direct functional outcome in aging, it is also essential to establish whether they depend on genetic, environmental or stochastic factors, and if they can be transmitted from one generation to the next. Here we discuss current knowledge about these matters and future directions in the field.     

Impact of aging on DNA methylation

The biochemistry of aging is complex, with biologically significant changes occurring in proteins, lipids and nucleic acids. One of these changes is in the methylation of DNA. DNA methylation is a mechanism modifying gene expression. The methylation of sequences in or near regulatory elements can suppress gene expression through effects on DNA binding proteins and chromatin structure. Both increases and decreases in methylation occur with aging, depending on the tissue and the gene. These changes can have pathologic consequences, contributing to the development of malignancies and autoimmunity with aging, and possibly to other disorders as well. Thus, while aging can impact on DNA methylation, the changes in DNA methylation can also impact on aging. This review summarizes current evidence for changes in the methylation status of specific genes with aging, their impact on diseases that develop with aging, and mechanisms that may contribute to the altered DNA methylation patterns. As this field is still developing, it is anticipated that new knowledge will continue to accumulate rapidly.     

表观遗传修饰改变与线粒体疾病

线粒体功能失调是导致线粒体疾病的主要原因,因此了解线粒体功能的调节机制非常重要。近期的研究表明,表观遗传修饰的对象不仅包括细胞核DNA还包括线粒体DNA,表观遗传修饰的变化对线粒体功能的调节机制有重要影响。文章主要概括了线粒体DNA甲基化、细胞核基因组的DNA甲基化和微RNA ( microRNA, miRNA)调控等表观遗传修饰与线粒体疾病发生的关联研究进展。     

Biohorology and biomarkers of aging: Current state-of-the-art,challenges and opportunities

The aging process results in multiple traceable footprints, which can be quantified and used to estimate an organism's age. Examples of such aging biomarkers include epigenetic changes, telomere attrition, and alterations in gene expression and metabolite concentrations. More than a dozen aging clocks use molecular features to predict an organism's age, each of them utilizing different data types and training procedures. Here, we offer a detailed comparison of existing mouse and human aging clocks, discuss their technological limitations and the underlying machine learning algorithms. We also discuss promising future directions of research in biohorology — the science of measuring the passage of time in living systems. Overall, we expect deep learning, deep neural networks and generative approaches to be the next power tools in this timely and actively developing field.     

Epidemiological and genetic overlap among biological aging clocks: New challenges in biogerontology

Estimators of biological age (BA) – defined as the hypothetical underlying age of an organism – have attracted more and more attention in the last years, especially after the advent of new algorithms based on machine learning and genetic markers. While different aging clocks reportedly predict mortality in the general population, very little is known on their overlap. Here we review the evidence reported so far to support the existence of a partial overlap among different BA acceleration estimators, both from an epidemiological and a genetic perspective. On the epidemiological side, we review evidence supporting shared and independent influence on mortality risk of different aging clocks - including telomere length, brain, blood and epigenetic aging – and provide an overview of how an important exposure like diet may affect the different aging systems. On the genetic side, we apply linkage disequilibrium score regression analyses to support the existence of partly shared genomic overlap among these aging clocks. Through multivariate analysis of published genetic associations with these clocks, we also identified the most associated variants, genes, and pathways, which may affect common mechanisms underlying biological aging of different systems within the body. Based on our analyses, the most implicated pathways were involved in inflammation, lipid and carbohydrate metabolism, suggesting them as potential molecular targets for future anti-aging interventions. Overall, this review is meant as a contribution to the knowledge on the overlap of aging clocks, trying to clarify their shared biological basis and epidemiological implications.     

Epigenetic aging in children from a small-scale farming society in The Congo Basin: Associations with child growth and family conflict

Developmental environments influence individuals' long-term health trajectories, and there is increasing emphasis on understanding the biological pathways through which this occurs. Epigenetic aging evaluates DNA methylation at a suite of distinct CpG sites in the genome, and epigenetic age acceleration (EAA) is linked to heightened chronic morbidity and mortality risks in adults. Consequently, EAA provides insights on trajectories of biological aging, which early life experiences may help shape. However, few studies have measured correlates of children's epigenetic aging, especially outside of the U.S. and Europe. In particular, little is known about how children's growth and development relate to EAA in ecologies in which energetic and pathogenic stressors are commonplace. We studied EAA from dried blood spots among Bondongo children (n = 54) residing in a small-scale, fisher-farmer society in a remote region of the Republic of the Congo. Here, infectious disease burdens and their resultant energy demands are high. Children who were heavier for height or taller for age, respectively, exhibited greater EAA, including intrinsic EAA, which is considered to measure EAA internal to cells. Furthermore, we found that children in families with more conflict between parents had greater intrinsic EAA. These results suggest that in contexts in which limited energy must be allocated to competing demands, more investment in growth may coincide with greater EAA, which parallels findings in European children who do not face similar energetic constraints. Our findings also indicate that associations between adverse family environments and greater intrinsic EAA were nonetheless observable but only after adjustment for covariates relevant to the energetically and immunologically demanding nature of the local ecology.     

小鼠外周组织时钟基因启动子区甲基化分析

 摘要：目的 建立一种简单快速经济的检测八个主要时钟基因BMAL1、BMAL2、CLOCK、NPAS2、PER1、PER2、CRY1和CRY2启动子区甲基化状态的方法。同时检测小鼠外周组织肝、心、肾、胸腺、睾丸时钟基因启动子区甲基化状态。方法 用偏重亚硫酸氢钠和对苯二酚对基因组DNA进行脱氨基修饰。修饰后的DNA为模板,两套不同的引物对：甲基化特异性引物对和非甲基化特异性引物扩增小鼠肝、心、肾、胸腺、睾丸组织时钟基因启动子区。PCR产物进行电泳和测序。结果 扩增产物与预期片段大小相符合。PCR产物经过直接测序得到进一步证实。结论 成功建立了检测小鼠时钟基因启动子区甲基化的方法,为检测小鼠周围组织时钟基因启动子区甲基化提供了新的方法。同时,成年小鼠所有的八个时钟基因均为非甲基化状态。     

The role of 5-hydroxymethylcytosine in development,aging and age-related diseases

DNA methylation at the fifth position of cytosines (5mC) represents a major epigenetic modification in mammals. The recent discovery of 5-hydroxymethylcytosine (5hmC), resulting from 5mC oxidation, is redefining our view of the epigenome, as multiple studies indicate that 5hmC is not simply an intermediate of DNA demethylation, but a genuine epigenetic mark that may play an important functional role in gene regulation.Currently, the availability of platforms that discriminates between the presence of 5mC and 5hmC at single-base resolution is starting to shed light on the functions of 5hmC. In this review, we provide an overview of the genomic distribution of 5hmC, and examine recent findings on the role of this mark and the potential consequences of its misregulation during three fundamental biological processes: cell differentiation, cancer and aging.