In my presentation Towards a Systems Theory of Aging I argue that the two theories Programmed epigenomic changes and Decline in functioning of the stem cell supply chain are complimentary and equivalent and have the potential for providing a framework for an overall systems view of aging that knits together a large collection of traditional special theories of aging. In this post, I review some research that is relevant to this assertion, especially with respect to the relationships between the Programmed epigenomic changes theories and the aging theories 6. Chronic Inflammation, 7. Immune System Compromise, 8. Neurological Degeneration, 10. Susceptibility to Cancers, and 11. Susceptibility to Cardiovascular Disease.
The 2010 publication Epigenetics in atherosclerosis and inflammation is a review study. “Atherosclerosis is a multifactorial disease with a severe burden on western society. Recent insights into the pathogenesis of atherosclerosis underscore the importance of chronic inflammation in both the initiation and progression of vascular remodelling. — Besides genetic factors also epigenetic mechanisms play an essential and fundamental role in the transcriptional control of gene expression. –. The concept of epigenetic regulation is gradually being recognized as an important factor in the pathogenesis of atherosclerosis. Recent research provides an essential link between inflammation and reprogramming of the epigenome.” The Programmed epigenomic changes theory of aging asserts that age-related reprogramming of the epigenome increases susceptibility to inflammation and inflammation-related diseases.
The 2008 publication Epigenetic regulation of gene expression in the inflammatory response and relevance to common diseases highlights the same points, extending their scope to autoimmune diseases and cancers. “It is clear that the epigenetic state is a central regulator of cellular development and activation. Emerging evidence suggests a key role for epigenetics in human pathologies, including in inflammatory and neoplastic disorders. The epigenome is influenced by environmental factors throughout life. Nutritional factors can have profound effects on the expression of specific genes by epigenetic modification, and these may be passed on to subsequent generations with potentially detrimental effects. Many cancers are associated with altered epigenetic profiles, leading to altered expression of the genes involved in cell growth or differentiation. Autoimmune and neoplastic diseases increase in frequency with increasing age, with epigenetic dysregulation proposed as a potential explanation. In support of this hypothesis, studies in monozygotic twins revealed increasing epigenetic differences with age. Differences in methylation status of CpG sites, monoallelic silencing, and other epigenetic regulatory mechanisms have been observed in key inflammatory response genes. The importance of the epigenome in the pathogenesis of common human diseases is likely to be as significant as that of traditional genetic mutations.”A number of studies have been concerned with identifying epigenomic changes associated with particular cancers. Although they are often highly technical, they show that complicated epigenomic/epigenetic changes are involved in cancer processes.
The 2007 publication Epigenetic profiling of multidrug-resistant human MCF-7 breast adenocarcinoma cells reveals novel hyper- and hypomethylated targets is an example. “Presently, two hypotheses, genetic and epigenetic, have been proposed to explain mechanisms of acquired cancer drug resistance. In the present study, we examined the alterations in epigenetic mechanisms in the drug-resistant MCF-7 human breast cancer cells induced by doxorubicin (DOX) and cisplatin (cisDDP), two chemotherapeutic drugs with different modes of action. Despite this difference, both of the drug-resistant cell lines displayed similar pronounced changes in the global epigenetic landscape showing loss of global DNA methylation, loss of histone H4 lysine 20 trimethylation, increased phosporylation of histone H3 serine 10, and diminished expression of Suv4-20h2 histone methyltransferase compared with parental MCF-7 cells. In addition to global epigenetic changes, the MCF-7/DOX and MCF-7/cisDDP drug-resistant cells are characterized by extensive alterations in region-specific DNA methylation, as indicated by the appearance of the number of differentially methylated DNA genes. A detailed analysis of hypo- and hypermethylated DNA sequences revealed that the acquisition of drug-resistant phenotype of MCF-7 cells to DOX and cisDDP, in addition to specific alterations induced by a particular drug only, was characterized by three major common mechanisms: dysfunction of genes involved in estrogen metabolism (sulfatase 2 and estrogen receptor alpha), apoptosis (p73, alpha-tubulin, BCL2-antagonist of cell death, tissue transglutaminase 2 and forkhead box protein K1), and cell-cell contact (leptin, stromal cell-derived factor receptor 1, activin A receptor E-cadherin) and showed that two opposing hypo- and hypermethylation processes may enhance and complement each other in the disruption of these pathways. These results provided evidence that epigenetic changes are an important feature of cancer cells with acquired drug-resistant phenotype and may be a crucial contributing factor to its development. Finally, deregulation of similar pathways may explain the existence and provide mechanism of cross-resistance of cancer cells to different types of chemotherapeutic agents.”
The 2008 publication Epigenetic mapping and functional analysis in a breast cancer metastasis model using whole-genome promoter tiling microarrays states “Breast cancer metastasis is a complex, multi-step biological process. Genetic mutations along with epigenetic alterations in the form of DNA methylation patterns and histone modifications contribute to metastasis-related gene expression changes and genomic instability. — . RESULTS: We integrated data from the tiling microarrays with targets identified by Ingenuity Pathways Analysis software and observed epigenetic variations in genes implicated in epithelial-mesenchymal transition and with tumor cell migration. We identified widespread genomic hypermethylation and hypomethylation events in these cells and we confirmed functional associations between methylation status and expression of the CDH1, CST6, EGFR, SNAI2 and ZEB2 genes by quantitative real-time PCR. Our data also suggest that the complex genomic reorganization present in cancer cells may be superimposed over promoter-specific methylation events that are responsible for gene-specific expression changes. CONCLUSION: This is the first whole-genome approach to identify genome-wide and gene-specific epigenetic alterations, and the functional consequences of these changes, in the context of breast cancer metastasis to lymph nodes. This approach allows the development of epigenetic signatures of metastasis to be used concurrently with genomic signatures to improve mapping of the evolving molecular landscape of metastasis and to permit translational approaches to target epigenetically regulated molecular pathways related to metastatic progression.”
The 2009 publication Pituitary tumours: all silent on the epigenetics front states “Investigation of the epigenome of sporadic pituitary tumours is providing a more detailed understanding of aberrations that characterise this tumour type. Early studies, in this and other tumour types adopted candidate-gene approaches to characterise CpG island methylation as a mechanism responsible for or associated with gene silencing. However, more recently, investigators have adopted approaches that do not require a priori knowledge of the gene and transcript, as example differential display techniques, and also genome-wide, array-based approaches, to ‘uncover’ or ‘unmask’ silenced genes. Furthermore, through use of chromatin immunoprecipitation as a selective enrichment technique; we are now beginning to identify modifications that target the underlying histones themselves and that have roles in gene-silencing events. Collectively, these studies provided convincing evidence that change to the tumour epigenome are not simply epiphenomena but have functional consequences in the context of pituitary tumour evolution. Our ability to perform these types of studies has been and is increasingly reliant upon technological advances in the genomics and epigenomics arena. In this context, other more recent advances and developing technologies, and, in particular, next generation or flow cell re-sequencing techniques offer exciting opportunities for our future studies of this tumour type.”Relating to almost all areas of medicine, starting in the early-2000s more and more research publications have been appearing pointing out the importance of epigenomic regulation in disease etiology and progression.
For example, the 2008 review publication Epigenetic Regulation of Vascular Endothelial Gene Expression “Epigenetics has emerged as an increasingly powerful paradigm to understand complex non-Mendelian diseases. For example, epigenetics provides a newer perspective for understanding how gene expression is perturbed in prevalent diseases of the human vascular system characterized by a dysfunctional endothelium.4”
The 2009 publication Epigenetics and periodontal disease: future perspectives states “Periodontitis is a multifactorial infection characterized by inflammation and destruction of tooth supporting tissues, as a result of the response of a susceptible host to bacterial challenge. Studies have demonstrated that epigenetic events are able to influence the production of cytokines, contributing to the development of inflammatory diseases. Epigenetic events act through the remodeling of chromatin and can selectively activate or inactivate genes, determining their expression. The epigenetic process, by inducing a change in cytokine profile, may subsequently influence the pathogenesis and determine the outcome of many infectious diseases. These findings may have relevance for inflammatory diseases in which the expression of cytokines is unregulated. The purpose of this review is to show evidence that supports the hypothesis that epigenetic alterations, such as hyper and hypomethylation, of cytokine genes, could help to understand the mechanisms related to periodontal disease activity. Therefore, epigenetics may have future impact on diagnosis and/or therapeutics of periodontal disease.“
The 2009 publication Epigenetic mechanisms that underpin metabolic and cardiovascular diseases relates to other critical disease fronts and focuses on lifelong changes in the epigenome and their affect on disease susceptibilities:
· “Developmental plasticity enables an organism to respond to environmental cues and adjust its phenotypic development to match its environment.
· Developmental plasticity is effected, at least in part, by epigenetic changes that are established in early life and modulate gene expression during development and maturity.
· In mammals, the window during which the epigenome is susceptible to nutritional cues extends from conception to at least weaning.
· Mismatch between the early and mature environments may result in inappropriate patterns of epigenetic changes and gene expression that increase subsequent susceptibility to metabolic and cardiovascular diseases.
· The available evidence suggests that interventions to prevent metabolic and cardiovascular diseases should focus on the prenatal and early postnatal periods.”
The 2008 publication Epigenetic principles and mechanisms underlying nervous system functions in health and disease states “Epigenetics and epigenomic medicine encompass a new science of brain and behavior that are already providing unique insights into the mechanisms underlying brain development, evolution, neuronal and network plasticity and homeostasis, senescence, the etiology of diverse neurological diseases and neural regenerative processes. Epigenetic mechanisms include DNA methylation, histone modifications, nucleosome repositioning, higher order chromatin remodeling, non-coding RNAs, and RNA and DNA editing. RNA is centrally involved in directing these processes, implying that the transcriptional state of the cell is the primary determinant of epigenetic memory. This transcriptional state can be modified not only by internal and external cues affecting gene expression and post-transcriptional processing, but also by RNA and DNA editing through activity-dependent intracellular transport and modulation of RNAs and RNA regulatory supercomplexes, and through trans-neuronal and systemic trafficking of functional RNA subclasses. These integrated processes promote dynamic reorganization of nuclear architecture and the genomic landscape to modulate functional gene and neural networks with complex temporal and spatial trajectories. Epigenetics represents the long sought after molecular interface mediating gene-environmental interactions during critical periods throughout the lifecycle. The discipline of environmental epigenomics has begun to identify combinatorial profiles of environmental stressors modulating the latency, initiation and progression of specific neurological disorders, and more selective disease biomarkers and graded molecular responses to emerging therapeutic interventions. Pharmacoepigenomic therapies will promote accelerated recovery of impaired and seemingly irrevocably lost cognitive, behavioral, sensorimotor functions through epigenetic reprogramming of endogenous regional neural stem cell fate decisions, targeted tissue remodeling and restoration of neural network integrity, plasticity and connectivity.”
The above is just a small sample of the river of applicable literature but enough to make the point: The Programmed epigenomic changes theory of aging is critically implicated in a large number of disease and disease progression processes. It will clearly take a lot more research to establish that this theory is capable of explaining all the phenomena described by all the other theories of aging but I strongly suspect that this will in time happen.
Epigenomic interventions to deal with various diseases are now in the clinical trials phase. Specifically, a number of histone deacetylase inhibitors are now in clinical trials, basically substances that keep apoptosis and other critical genes active. Describing these will be the subject of a subsequent post. I also hope to characterize some interesting research relating lifelong nutrition patterns to epigenomic changes.