Progressive age-related drifts in gene expression remains an alternative hypothesis for the stochastic distributions of the lesions, at least for one or more steps in what is clearly a complex set of pathogenetic mechanisms, certainly including inflammatory and proliferative components (Woollard and Geissmann, 2010). the quasi-stochastic distributions of major types of geriatric pathologies, including the big three of Alzheimer’s disease, atherosclerosis and, via the induction of hyperplasis, malignancy. They may be responsible for altered stoichiometries of heteromultimeric mitochondrial complexes, potentially leading to such disorders as sarcopenia, nonischemic cardiomyopathy and Parkinson’s disease. locus, the individual atheromas were either type A or B (Benditt and Benditt, 1973). A monoclonal end result for the proliferation of normal diploid somatic cells, however, could be the result of a process of clonal attenuation and selection rather than mutation (Martin et al., 1974). Progressive age-related drifts in gene expression remains an alternative hypothesis for the stochastic distributions of the lesions, at least for one or more actions in what is clearly a complex set of pathogenetic mechanisms, certainly including inflammatory and proliferative components (Woollard and Geissmann, 2010). An epigenetic process has recently been suggested for atherogenesis in the context of late effects of ionizing radiation (Baverstock and Karotki, 2011). 9. Neoplasia The age-specific incidences of a wide variety of benign and malignant neoplasms increase as functions of age. Particularly robust evidence that cancers are strongly coupled Lobetyolin to the biology of ageing comes from comparative gerontological studies showing kinetics that are proportional to lifespan (observe, e.g., (Albert et al. 1994). Malignant neoplasms are characterized by large numbers of somatic mutations (http://www.sanger.ac.uk/genetics/CGP/cosmic/). As Larry Loeb has pointed out, key events in the pathogenesis appear to be mutations at loci that result in a great acceleration of the flux of somatic mutations C i.e., the emergence of mutator strains (Loeb, 2010; CD264 Loeb et al., 1974). Epimutations, including constitutional epimutations (Hitchins, 2010) also play important functions in the pathogenesis of malignancy. Many neutral mutations have been recently documented in the non-cancerous tissues surrounding a neoplasm (Salk et al., 2009). I suggest that there is an even earlier stage in the somatic development of neoplasia, one that may in fact be the very first step in the pathogenesis of the common carcinomas of ageing. This first step may be related to epigenetic drifts in the gene expressions of loci that determine whether or not a cell exits the G0 stage of the cell cycle. The loss of proliferative homeostasis is usually a canonical phenotype of ageing mammalian tissues (Martin, 1979, 2007). This results in both atrophy and hyperplasia, often seen side by side. Physiological homeostasis presumably regulates the cell cycle behavior of various subsets of stem cells. The genesis of senescent atrophies and hyperplasias can be presumed to be related to aberrant Lobetyolin stem cell behavior, perhaps driven by epigenetic drifts of relevant control loci. Such a scenario can explain the quasi-stochastic distributions of neoplasms. This is a testable hypothesis in that one would predict enhanced degrees of variegated gene expressions within a field of tissue surrounding the emerging or emerged neoplasm. A good example of a wide range of molecular markers that have been shown to be altered in hyperplasias associated with ongogenesis is usually given in a review of endometrial hyperplasias (Steinbakk et al., 2011). Many of these markers could be utilized for the determination of the degrees of variegation of gene expressions in normal tissues and tissues that juxtapose a range of neoplasms. Such neighboring tissues, according to the hypothesis of epigenetic drift, are predicted to exhibit enhanced variegation associated with markers of hyperplasia. Suitable methods would include quantitative immunofluorescent analysis of proteins or in-situ hybridizations and quantitative PCR for the quantitation of RNA species for single cell; the latter has been successfully used to demonstrate enhanced cell to cell variations of many RNA species among isolated myocardial cells from aged mice (Bahar et al., 2006). 10. A few other geriatric pathologies that may.While highly speculative, these are testable hypotheses, particularly given improvements in single cell analysis such as qPCR and semi-quantitative immunocytochemistry. distributions of major types of geriatric pathologies, including the big three of Alzheimer’s disease, atherosclerosis and, via the induction of hyperplasis, malignancy. They may be responsible for altered stoichiometries of heteromultimeric mitochondrial complexes, potentially leading to such disorders as sarcopenia, nonischemic cardiomyopathy and Parkinson’s disease. locus, the individual atheromas were either type A or B (Benditt and Benditt, 1973). A monoclonal end result for the proliferation of normal diploid somatic cells, however, could be the result of a process of clonal attenuation and selection rather than mutation (Martin et al., 1974). Progressive age-related drifts in gene expression remains an alternative hypothesis for the stochastic distributions of the lesions, at least for one or more actions in what is clearly a complex set of pathogenetic mechanisms, certainly including inflammatory and proliferative components (Woollard and Geissmann, 2010). An epigenetic process has recently been suggested for atherogenesis in the context of late effects of ionizing radiation (Baverstock and Karotki, 2011). 9. Neoplasia The age-specific incidences of a wide variety of benign and malignant neoplasms increase as functions of age. Particularly robust evidence that cancers are strongly coupled to the biology of ageing comes from comparative gerontological studies Lobetyolin showing kinetics that are proportional to lifespan (see, e.g., (Albert et al. 1994). Malignant neoplasms are characterized by large numbers of somatic mutations (http://www.sanger.ac.uk/genetics/CGP/cosmic/). As Larry Loeb has pointed out, key events in the pathogenesis appear to be mutations at loci that result in a great acceleration of the flux of somatic mutations C i.e., the emergence of mutator strains (Loeb, 2010; Loeb et al., 1974). Epimutations, including constitutional epimutations (Hitchins, 2010) also play important roles in the pathogenesis of cancer. Many neutral mutations have been recently documented in the non-cancerous tissues surrounding a neoplasm (Salk et al., 2009). I suggest that there is an even earlier stage in the somatic evolution of neoplasia, one that may in fact be the very first step in the pathogenesis of the common carcinomas of ageing. This first step may be related to epigenetic drifts in the gene expressions of loci that determine whether or not a cell exits the G0 stage of the cell cycle. The loss of proliferative homeostasis is a canonical phenotype of ageing mammalian tissues (Martin, 1979, 2007). This results in both atrophy and hyperplasia, often seen side by side. Physiological homeostasis presumably regulates the cell cycle behavior of various subsets of stem cells. The genesis of senescent atrophies and hyperplasias can be presumed to be related to aberrant stem cell behavior, perhaps driven by epigenetic drifts of relevant control loci. Such a scenario can explain the quasi-stochastic distributions of neoplasms. This is a testable hypothesis in that one would predict enhanced degrees of variegated gene expressions within a field of tissue surrounding the emerging or emerged neoplasm. A good example of a wide range of molecular markers that have been shown to be altered in hyperplasias associated with ongogenesis is given in a review of endometrial hyperplasias (Steinbakk et al., 2011). Many of these markers could be utilized for the determination of the degrees of variegation of gene expressions in normal tissues and tissues that juxtapose a range of neoplasms. Such neighboring tissues, according to the hypothesis of epigenetic drift, are predicted to exhibit enhanced variegation associated with markers of hyperplasia. Suitable methods would include quantitative immunofluorescent analysis of proteins or in-situ hybridizations and quantitative PCR for the quantitation of RNA species for single cell; the latter has been successfully used to demonstrate enhanced cell to cell variations of many RNA species among isolated myocardial cells from old mice (Bahar et al., 2006). 10. A few other geriatric pathologies that may be driven by epigenetic drifts of gene expression The arguments above could readily be used for the case of benign prostatic hyperplasia (BPH), a disorder of proliferative homeostasis that involves both glandular and stromal tissue. Both types of lesions are quasi-stochastic in their distributions within the prostate. There are a number of pathogenetic factors, including inflammatory factors and hormonal growth factors, plus their inhibitors, their receptors and downstream signal transduction pathways (Rick et al., 2011). There are therefore many opportunities for mischief related to increasing degrees of variegated gene expression. Another extremely common geriatric disorder with quasi-stochasic distributions of its lesions is osteoarthritis, the pathology of which is characterized by atrophy.