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Anti-Aging and Regenerative Medicine
Published in Aruna Bakhru, Nutrition and Integrative Medicine, 2018
In the 1950s, theorists suggested that the evolutionary process has a neutral effect on aging and that Darwin's theory of survival of the fittest is only applicable to the young generation (http://www.programmed-aging.org/aging-theory-summary.html).“Mutation accumulation theory” (1952) was based on Medawar's hypothesis and proposed that aging occurred due to random mutations which further lead to adverse aging characteristics (http://www.programmed-aging.org/theories/mutation_accumulation.html). William's (1957) theory called “Antagonistic pleiotropy theory” proposed that the combined effect of many pleiotropic genes leads to aging. Although, these genes had a beneficial effect when an animal is young, but leads to adverse effects in older age (http://www.programmed-aging.org/theories/antagonistic_pleiotropy.html).
Mitochondrial DNA Mutations and Aging
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Rebecca Gordon, Sara C. Zapico
A clear association was found between mtDNA point mutations accumulation and aging in an extensive variability of tissues, indicating the presence of a differential pattern of mtDNA point mutation accumulation between tissues. These point mutations were mainly found to occur in the control region of the mitochondrial genome. Different studies have found an accumulation of point mutations in this region including A189G, T408A and T414G with aging (Michikawa et al. 1999, Calloway et al. 2000, Del Bo et al. 2002, Del Bo et al. 2003, Theves et al. 2006, McInerny et al. 2009, Wang et al. 2001). Theves et al. (Theves et al. 2006) analyzed A189G mutation in the buccal cells as well as the skeletal muscle of unrelated individuals age 1–97. They found a higher percentage of mutations in the skeletal muscle of older individuals than in their buccal cells. Wang et al. (Wang et al. 2001) studied eight different tissues from 40 individuals and reported that A189G and T408G mutations have a tissue-specific frequency, presenting their highest values in muscle. However, the most frequent fibroblast-specific mutation, T414G, has been described in skin, but not in muscle. This tissue-specific accumulation of point mutations may be related to the metabolic characteristics of the tissue (McInerny et al. 2009).
Methods for Genetic Testing II
Published in Peter G. Shields, Cancer Risk Assessment, 2005
Laura Gunn, Luoping Zhang, Martyn T. Smith
Since the original model of colon cancer, a few other models have emerged demonstrating similar patterns of mutation accumulation. Figure 1 shows three hypothetical models for three different cancer types. It is important to observe the differences in mutation pattern in each cancer type; for example, p53 mutations are believed to be early events in astrocytoma, in contrast to p53 mutations in colon cancer, which are later events. However, although the specific mutation varies among different cancers, the pattern of accumulation of mutation and the progressive impact of each mutation on cell proliferation and morphology are similar in each.
Adnexal squamous cell carcinoma: incidence of eyelid margin involvement
Published in Orbit, 2023
Alison H. Watson, Sabah Akbani, Natalie Homer, Marie Somogyi, Vikram Durairaj
Cumulative ultraviolet (UV) exposure is thought to play a major role in the development of ocular adnexal and facial SCC.6 There are two proposed putative cells of SCC origin. One is thought to exist within the hair follicle, specifically, due to transformation of the stem cell of the hair follicle bulge.6 The other potential progenitor cell is from the basal layer of interfollicular cells.6 The periorbital region maintains different types of hair follicles, those of the cilia present at the eyelid margin, and non-marginal vellus hairs similar to those on the rest of the face. Regardless of hair follicle subtype, all hair follicles spend time in a very defined cycle of growth (anagen phase), involution (catagen phase), and a resting stage or telogen phase.7 Different follicle subtypes spend differing amounts of time in these phases.8,9 Research has investigated which phases are vulnerable to carcinogenic accumulation and when uncontrolled tumorigenesis may occur.7,10–12 Differences in the life cycle of the lash follicles may result in a heightened vulnerability to mutation accumulation and cancer development.11 The vulnerability of these cells in turn may be expected to result in more frequent occurrence of SCC at the eyelid margin rather than along the non-marginal eyelid.
Integrated analysis of the immunological and genetic status in and across cancer types: impact of mutational signatures beyond tumor mutational burden
Published in OncoImmunology, 2018
Jan Budczies, Anja Seidel, Petros Christopoulos, Volker Endris, Matthias Kloor, Balázs Győrffy, Barbara Seliger, Peter Schirmacher, Albrecht Stenzinger, Carsten Denkert
Explaining the different correlations we observed for different types of MutSigs we believe that, additionally to a possible contribution of the sequence composition, the mutational processes behind the signatures and the associated specific dynamics of mutation accumulation represent an important factor for immunogenicity. Specifically, as the average number of mutations per cell division is higher for fast mutational processes such as MutSig 6 (defective mismatch repair associated) and MutSig2 (APOBEC related) than for slow mutational processes such as MutSig 1 (clock-like process and accumulation of mutations during life time) adaption to evade the immune system might be more difficult when mutations are generated by the former processes. Therefore, MutSigs could help to read out otherwise hidden aspects of tumor evolution and to integrate these in therapy planning.
Advances on potential therapeutic options for epidermolysis bullosa
Published in Expert Opinion on Orphan Drugs, 2018
Laura De Rosa, Ulrich Koller, Johann W. Bauer, Michele De Luca, Julia Reichelt
In addition to EpSCs, iPSCs derived from EB fibroblasts, keratinocytes, or possibly other cell types may provide an alternative target for gene therapy in EB (Figure 1). The number of EpSCs in the skin declines with age in JEB patients. An important consideration is that chronic wounding and subepidermal blistering in severe JEB patients are likely to lead to exhaustion of EpSCs [10], as well as other SC types within the skin. Although patients can still regenerate epidermis, it is often difficult or impossible to obtain clonogenic and holoclone-forming cells from most of the patient’s skin, especially in adult JEB patients [10]. In these cases, iPSCs derived from autologous cells, followed by gene correction and differentiation into EpSCs, along with rigorous quality assurance and controls to remove the risk of reprogramming-based or prolonged cell cultivation-induced mutation accumulation may hold great promise for EB therapy [10,48–52].