Lifespan of Population - Essay Example

The significant advances in medical and scientific field, healthcare awareness, and improved standards of living are contributing factors to increaselife span of general population. An appearance of wounds in the elderly persons is more since they are more susceptible to many diseases and infections as compared to younger ones. The wound repair mechanism is delayed in elderly individuals causing increased morbidity and mortality (McMahon et al. 1996). Therefore, there is a growing interest to know molecular and cellular targets which are involved in the process of wound healing. This might help to identify the targets for novel and effective drug therapy. Normal wound healing is innate host immune response for tissue regeneration and repair involving coagulation, inflammation, epithelialization, formation of granulation tissue and tissue remodeling (Ashcroft et al. 2002). In response to injury stages of wound healing are depicted in figure 1 (Gosain and DiPietro 2004). Figure 1: stages of wound healing (Gosain and DiPietro 2004) The number of polypeptide growth factors and cytokines like epidermal growth factor (EGF), basic fibroblast growth factor (β-FGF), platelet derived growth factor (PDGF) A & B isoforms, the transforming growth factor (TGF-β), vascular endothelial growth factor (VEGF) plays an important role in wound healing process. It is demonstrated that delayed wound healing in both elderly animal and human individuals is due to decreased inflammatory and proliferative responses, delayed angiogenesis, delayed remodeling and slower reepithelialization (Strigini and Ryan, 1996). Morphology of skin changes with aging process. It involves flattening of the dermo-epidermal junction, disorganized microcirculation, decrease in number of cells as well as dermal cell constituents like fibroblasts, mast cells, macrophages. Also, the morphology, properties and quantity of dermal extracellular matrix content such as collagen, elastin, glucosaminoglycans changes with aging. These variations lead to delayed cellular proliferation, migration, modified binding of growth factor to matrix, alteration in adhesion molecule synthesis and changes in molecular signaling (Ashcroft et al. 2002). These changes affect functional cell response to all the stimuli. The age-related changes in the individual phases of healing are summarized in Table 1 (Goain and DiPietro 2004). Table 1. Summary of the age-related changes in the individual phases of healing (Gosain and DiPietro 2004). The animal models which are used to study the impact of aging on wound healing are not suitably characterized. Therefore the reported evidences itself are contradictory (Ashcroft et al., 1995). Only well characterized animal models might be helpful for extrapolation of the therapeutic data from animals to humans. Ashcroft et al. (1997) has demonstrated the temporal relationship between the various cytokines and their receptors during incisional wound healing in well characterized aging mouse colony. EGF binds to EGF receptor protein tyrosine kinase and promotes keratinocytes to migrate from the basal layer to the skin outer surface. Wounded ECM is degraded by kertinocytes and fibroblasts secreted EGF regulated matrix metalloproteinases (MMPs: collagenases, stromelysins, and gelatinases). Once degradation process is finished MMPs inhibitors inhibit MMPs to stop further degradation (Gosain and DiPietro 2004). Martisan et al 1987 reported that number of EGF-R remains constant during invitro cellular aging. Contradictory to this report Reenstra et al reported decrease in EGF receptor number and internalization with age. The delayed and reduced EGF effect in aging mouse colony (30 months) is compared to their young counterparts (Ashcroft et al. 2002). EGF-R gene delivery might be a good option for wound healing. bFGF induces DNA synthesis, angiogenesis, ECM synthesis, down-regulates collagen type I synthesis in vivo. It has been reported that it stimulates wound healing in diabetic and db/db mice. PDGF stimulates fibronectin, glycosaminoglycan, and collagen synthesis; and attracts inflammatory cells and fibroblasts. Cells responsiveness towards PDGF decreases with age. Mammalian TGF-β1 and 2 produced from keratinocytes attracts monocytes, fibroblasts, increases ECM deposition and regulates protease expression. Local application of TGF-β1 and 2 antibodies decreases inflammation, fibrosis and angiogenesis. Though TGF-β secretion is decreased with aging, local/systemic administration of TGF-β enhances wound healing only in small group of old rodents (Ashcroft et al. 1997). It has been studied that estrogen treatment can restore TGF-β levels in aged cells by increasing collagen expression. It has been examined that in old mouse models as well as aged humans, there is a delayed secretion in addition to less sensitivity of growth factors and their receptors to stimulate fibroblasts (Ashcroft et al. 2002). This in turn opens up the therapeutic option for treating impaired wound healing process by administering growth factors locally and/or systemically. These growth factors are reported to show positive effects in wound healing in animal models (Gosain and DiPietro 2004). Fibronectin helps in reepithelialization, collagen deposition and wound contraction. In older people fibronectin levels are lessened and elatase levels are increased causing more degradation of collagen, fibronectin and proteoglycans in wound. The rate of wound healing can be increased by targeting the treatment to reduce elastase levels (by reducing neutrophil numbers) which could assist matrix deposition instead of degradation (Ashcroft et al., 1999). Oxygen delivery to the wound site is limited (hypoxia) in elderly patients causing impaired reepithelialization in clinical as well as animal studies. The exposure to hypoxia affects induction of TGF-β and metalloproteinase in aged cells, resulting in depressed keratinocytes migratory activity (Xia et al. 2001). In such cases, hyperbaric oxygen (HBO) therapy is demonstrated to assist wound healing in clinical trials. HBO and/or TGF- β3 is reported to improve wound healing in aged rabbits (Bonomo et al. 2000). Local and systemic administration of keratinocyte growth factor-2 (KGF-2) or Fibroblast growth factor-10 (FGF-10) in young and old ischemia-impaired rabbit dermal ulcer model stimulates granulation tissue formation and epithelial growth. No scar formation is reported on supplementation of KGF-2 in a rabbit wounded model (Xia et al. 1999). It has been investigated that reendothelialization in response to endothelial injuries in old rabbits decreases as compared to young ones, due to reduction in VEGF expression. Local delivery of VEGF in old rabbits accelerates reendothelialization process, and improves vascular healing. This strategy may prove useful to reduce age-dependent impairment of reendothelialization process in humans (Gennaro et al. 2003). Low levels of antioxidants and production of oxygen free radicals during tissue inflammation delays wound healing in aged rats (Rasik and Shukla 2000). It is inspected that potent antioxidants (RRR-α-tocopherol, coenz Q10), combine with mild prooxidants (soyphospholipids, L-methionine) have beneficial effects (skin healing, trophism, increased reepithelialization) in experimentally burned and chemically peeled Wistar rats (de Luca et al. 2007). This strategy can be extended to treat elderly humans in the skin rejuvenation techniques. Age related reduction in systemic hormone levels vitiate wound healing process. Topical and systemic estrogen administration increases wound healing in older men and women as well as animals by reducing neutrophil elastase expression, macrophage migratory factor inhibition and, increasing fibronectin and collagen levels. The rate of wound healing is faster in postmenopausal women seeking hormone replacement therapy (Ashcroft et al. 1999). Thus well characterized animal models and experimental design might lead to new approaches to reduce the effects that ageing has on wound healing in humans. . References Ashcroft, G. S. Horan, M. A., & Ferguson, M.W. J. (1997) The effects of ageing on wound healing: immunolocalisation of growth factors and their receptors in a murine incisional model, Journal of Anatomy, 190, November1996, pp. 351-365. Ashcroft, G. S. Horan, M. A., & Ferguson, M.W. J. (1995) The effects of ageing on cutaneous wound healing in mammals, Journal of Anatomy, 187, January 1995, pp. 1-26. Ashcroft, G. S. Greenwell-Wild, Horan, M. A. Wahl, S. M. and & Ferguson, M.W. J. (1999) Topical Estrogen Accelerates Cutaneous Wound Healing in Aged Humans associated with an Altered Inflammatory Response, American Journal of Pathology, 155(4), October 1999 , pp 1137–1146. Ashcroft, G. S. Mills, S. J. & Ashworth, J. J. (2002) Ageing and wound healing, Biogerontology, 3, May 2002, pp. 337–345. Bonomo, S. R. Davidson, J. D. Tyrone, J. W. Lin, X. & Mustoe, T. A. (2000) Enhancement of wound healing by hyperbaric oxygen and transforming growth factor beta3 in a new chronic wound model in aged rabbits, Arch Surg., 135(10), Oct 2000, pp. 1148-1153. de Luca, C. Deeva, I. MikhalChik, E. & Korkina, L. (2007) Beneficial effects of pro-/antioxidant-based nutraceuticals in the skin rejuvenation techniques. Cell Mollcular Biology, 53(1), Apr 2007, pp. 94-101. Gennaro, G. Ménard, C. 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Strigini, L. & Ryan, T. (1996) Wound Healing in Elderly Human Skin, Clinics in Dermatology, 14(2), April 1996, pp.197-206. Xia, Y. P. Zhao, Y. Marcus, J. Jimenez, P. A. Ruben, S. M. Moore, P. A. Khan, F. & Mustoe, T. A. Effects of keratinocyte growth factor-2 (KGF-2) on wound healing in an ischaemia-impaired rabbit ear model and on scar formation, Journal of Pathology, 188 (4), Aug 1999, pp. 431-438. Xia, Y. P. Zhao, Y. Tyrone, J. W. Chen, A. & Mustoe, T.A. Differential activation of migration by hypoxia in keratinocytes isolated from donors of increasing age: implication for chronic wounds in the elderly, Journal of Investigative Dermatology., 116(1), Jan 2001, pp. 50-56. Read More