Abstract
Ageing disorders can be defined as the progressive and cumulative outcome of several defective cellular mechanisms as well as metabolic pathways, consequently resulting in degeneration. Environment plays an important role in its pathogenesis. In contrast, developmental disorders arise from inherited mutations and usually the role of environmental factors in development of disease is minimal. Age related macular degeneration (AMD) is one such retinal degenerative disorder which starts with the progression of age. Metabolism plays an important role in initiation of such diseases of ageing. Cholesterol metabolism and their oxidized products like 7-ketocholesterol have been shown to adversely impact retinal pigment epithelium (RPE) cells. These molecules can initiate mitochondrial apoptotic processes and also influence the complements factors and expression of angiogenic proteins like VEGF etc. In this review we highlight why and how AMD is an ageing disorder and not a developmental disease substantiated by disrupted cholesterol metabolism common to several age related diseases.
Highlights
Age related macular degeneration (AMD) is described by irreversible vision loss in older age
Sene et al have demonstrated that impaired cholesterol transport in macrophages could influence the macrophages polarization into particular cell type impacting the pathological hallmarks in AMD (Sene et al, 2013). These studies have suggetsed the importance of lipid/cholesterol metabolites in inducing the AMD pathological hallmarks by several regulatory components of innate immunity. These studies demontrate that lipids/cholesterol metabolites have their impact on regulation of complement factors, interaction with protective variant of complement factor H (CFH) and its modulation, macrophage infiltration, and regulation of proinflammatory/inflammatory genes suggesting the role of cholesterol metabolism and its metabolites on the complement pathway
Even though the activation of complement factor can alter the expression of metalloproteases 2/9 as well as their activity along with imbalance in VEGF to PEDF ratio, these results suggest the effect of activated complement which could further induce the proangiogenic environment for neovascularization in AMD (Bandyopadhyay and Rohrer, 2012)
Summary
Age related macular degeneration (AMD) is described by irreversible vision loss in older age. As AMD symptoms appear, characteristic features such as formation of drusen, consisting of active and inactive complement associated inflammatory products, aggregate of lipoprotein, cell debris, oxysterols, oxidized phospholipids and Alu RNA deposits begin to emerge later in life and not during development. AMD is an ageing disease not a developmental disorder complex manner such that the effects are not manifest early in life Several environmental factors such as age, sex, diet, smoking and demographic distribution have been reported to be strongly associated with AMD pathology (Figure 1), unlike a developmental disorder. Ageing can influence the methylation pattern of the genome (Bollati et al, 2009) These studies suggest that apart from the inherited epigenetic changes, these changes can be introduced by several modulatory environmental factors especially smoking and deficiency of anti-oxidants in diets in a later stage of life than at the developmental stage. In general the components of innate immunity have predominant role in progression of AMD
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