Age-related macular degeneration: A two-level model hypothesis

Age-related diseases, including age-related macular degeneration (AMD), are of growing importance in a world where population ageing has become a dominant global trend. Although a wide variety of risk factors for AMD have been identified, age itself remains by far the most important risk factor, making it an urgent priority to understand the connections between underlying ageing mechanisms and pathophysiology of AMD. Ageing is both multicausal and variable, so that differences between individuals in biological ageing processes are the focus of a growing number of pathophysiological studies seeking to explain how ageing contributes to chronic, age-related conditions. The aim of this review is to integrate the available knowledge on the pathophysiology of AMD within the framework of the biology of ageing. One highly significant feature of biological ageing is systemic inflammation, which arises as a second-level response to a first level of molecular damage involving oxidative stress, mutations etc. Combining these insights, the various co-existing pathophysiological explanations in AMD arrange themselves according to a two-level hypothesis. Accordingly, we describe how AMD can be considered the consequence of age-related random accumulation of molecular damage at the ocular level and the subsequent systemic inflammatory host response thereof. We summarize evidence and provide original data to enlighten where evidence is lacking. Finally, we discuss how this two-level hypothesis provides a foundation for thoughts and future studies in prevention, prognosis, and intervention.