**1. Introduction**

Blindness due to AMD is of great concern to the ageing elderly population since the prevalence of the disease in Europe, in those aged 60 years and over has been estimated to be 27.7% with a projected increase in numbers from 67 to 77 million by 2050 [1]. Clinically, AMD is broadly divided into early, intermediate and late (or advanced) forms. Early AMD is characterised by the presence of large drusen and pigmentary abnormalities such as hypo- or hyperpigmentation of the fundus. Progression to the late form results in geographic atrophy of the RPE followed by photoreceptor degeneration, known as 'dry' AMD. The late phase is also associated with secondary complications of neovascular episodes (comprising 10-20% patients), these being designated as 'wet' AMD.

The wet form of the disease can lead to rapid visual loss and considerable efforts at intervention have resulted in anti-vascular endothelial growth factor (anti-VEGF) intra-vitreal injections with a considerable degree of success in managing the neovascularisation, but the underlying progression of the disease is not altered. Thus, the vast majority of AMD patients (falling in the 'dry' AMD category) still await the development of a suitable treatment modality that can either slow or arrest the progression of the disease [2, 3].

The pathophysiology of AMD is highly complex due to the diverse genetic associations and considerable gene-environmental interactions exacerbated by the additional association of dietary and cardiovascular risk factors [4–6]. Furthermore, all these factors are superimposed on the normal ageing changes in the visual unit making it very difficult to nominate specific targets for intervention. Since age is the highest risk factor for the development of AMD, an understanding of the inherent stresses in the visual system would allow us to predict the likely effect of additional risk factors providing a more targeted approach towards therapy.

Briefly, in the visual unit, the photoreceptor is the primary site of sustained damage producing highly toxic compounds that can trigger an inflammatory response. However, this damage is rapidly transferred to the RPE by the daily shedding of outer segment discs and phagocytosis. Since the RPE also operates in the same oxidative environment as the photoreceptor cell, the engulfed discs undergo further damage resulting in compromised lysosomal degradation. Non-degradable material, comprising mainly lipofuscin-related products is either packaged and stored in the RPE or extruded as membraneous debris onto Bruch's membrane. With age, this debris accumulates in Bruch's compromising its ability to transport nutrients, anti-oxidants, and vitamins essential for RPE and photoreceptor function. The toxic metabolites in Bruch's are pro-inflammatory mediators and in the normal elderly, lead to a low-grade inflammatory response [7]. In advanced ageing associated with AMD, a chronic inflammatory response is precipitated leading to the death of RPE and photoreceptors.

For therapeutic intervention to be effective, the functional aspects of the RPE and Bruch's membrane need to be restored. We will examine the compositional and functional alterations of ageing RPE and Bruch's membrane, nominate suitable targets for intervention, and assess the potential for amphipathic saponin molecules to reverse these ageing changes as a potential therapy for dry AMD.
