The daily ingestion of shed OS tips from photoreceptors by the RPE is critical for photoreceptor health and function. As the RPE is a mostly postmitotic tissue, the phagocytic burden for each cell over a lifetime is immense. Incomplete degradation of OS material contributes, in part, to the development of autofluorescent intracellular inclusions termed lipofuscin.
1 Lipofuscin accumulates over a lifetime, occupying major portions of the RPE cell in elderly individuals.
2–4 It contains numerous components, including a complex mixture of bisretinoids derived from covalent linkage of monoretinoids used in the visual cycle, oxidized lipid products, and cross-linked protein.
5 Whether this accumulated waste is toxic to the RPE, and in what diseases, is heavily debated.
6,7 In support of lipofuscin toxicity, animal models lacking the ABCA4 gene, mimicking the defect seen in Stargardt disease, accumulate lipofuscin at an accelerated rate and demonstrate retinal degeneration.
8 Numerous components of lipofuscin, in particular the bisretinoid N-retinylidene-N-retinylethanolamine (A2E), have been shown in cell culture and animal models to dysregulate complement activity, induce photo-oxidative damage, and disrupt lysosomal integrity.
9,10 On the other hand, lipofuscin-related fundus autofluorescence from patients with early- or intermediate-stage AMD is no higher than age-matched controls.
6 Further, the concentration of A2E or its oxidized components is no higher in RPE underlying the macula compared to the retinal periphery, despite AMD being a macular disease.
11 Additionally, there is minimal evidence supporting a link between lipofuscin and the pathologic hallmark of AMD, extracellular accumulation of lipid-rich deposits above (termed reticular pseudodrusen) and below (termed drusen) the RPE; while lipofuscin accumulates in the RPE of all persons as they age, only a subset develop pathologic drusen or reticular pseudodrusen. While levels of lipofuscin may not correlate with drusen formation or retinal toxicity, the lipofuscin granules in patients with AMD have been reported to be larger and more irregular than granules simply associated with age.
3 The significance of this difference is unknown.