Age related macular degeneration (AMD) is the most common blinding disease in those over 60 years. In 50% of cases it is associated with polymorphisms of complement factor H (FH), implicating immune vulnerability. But such individuals may exhibit abnormal outer retinal blood flow decades before disease initiation, suggesting an early disease footprint. FH is expressed in the retinal pigmented epithelium (RPE). During development the RPE is adjacent to the site of retinal mitosis and complex regulatory interactions occur between the relatively mature RPE and retinal neuronal precursors that control the cell cycle. Here we ask if the absence of FH from the RPE influences retinal development using a mouse CFH knockout (Cfh−/−) with an aged retinal degenerative phenotype. We reveal that from birth, these mice have significantly disrupted and delayed retinal development. However, once development is complete, their retinae appear relatively normal, although many photoreceptor and RPE mitochondria are abnormally large, suggesting dysfunction consistent with premature ATP decline in Cfh−/−. Total retinal mtDNA is also reduced and these deficits are associated shortly after with reduced retinal function. Cfh−/+ mice also show significant abnormal patterns of cell production but not as great as in Cfh−/−. These results reveal that not only is FH an important player in sculpting retinal development but also that the developmental abnormality in Cfh−/− likely establishes critical vulnerability for later aged retinal degeneration.

The age spectrum of human populations is shifting towards the elderly with larger proportions suffering physical decline. Mitochondria influence the pace of ageing as the energy they provide for cellular function in the form of adenosine triphosphate (ATP) declines with age. Mitochondrial density is greatest in photoreceptors, particularly cones that have high energy demands and mediate colour vision. Hence, the retina ages faster than other organs, with a 70% ATP reduction over life and a significant decline in photoreceptor function.

Increased blue light exposure has become a matter of concern as it has a range of detrimental effects, but the mechanisms remain unclear. Mitochondria absorb short wavelength light but have a specific absorbance at 420nm at the lower end of the human visual range. This 420nm absorption is probably due to the presence of porphyrin. We examine the impact of 420nm exposure on drosophila melanogaster mitochondria and its impact on fly mobility. Daily 15 mins exposures for a week significantly reduced mitochondrial complex activities and increased mitochondrial inner membrane permeability, which is a key metric of mitochondrial health. Adenosine triphosphate (ATP) levels were not significantly reduced and mobility was unchanged. There are multiple options for energy/time exposure combinations, but we then applied single 420nm exposure of 3h to increase the probability of an effect on ATP and mobility, and both were significantly reduced. ATP and mitochondrial membrane permeability recovered and over corrected at 72h post exposure. However, despite this, normal mobility did not return. Hence, the effect of short wavelengths on mitochondrial function is to reduce complex activity and increasing membrane permeability, but light exposure to reduce ATP and to translate into reduced mobility needs to be sustained.

Mitochondrial decline in ageing robs cells of ATP. However, animal studies show that long wavelength exposure (650–900 nm) over weeks partially restores ATP and improves function. The likely mechanism is via long wavelengths reducing nanoscopic interfacial water viscosity around ATP rota pumps, improving their efficiency. Recently, repeated 670 nm exposures have been used on the aged human retina, which has high-energy demands and significant mitochondrial and functional decline, to improve vision. We show here that single 3 min 670 nm exposures, at much lower energies than previously used, are sufficient to significantly improve for 1 week cone mediated colour contrast thresholds (detection) in ageing populations (37–70 years) to levels associated with younger subjects. But light needs to be delivered at specific times. In environments with artificial lighting humans are rarely dark-adapted, hence cone function becomes critical. This intervention, demonstrated to improve aged mitochondrial function can be applied to enhance colour vision in old age.

Photoreceptors have high metabolic demands and age rapidly, undermining visual function. We base our understanding mainly on ageing mice where elevated inflammation, extracellular deposition, including that of amyloid beta, and rod and cone photoreceptor loss occur, but cones are not lost in ageing primate although their function declines, revealing that primate and mouse age differently. We examine ageing primate retinae and show elevated stress but low inflammation. However, aged primates have a >70% reduction in adenosine triphosphate (ATP) and a decrease in cytochrome c oxidase. There is a shift in cone mitochondrial positioning and glycolytic activity increases. Bruch’s membrane thickens but unlike in mice, amyloid beta is absent. Hence, reduced ATP may explain cone functional decline in ageing but their retained presence offers the possibility of functional restoration if they can be fuelled appropriately to restore cellular function. This is important because as humans we largely depend on cone function to see and are rarely fully dark adapted. Presence of limited aged inflammation and amyloid beta deposition question some of the therapeutic approaches taken to resolve problems of retinal ageing in humans and the possible lack of success in clinical trials in macular degeneration that have targeted inflammatory agents.