Fundamental differences in patterns of retinal ageing between primates and mice

Jaimie Hoh Kam,Michael B Powner,Glen Jeffery,Harpreet Shinhmar,Asmaa Aboelnour,Nicholas W Roberts,Tobias W Weinrich

doi:10.1038/s41598-019-49121-0

Jaimie Hoh Kam, Michael B Powner + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-49121-0

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Abstract

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.

Highlights

The central nervous system (CNS) has high metabolic demand and this contributes to the pace of ageing as energy consumption and ageing are linked at the level of the organism and the organ[1,2,3,4,5]
Mitochondria are densely packed in photoreceptor inner segments and their adenosine triphosphate (ATP) production declines with age, undermining function[16,17]
In primates the key feature of aged decline is the significant reduction in mitochondrial function and ATP production that reduces available cellular energy in a metabolically demanding environment

Summary

Introduction

The central nervous system (CNS) has high metabolic demand and this contributes to the pace of ageing as energy consumption and ageing are linked at the level of the organism and the organ[1,2,3,4,5]. Mitochondria are densely packed in photoreceptor inner segments and their ATP production declines with age, undermining function[16,17] They have the ability to signal cell death[18], which becomes a key feature of the aged outer retina with a 30% photoreceptor loss in the rod population[7,13,14]. Even in age related macular degeneration (AMD) where there is progressive central atrophy, cones persist at the margin of the atrophic region when surrounding rods have died[7] Their survival may be linked with the specific accumulation of phosphorylated tau in their inner segments that likely undermines mitochondrial function[21], but which blocks cell death by reducing cytochrome c release and caspase activity[22]. We reveal key features and mark how they differ significantly from mouse models, questioning the relevance of these models for human retinal ageing research

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