Abstract
Aging is associated with increased risk of ocular disease, suggesting that age-associated molecular changes in the eye increase its vulnerability to damage. Although there are common pathways involved in aging at an organismal level, different tissues and cell types exhibit specific changes in gene expression with advanced age. Drosophila melanogaster is an established model system for studying aging and neurodegenerative disease that also provides a valuable model for studying age-associated ocular disease. Flies, like humans, exhibit decreased visual function and increased risk of retinal degeneration with age. Here, we profiled the aging proteome and metabolome of the Drosophila eye and compared these data with age-associated transcriptomic changes from both eyes and photoreceptors to identify alterations in pathways that could lead to age-related phenotypes in the eye. Of note, the proteomic and metabolomic changes observed in the aging eye are distinct from those observed in the head or whole fly, suggesting that tissue-specific changes in protein abundance and metabolism occur in the aging fly. Our integration of the proteomic, metabolomic, and transcriptomic data reveals that changes in metabolism, potentially due to decreases in availability of B vitamins, together with chronic activation of the immune response, may underpin many of the events observed in the aging Drosophila eye. We propose that targeting these pathways in the genetically tractable Drosophila system may help to identify potential neuroprotective approaches for neurodegenerative and age-related ocular diseases. Data are available via ProteomeXchange with identifier PXD027090.
Highlights
Aging is associated with increased risk of ocular disease, suggesting that age-associated molecular changes in the eye increase its vulnerability to damage
We performed proteomic studies in male flies expressing a nuclear membrane-localized GFP tag in R1–R6 photoreceptors, which facilitates photoreceptorspecific gene expression profiling: Rh1-Gal4>GFPKASH [11] (Fig. 1B). We selected this genotype for proteomic studies in the eye because it has been used for transcriptome and chromatin profiling of photoreceptors during aging or under other environmental stress conditions by our group [11, 19, 20], enabling us to compare these datasets within the same genotype. We note that these flies have pigmented eyes like wildtype fly strains such as OregonR and show significant decreases in visual behavior between day 10 and day 40 but do not exhibit retinal degeneration until after day 40 [11]
Some “wildtype” fly strains that have white eyes such as w1118 undergo premature retinal degeneration beginning between day 15 and day 30 that is caused by the lack of protective eye pigment [21]
Summary
In Brief Hall et al profiled the proteome, transcriptome, and metabolome of the aging Drosophila eye. Our integration of the proteomic, metabolomic, and transcriptomic data reveals that changes in metabolism, potentially due to decreases in availability of B vitamins, together with chronic activation of the immune response, may underpin many of the events observed in the aging Drosophila eye. Drosophila exhibit decreases in visual behavior with age that coincide with changes in gene expression and splicing, in the light-sensing photoreceptor neurons [3, 11, 12]. It is unclear whether these changes in gene expression are a cause or a consequence of other processes that become altered in the aging eye. Since recent studies have examined the aging proteome of Drosophila heads, containing both the brain and eye [13, 14], this provided the opportunity to ask whether the eye experiences unique proteomic changes that could explain its susceptibility to age-associated retinal degeneration
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