PURPOSE: Aging is a significant risk factor for various retinal degenerative diseases. However, its impact on diurnal transcriptional profile of the retina remains largely unexplored. Addressing this knowledge gap is crucial given the rising prevalence of age-related retinal diseases.
METHODS: We conducted high-throughput RNA sequencing on retinal samples collected at 4-h intervals (n = 24 per group) from young (6-week-old) and aged (20-month-old) C57BL/6 mice maintained under a 12h:12h light-dark cycle. Differential expression analysis was performed using edgeR (FDR <0.05, |FC| > 1.5). Rhythmicity analysis was conducted using the MetaCycle package, which integrates JTK_CYCLE and Lomb-Scargle algorithms, while differential rhythmicity analysis was performed using the CircaCompare package.
RESULTS: A total of 361 differentially expressed genes (DEGs) were identified between young and aging retinas, with enrichment in immunity-related pathways, including antigen processing and presentation, as well as the AGE-RAGE signaling pathway. A total of 4151 genes (16 %) were identified as rhythmic expressed genes (REGs) in the young group, whereas 2999 genes (11 %) were detected in the aging group. Notably, aging reduced rhythmic gene proportion by 28 % (1152 genes). Additionally, aging altered rhythmic pathway dynamics: genes associated with RNA degradation and the proteasome pathway lost rhythmicity, whereas genes related to immune responses, and age-related macular degeneration (AMD)-associated pathways, including MAPK and WNT signaling, exhibited rhythmicity in the aging retina. In the differential rhythmicity analysis of 2036 overlapping rhythmic genes, 387 genes exhibited differences in MESOR, 78 showed differences in amplitude, and 72 displayed phase shifts.
CONCLUSIONS: Aging significantly reshapes the rhythmic transcriptome in the retina, altering both the composition and temporal distribution of rhythmic pathways. This study provides a valuable dataset elucidating the interplay between aging, diurnal rhythms, and gene expression in the retina, offering insights into potential molecular mechanisms underlying age-related retinal diseases.
