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BACKGROUND: Chlorogenic acid (CGA) and taurine are well-known antioxidant compounds reported to reduce skin cellular senescence. However, the biological mechanisms underlying their skin-protective effects remain unclear.METHODS: In this study, we conducted transcriptome-wide RNA sequencing to profile gene expression changes in human epidermal keratinocytes, melanocytes, and fibroblasts following treatment with CGA, taurine, or their combination. To identify aging-related genes, we integrated evidence from aging databases, perceived-age GWAS, enrichment in aging-related gene ontology and pathways, and drug-gene interaction annotations. Validation of representative genes was performed using quantitative real-time PCR.RESULTS: A total of 197 differentially expressed genes (DEGs) were identified, of which 62 were prioritized as aging-related DEGs (AR-DEGs) based on their relevance to skin aging anti-senescence-associated pathways, highlighting regulatory transcription factors including , , and . Co-treatment enhanced the transcriptional effects of CGA and taurine, with several genes exhibiting synergistic responses. Targeted transcriptome-wide association analysis indicated potential links between specific AR-DEGs, such as FST, and phenotypes including perceived age and skin pigmentation.CONCLUSION: By identifying key genes and pathways that contribute to cellular longevity in human skin, this study provides molecular insights for developing anti-aging strategies with potential applications in dermatology.