High-Resolution Spatial Transcriptomics Unveils Spatially Resolved Gene Modules and Fatty Acid Metabolism Dysregulation in Human Skin Aging

Human skin aging involves intricate micrometer-scale changes in cellular organization. High-resolution spatial transcriptomic analysis is crucial for deciphering the complex interplay of cell types and molecular processes underlying skin aging. In this study, the spatially enhanced-resolution omics-sequencing technique was employed to generate a high-resolution spatial transcriptomic atlas of human eyelid skin, capturing age-related alterations in gene expression. Integrating this atlas with multiplexed FISH, we spatially mapped known cell populations, identified 8 spatial tissue clusters, and uncovered 18 spatially correlated gene modules in human skin. Our analysis revealed that human eyelid skin aging is characterized not only by dermal atrophy and chronic inflammation but also by reduced dermal-epidermal communication, decreased epidermal fatty acid synthesis, potential loss of epidermal cell identity, and diminished c-FOS expression in the epidermis. Functional studies using primary human keratinocytes and a reconstructed full-thickness skin model (T-SkinTM) demonstrated that reduced activity of fatty acid synthesis enzymes farnesyl diphosphate synthase and fatty acid synthase promoted epidermal senescence and barrier dysfunction. This spatially resolved transcriptomic analysis provides, to our knowledge, previously unreported insights into the molecular mechanism driving skin aging, offering a potential target for aging intervention strategies.