Molecular Mechanisms of Age‐Related Taste Dysfunction Deciphered by Spatiotemporal Transcriptomics

Age-related taste dysfunction impairs nutrition and quality of life, contributing to metabolic disorders and frailty in the elderly, yet its cellular and molecular basis remains poorly understood. By integrating single-cell RNA and spatial transcriptomics sequencing, we systematically mapped murine taste bud aging across five developmental stages from neonatal to aged. Our findings reveal that age-associated taste impairment is driven by the progressive depletion of stem/progenitor cell differentiation capacity, predominantly characterized in the posterior tongue, and mediated by inflamm-aging responses and micro-environmental alterations. Specifically, we identified macrophage infiltration and polarization shifts in aged circumvallate and foliate papillae, underscoring the crucial role of macrophages in age-related taste decline. A co-culture model using taste organoids with conditioned media from polarized macrophage revealed that M1-polarized cells suppress taste organoid proliferation and differentiation. Mechanistically, this inhibition may be mediated by macrophage-derived Thbs1, as recombinant Thbs1 treatment directly suppressed taste progenitor cell expansion in vitro. Together, this study provides the first comprehensive spatiotemporal atlas of taste bud aging and identifies novel therapeutic targets for the treatment of age-related taste disorders.