Identification of miR-106b-5p as a senolytic miRNA

Background: Cellular senescence contributes to ageing and age-related diseases. While miR-106b-5p is elevated in centenarians and GH-deficient models of healthy ageing, its role in senescence was unclear. Methods: Senolytic effects of miR-106b-5p were evaluated in etoposide-induced senescent IMR90 fibroblasts and HUVECs, and in male naturally aged mice using liposome-mediated delivery. Cellular assays, qPCR, Western blotting, and RNA-seq were performed to assess senescence and SASP markers, apoptosis pathways, and molecular mechanisms. Findings: miR-106b-5p selectively eliminated senescent cells without affecting non-senescent cells. It enhanced p53 K120 acetylation and upregulated PUMA, while reducing PCAF expression. In male aged mice, systemic delivery of miR-106b-5p reduced markers of senescence and SASP in multiple tissues and lowered serum IL-6 levels. Interpretation: miR-106b-5p functions as a senolytic miRNA via modulation of the p53-PUMA axis and SASP suppression. It holds promise as a therapeutic agent to mitigate age-related cellular dysfunction and inflammation. Funding: Supported by NIH (U19 AG056278, R01 AG063543, P01 AG062413, U54 AG079754, U54 AG076041, R01 AG069819, P01 AI172501), the Glenn Foundation, and NSF grant 2317758.