AI-Driven Robotics Laboratory Identifies Pharmacological TNIK Inhibition as a Potent Senomorphic Agent

摘要

Assessing impact on the hallmarks of aging has emerged as a novel method for prioritizing dual-purpose longevity therapeutic targets and developing drugs simultaneously targeting aging and disease. Cellular senescence, a central hallmark of aging, progressively induces cellular growth arrest and accelerates the production of a pro-inflammatory senescence-associated secretory phenotype (SASP). TGF-β signaling is situated at the center of multiple senescence-associated and aging-associated signaling pathways, and its inhibition may be favorable for aging-related disorders. A recently developed Traf2- and Nck-interacting kinase (TNIK) inhibitor, INS018_055, was identified as a potent, novel anti-fibrotic agent affecting multiple hallmarks of aging across fibrotic diseases. Thus, we hypothesized that TNIK is a potential senescence modulator and INS018_055 could attenuate senescent cell accumulation to treat specific age-related pathological processes. Using a fully automated robotics laboratory designed for automated, highly parallel, and iterative phenotypic and multi-omic analyses, we determined that pharmacological or siRNA-mediated TNIK inhibition decreased cellular senescence in multiple experimental senescence models. INS018_055 mechanistically demonstrated senomorphic activity through its reduction of SASP. Furthermore, transcriptomics analysis revealed that INS018_055 treatment reduced aging signatures and extracellular matrix fibronectin through TGF-β signaling. These findings reveal TNIK's previously unappreciated role in cellular senescence and INS018_055's senomorphic potential in mitigating processes well-established as driving organismal aging. Thus, TNIK inhibition as a novel senomorphic strategy may inform future therapeutic approaches for diverse aging-related diseases.