AI-Driven Robotics Laboratory Identifies Pharmacological TNIK Inhibition as a Potent Senomorphic Agent
Qiuqiong Tang, Deyong Xiao, Alexander Veviorskiy, Ying Xin, Sarah W.Y. Lok, Fadi E. Pulous, Peiran Zhang, Yunfeng Zhu, Yongming Ma, Xiao Hu, Shoulai Gu, Chenting Zong, Sabina Mukba, Mikhail Korzinkin, Frank W. Pun, Man Zhang, Alexander Aliper, Lijuan Wu, Feng Ren, Li Zhang, Alex Zhavoronkov
Abstract
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.