Aging is a gradual process of natural change that occurs after reaching sexual maturity. It is also a known risk factor for many chronic diseases. Recent research has shown that senolytics can extend the lifespans and health spans of model organisms, and they have also been demonstrated effective in treating age-related diseases. In this study, we conducted a high-throughput screening of 156 drugs that targeted the PI3K/AKT/mTOR pathway to identify potential senolytic medications. Among these drugs, PF-04691502 was selected for further investigation to understand its molecular mechanism of action. Our findings indicate that PF-04691502, a dual inhibitor of PI3K/AKT and mTOR, specifically eliminates senescent cells. It reduces the expression levels of key markers of cellular senescence, such as SA-β-Gal, senescence-associated secretory phenotypes (SASPs) and p16^INK4a. Additionally, PF-04691502 inhibits the phosphorylation of S6K and AKT, leading to the apoptosis of senescent cells. These results suggest that PF-04691502 holds promise as a new senolytic drug. This paper provides important insights into the potential application of PF-04691502 in the study of cell senescence.

衰老是性成熟后发生的自然变化的逐渐过程。它也是许多慢性疾病的已知危险因素。最近的研究表明，senolytics 可以延长模式生物的寿命和健康寿命，并且它们也被证明可以有效治疗与年龄相关的疾病。在这项研究中，我们对 156 种针对 PI3K/AKT/mTOR 通路的药物进行了高通量筛选，以鉴定潜在的抗衰老药物。在这些药物中，选择PF-04691502进行进一步研究，以了解其分子作用机制。我们的研究结果表明 PF-04691502 是 PI3K/AKT 和 mTOR 的双重抑制剂，可特异性消除衰老细胞。它降低细胞衰老关键标志物的表达水平，例如 SA-β-Gal、衰老相关分泌表型 (SASP) 和 p16 ^INK4a 。此外，PF-04691502 抑制 S6K 和 AKT 的磷酸化，导致衰老细胞凋亡。这些结果表明 PF-04691502 有希望成为一种新的抗衰老药物。本文为 PF-04691502 在细胞衰老研究中的潜在应用提供了重要见解。