Cellular senescence has evolved as a protective mechanism to arrest growth of cells with oncogenic potential but is accompanied by the often pathologically deleterious senescence-associated secretory phenotype (SASP). Here we demonstrate an H₂O₂-dependent functional disruption controlling senescence-associated Ca²⁺ homeostasis and the SASP. Senescent cells fail to respond to H₂O₂-dependent plasma lamellar Ca²⁺ entry when compared to pre-senescent cells. Limiting exposure to senescence-associated H₂O₂ restores H₂O₂-dependent Ca²⁺ entry as well as transient receptor potential cation channel subfamily C member 6 (TRPC6) function. SA-TRPC6 and SASP expression is blocked by restoring Ca²⁺ entry with the TRP channel antagonist SKF-96365 or by the mTOR inhibitors rapamycin and Ku0063794. Together, our findings provide compelling evidence that redox and mTOR-mediated regulation of Ca²⁺ entry through TRPC6 modulates SASP gene expression and approaches which preserve normal Ca²⁺ homeostasis may prove useful in disrupting SASP activity.

Impact statement

Through its ability to evoke responses from cells in a paracrine fashion, the senescence-associated secretory phenotype (SASP) has been linked to numerous age-associated disease pathologies including tumor invasion, cardiovascular dysfunction, neuroinflammation, osteoarthritis, and renal disease. Strategies which limit the amplitude and duration of SASP serve to delay age-related degenerative decline. Here we demonstrate that the SASP regulation is linked to shifts in intracellular Ca²⁺ homeostasis and strategies which rescue redox-dependent calcium entry including enzymatic H₂O₂ scavenging, TRP modulation, or mTOR inhibition block SASP and TRPC6 gene expression. As Ca²⁺ is indispensable for secretion from both secretory and non-secretory cells, it is exciting to speculate that the expression of plasma lamellar TRP channels critical for the maintenance of intracellular Ca²⁺ homeostasis may be coordinately regulated with the SASP.

中文翻译：

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血浆层状钙流入的氧化还原和 mTOR 依赖性调节控制着衰老相关的分泌表型。

细胞衰老已发展成为一种保护机制，可阻止具有致癌潜力的细胞生长，但同时伴随着通常具有病理学有害的衰老相关分泌表型（SASP）。在这里，我们证明了 H ₂ O ₂依赖性功能破坏控制衰老相关的 Ca ²⁺稳态和 SASP。与衰老前细胞相比，衰老细胞无法响应 H ₂ O ₂依赖的血浆层状 Ca ^2+进入。限制与衰老相关的 H ₂ O ₂暴露可恢复 H ₂ O ₂依赖性 Ca ²⁺进入以及瞬时受体电位阳离子通道亚家族 C 成员 6 (TRPC6) 功能。SA-TRPC6 和 SASP 表达可通过 TRP 通道拮抗剂 SKF-96365恢复 Ca ²⁺进入或 mTOR 抑制剂雷帕霉素和 Ku0063794来阻断。总之，我们的研究结果提供了令人信服的证据，表明氧化还原和 mTOR 介导的 Ca ²⁺进入通过 TRPC6 调节 SASP 基因表达，而保持正常 Ca ²⁺稳态的方法可能有助于破坏 SASP 活性。

影响报告

通过其以旁分泌方式引起细胞反应的能力，衰老相关分泌表型（SASP）与许多与年龄相关的疾病病理有关，包括肿瘤侵袭、心血管功能障碍、神经炎症、骨关节炎和肾脏疾病。限制 SASP 幅度和持续时间的策略可以延缓与年龄相关的退行性衰退。^{在此，我们证明 SASP 调节与细胞内 Ca 2+}稳态的变化以及拯救氧化还原依赖性钙进入的策略有关，包括酶促 H ₂ O ₂清除、TRP 调节或 mTOR 抑制阻断 SASP 和 TRPC6 基因表达。由于Ca ²⁺对于分泌细胞和非分泌细胞的分泌都是必不可少的，因此令人兴奋的是推测对于维持细胞内Ca ²⁺稳态至关重要的血浆层状TRP 通道的表达可能与SASP 协调调节。