Ageing is intimately connected to the induction of cell senescence^1,2, but why this is so remains poorly understood. A key challenge is the identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing³. Here we connected the structural and functional decline of ageing tissues to attenuated function of the master effectors of cellular mechanosignalling YAP and TAZ. YAP/TAZ activity declines during physiological ageing in stromal cells, and mimicking such decline through genetic inactivation of YAP/TAZ in these cells leads to accelerated ageing. Conversely, sustaining YAP function rejuvenates old cells and opposes the emergence of ageing-related traits associated with either physiological ageing or accelerated ageing triggered by a mechano-defective extracellular matrix. Ageing traits induced by inactivation of YAP/TAZ are preceded by induction of tissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS–STING signalling, to the extent that inhibition of STING prevents tissue senescence and premature ageing-related tissue degeneration after YAP/TAZ inactivation. Mechanistically, YAP/TAZ-mediated control of cGAS–STING signalling relies on the unexpected role of YAP/TAZ in preserving nuclear envelope integrity, at least in part through direct transcriptional regulation of lamin B1 and ACTR2, the latter of which is involved in building the peri-nuclear actin cap. The findings demonstrate that declining YAP/TAZ mechanotransduction drives ageing by unleashing cGAS–STING signalling, a pillar of innate immunity. Thus, sustaining YAP/TAZ mechanosignalling or inhibiting STING may represent promising approaches for limiting senescence-associated inflammation and improving healthy ageing.

衰老与细胞衰老的诱导密切相关^1,2 ，但其原因仍知之甚少。一个关键的挑战是识别通常抑制衰老、在衰老过程中丢失以及在功能上与抵抗衰老相关的途径³ 。在这里，我们将衰老组织的结构和功能衰退与细胞机械信号 YAP 和 TAZ 主效应器的功能减弱联系起来。 YAP/TAZ 活性在基质细胞的生理衰老过程中下降，通过这些细胞中 YAP/TAZ 的基因失活来模拟这种下降会导致加速衰老。相反，维持 YAP 功能可以使衰老细胞恢复活力，并阻止与生理衰老或由机械缺陷细胞外基质引发的加速衰老相关的衰老相关特征的出现。 YAP/TAZ 失活诱导的衰老特征先于组织衰老的诱导。发生这种情况是因为 YAP/TAZ 机械转导抑制了 cGAS-STING 信号传导，在某种程度上，抑制 STING 可以防止 YAP/TAZ 失活后组织衰老和过早衰老相关的组织变性。从机制上讲，YAP/TAZ 介导的 cGAS-STING 信号传导控制依赖于 YAP/TAZ 在保持核膜完整性方面的意外作用，至少部分是通过核纤层蛋白 B1 和 ACTR2 的直接转录调节，后者参与构建核周肌动蛋白帽。研究结果表明，YAP/TAZ 机械转导的下降通过释放 cGAS-STING 信号（先天免疫的支柱）来促进衰老。 因此，维持 YAP/TAZ 机械信号传导或抑制 STING 可能是限制衰老相关炎症和改善健康衰老的有前途的方法。