Hippo signaling pathway

Telomere

Ageing

Effector

Biology

Gene

Mechanotransduction

Cell biology

Senescence

Genetics

Nature

Ageing is intimately connected to&nbsp;the induction of cell senescence1,2, but why this is so remains poorly understood. A key challenge is the identification of pathways that&nbsp;normally suppress senescence, are&nbsp;lost during ageing and are&nbsp;functionally relevant to oppose ageing3. Here we connected the structural and functional decline of ageing tissues to attenuated function of the&nbsp;master effectors of cellular mechanosignalling&nbsp;YAP and TAZ. YAP/TAZ activity declines during physiological ageing in stromal cells, and mimicking such decline through genetic inactivation of&nbsp;YAP/TAZ&nbsp;in these cells&nbsp;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&nbsp;YAP/TAZ are preceded by induction of tissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS–STING signalling, to the extent that&nbsp;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&nbsp;relies on the&nbsp;unexpected role&nbsp;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&nbsp;involved in building the peri-nuclear actin cap. The findings demonstrate that declining&nbsp;YAP/TAZ mechanotransduction drives ageing by unleashing cGAS–STING&nbsp;signalling, a pillar of innate immunity. Thus, sustaining YAP/TAZ mechanosignalling or inhibiting STING may represent promising approaches for limiting&nbsp;senescence-associated inflammation and improving healthy ageing. tDeclining YAP/TAZ mechanotransduction drives ageing by unleashing cGAS–STING&nbsp;signalling, a pillar of innate immunity, so sustaining YAP/TAZ mechanosignalling or inhibiting STING present promising approaches for limiting senescence-associated inflammation and improving&nbsp;healthy ageing.

YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS–STING