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

Ageing is intimately connected to the induction of cell senescence(1,2), but why this is so remains poorly understood. A key challenge isthe identification of pathways that normally suppress senescence, are lost during ageing and are functionally relevant to oppose ageing(3). 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 oftissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS-STING signalling, tothe extent that inhibition of STING preventstissue 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 Bland 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.

Automated summary

Ageing is closely related to the induction of cell senescence, with YAP/TAZ mechanotransduction playing a key role in the process. Declining YAP/TAZ activity during ageing leads to accelerated ageing and tissue degeneration, as it unleashes cGAS-STING signalling and promotes senescence. Sustaining YAP/TAZ mechanosignalling or inhibiting STING may be potential strategies to limit senescence-associated inflammation and improve healthy ageing.