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

Abstract

Ageing is intimately connected tothe induction of cell senescence1,2, but why this is so remains poorly understood. A key challenge is the identification of pathways thatnormally suppress senescence, arelost during ageing and arefunctionally relevant to oppose ageing3. Here we connected the structural and functional decline of ageing tissues to attenuated function of themaster effectors of cellular mechanosignallingYAP and TAZ. YAP/TAZ activity declines during physiological ageing in stromal cells, and mimicking such decline through genetic inactivation ofYAP/TAZin these cellsleads 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 ofYAP/TAZ are preceded by induction of tissue senescence. This occurs because YAP/TAZ mechanotransduction suppresses cGAS-STING signalling, to the extent thatinhibition of STING prevents tissue senescence and premature ageing-related tissue degeneration after YAP/TAZ inactivation. Mechanistically, YAP/TAZ-mediated control of cGAS-STING signallingrelies on theunexpected roleof YAP/TAZ in preserving nuclear envelope integrity, at least in part through direct transcriptional regulation of lamin B1 and ACTR2, the latter of which isinvolved in building the peri-nuclear actin cap. The findings demonstrate that decliningYAP/TAZ mechanotransduction drives ageing by unleashing cGAS-STINGsignalling, a pillar of innate immunity. Thus, sustaining YAP/TAZ mechanosignalling or inhibiting STING may represent promising approaches for limitingsenescence-associated inflammation and improving healthy ageing.