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

Ageing is intimately connected to the induction of cell senescence1,2, 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.

Mechanosignaling in vertebrate development.

Myriads forces are at play during morphogenesis. Their concerted activity shapes individual cells, tissues and the whole embryo, representing the most awe-inspiring marvel of developmental biology. In spite of their prevalence, the potential instructive role of cell mechanics in fate determination and patterning has remained long neglected, in part due to the difficulties in translating the physical world of cells in molecular terms. The recent discovery of the principles of mechanotransduction, of how these impact on gene expression, is however starting to change this scenario, making mechanotransduction finally amenable to experimental dissection through genetics, molecular and bioengineering approaches. Here we review this emerging field, and a series of discoveries that potently bring back cell mechanics at the centerstage of vertebrate developmental biology. We discuss the role of actomyosin contractility as integrating platform between morphogens, lateral inhibition and mechanosignaling. We also review data indicating that supracellular pulling forces, coupled with solid-to-fluid changes in the material contexture of embryonic fields, may act as overarching mechanical "organizers". The evidence also indicates that a continuum of forces is what ultimately locks "self-organizing" movements with cell fate, from the earliest pre-implantation decisions to the fine details of organogenesis. Notably, similar mechanisms are reawakened in organoids and in adult tissues during regeneration. Developmental biology has been correctly depicted, but recently often forgotten, as the "mother" of all biological disciplines. Investigations in developmental mechanics may revamp interest, and have a broad impact in the fields of regenerative medicine, stem cells and cancer biology.