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De Novo Generation of Somatic Stem Cells by YAP/TAZ
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YAP/TAZ activity in stromal cells prevents ageing by controlling cGAS-STING

Hanna Lucie Sladitschek-Martens1, Alberto Guarnieri1, Giulia Brumana1

  • 1Department of Molecular Medicine, University of Padua, Padua, Italy.

Nature
|June 29, 2022
PubMed

Insights

Declining YAP/TAZ mechanotransduction drives ageing by activating cGAS-STING innate immunity signalling. Sustaining YAP/TAZ or inhibiting STING may limit senescence and improve healthy ageing.

Area of Science:

  • Cellular Biology
  • Aging Research
  • Immunology

Background:

  • Cellular senescence is closely linked to aging, but the underlying mechanisms are not fully understood.
  • Identifying pathways that suppress senescence and are lost during aging is crucial for developing anti-aging strategies.
  • The role of cellular mechanotransduction in aging and senescence remains an active area of investigation.

Purpose of the Study:

  • To investigate the connection between the decline of tissue structure and function during aging and the activity of YAP and TAZ mechanotransduction pathways.
  • To determine if YAP/TAZ activity in stromal cells influences physiological aging and senescence.
  • To explore the potential of modulating YAP/TAZ signaling or STING pathway for therapeutic interventions against aging and senescence.

Main Methods:

  • Assessed YAP/TAZ activity in stromal cells during physiological aging.
  • Genetically inactivated YAP/TAZ in stromal cells to mimic age-related decline.
  • Investigated the effects of YAP/TAZ inactivation on tissue senescence and aging traits.
  • Examined the role of YAP/TAZ in regulating cGAS-STING signaling and nuclear envelope integrity.
  • Evaluated the impact of STING inhibition on YAP/TAZ inactivation-induced senescence and aging.

Main Results:

  • YAP/TAZ activity declines during physiological aging in stromal cells, and its inactivation accelerates aging.
  • Sustaining YAP function rejuvenates aged cells and counteracts aging-related traits.
  • YAP/TAZ inactivation induces tissue senescence by unleashing cGAS-STING signaling.
  • YAP/TAZ preserves nuclear envelope integrity, partly via regulating lamin B1 and ACTR2.
  • Inhibiting STING prevents senescence and degeneration following YAP/TAZ inactivation.

Conclusions:

  • Declining YAP/TAZ mechanotransduction is a key driver of aging, primarily by activating the cGAS-STING innate immunity pathway.
  • Maintaining YAP/TAZ mechanosignaling or inhibiting STING are potential strategies to combat senescence-associated inflammation and promote healthy aging.

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