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<p>Cellular senescence is a multifaceted stress response marked by stable proliferative arrest and the secretion of diverse biologically active factors, collectively known as the senescence-associated secretory phenotype (SASP). The senescent phenotype is remarkably variable and subject to various regulatory influences. We previously demonstrated that mitochondrial dysfunction induced by diverse stimuli, including the loss of sirtuin 3 (SIRT3), leads to the hyperactivation of AMPK and p53, culminating in senescence while concurrently suppressing much of the proinflammatory SASP. Here, we extend our findings by revealing that the absence of SIRT3 can suppress segments of the SASP even in the absence of p53. Intriguingly, SIRT3 deficiency renders cells resistant to stimulation by exogenous cytokines, such as interleukin-1. Fibroblasts derived from Sirt3 knockout mice exhibit a diminished SASP, including reduced levels of <i>Pdgfa</i>, and these mice display impaired wound healing and a more expansive granulation area. Furthermore, aged Sirt3 knockout mice show disrupted patterns of senescence relative to wild type controls, including increases in senescence markers in adipose tissue, but surprisingly also decreases in liver and heart. Collectively, these data underscore a role for SIRT3 in orchestrating cellular senescence phenotypes, shedding light on its regulatory influence beyond the p53-dependent pathway.</p>

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Loss of sirtuin 3 disrupts cellular senescence signaling pathways

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月6日

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  • Niharika Kura,
  • Bronwyn A. Mogck,
  • Samantha T. Jezak,
  • Michael C. Velarde,
  • Christopher D. Wiley

摘要

Cellular senescence is a multifaceted stress response marked by stable proliferative arrest and the secretion of diverse biologically active factors, collectively known as the senescence-associated secretory phenotype (SASP). The senescent phenotype is remarkably variable and subject to various regulatory influences. We previously demonstrated that mitochondrial dysfunction induced by diverse stimuli, including the loss of sirtuin 3 (SIRT3), leads to the hyperactivation of AMPK and p53, culminating in senescence while concurrently suppressing much of the proinflammatory SASP. Here, we extend our findings by revealing that the absence of SIRT3 can suppress segments of the SASP even in the absence of p53. Intriguingly, SIRT3 deficiency renders cells resistant to stimulation by exogenous cytokines, such as interleukin-1. Fibroblasts derived from Sirt3 knockout mice exhibit a diminished SASP, including reduced levels of Pdgfa, and these mice display impaired wound healing and a more expansive granulation area. Furthermore, aged Sirt3 knockout mice show disrupted patterns of senescence relative to wild type controls, including increases in senescence markers in adipose tissue, but surprisingly also decreases in liver and heart. Collectively, these data underscore a role for SIRT3 in orchestrating cellular senescence phenotypes, shedding light on its regulatory influence beyond the p53-dependent pathway.