Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development and wound healing. Factors secreted by senescent cells affect their microenvironment and can induce spreading of senescence locally. Acute severe liver disease is associated with hepatocyte senescence and frequently progresses to multi-organ failure. Why the latter occurs is poorly understood. Here we demonstrate senescence development in extrahepatic organs and associated organ dysfunction in response to liver senescence using liver injury models and genetic models of hepatocyte-specific senescence. In patients with severe acute liver failure, we show that the extent of hepatocellular senescence predicts disease outcome, the need for liver transplantation and the occurrence of extrahepatic organ failure. We identify the TGFβ pathway as a critical mediator of systemic spread of senescence and demonstrate that TGFβ inhibition in vivo blocks senescence transmission to other organs, preventing liver senescence induced renal dysfunction. Our results highlight the systemic consequences of organ-specific senescence, which, independent of ageing, contributes to multi-organ dysfunction.

细胞衰老不仅与衰老有关，还会影响生理和病理过程，例如胚胎发育和伤口愈合。衰老细胞分泌的因子会影响它们的微环境，并可诱导衰老局部扩散。急性重度肝病与肝细胞衰老有关，并经常进展为多器官衰竭。后者发生的原因知之甚少。在这里，我们使用肝损伤模型和肝细胞特异性衰老的遗传模型来证明肝外器官的衰老发展和相关器官功能障碍响应肝脏衰老。在严重急性肝衰竭患者中，我们表明肝细胞衰老的程度可预测疾病结果、肝移植的需要和肝外器官衰竭的发生。我们确定 TGFβ 通路是衰老全身扩散的关键介质，并证明体内 TGFβ 抑制可阻断衰老向其他器官的传递，防止肝衰老诱导的肾功能不全。我们的结果强调了器官特异性衰老的系统性后果，这与衰老无关，会导致多器官功能障碍。