Senescence, Aging and Disease Throughout the Gastrointestinal System

Senescence is an irreversible cell cycle arrest-characterized by morphologic alterations, genomic instability, and secretome changes-that profoundly affects the tissue structure and function. Accumulating evidence indicates that senescence plays a relevant role in gastrointestinal pathologies: senescence contributes to salivary gland hypofunction, is instrumental in the development of oral submucous fibrosis, drives age-dependent hepatic steatosis, and regulates the clinical progression of steatotic liver disease. Senescence in the biliary tract develops in response to ischemic injury in biliary complications and is characteristic of biliary conditions such as biliary atresia, primary sclerosing cholangitis, and primary biliary cirrhosis. Senescence also contributes to acute pancreatitis, plays a major role in the dysfunction of pancreatic β-cells, and is a hallmark of a number of gastrointestinal conditions such as inflammatory bowel disease and colorectal cancer. These examples illustrate the widespread effect of cellular senescence in the gastrointestinal tract, not just as a consequence of the disease but also as a driver of pathology and a potential therapeutic target. In this review we describe the mechanisms, hallmarks, and consequences of cellular senescence as well as the therapeutic potential of senescence-targeting interventions. We aim to highlight the importance of understanding the molecular basis of senescence in gastroenterology while connecting the worlds of research and clinical practice.