Cellular senescence: the good, the bad and the unknown

Abstract

Cellular senescence is a ubiquitous process with roles in tissue remodelling, including wound repair and embryogenesis. However, prolonged senescence can be maladaptive, leading to cancer development and age-related diseases. Cellular senescence involves cell-cycle arrest and the release of inflammatory cytokines with autocrine, paracrine and endocrine activities. Senescent cells also exhibit morphological alterations, including flattened cell bodies, vacuolization and granularity in the cytoplasm and abnormal organelles. Several biomarkers of cellular senescence have been identified, including SA-βgal, p16 and p21; however, few markers have high sensitivity and specificity. In addition to driving ageing, senescence of immune and parenchymal cells contributes to the development of a variety of diseases and metabolic disorders. In the kidney, senescence might have beneficial roles during development and recovery from injury, but can also contribute to the progression of acute kidney injury and chronic kidney disease. Therapies that target senescence, including senolytic and senomorphic drugs, stem cell therapies and other interventions, have been shown to extend lifespan and reduce tissue injury in various animal models. Early clinical trials confirm that senotherapeutic approaches could be beneficial in human disease. However, larger clinical trials are needed to translate these approaches to patient care.

Abstract

Cellular senescence has beneficial functions in embryonic development, wound healing and tumour suppression but can also be maladaptive, contributing to cancer development and disease. This Review describes the mechanisms, hallmarks and consequences of senescence, as well as the therapeutic potential of senescence-targeting interventions.

Key points

• Cellular senescence regulates physiological and homeostatic processes, particularly during embryonic development and wound healing, but can also be a pathological process that contributes to ageing, various diseases and metabolic disorders.

• Senescent cells are characterized by morphological alterations including large, flat bodies and organelle abnormalities, as well as loss of physiological functions, an inability to proliferate and the senescence-associated secretory phenotype.

• SABG, p21 and p16 are the most commonly used senescence markers but have limitations; novel non-invasive approaches are needed to detect cellular senescence with high sensitivity and specificity in vitro.

• Cellular senescence is involved in the pathogenesis of chronic kidney disease and acute kidney injury, but also seems to have a protective role in the early stages of acute kidney injury.

• Senescence-targeting interventions, including senolytic drugs conjugated to antibodies against β2-microglobulin, chimeric antigen receptor T cells and anti-ageing vaccines, show promise for clinical application.

• Clinical trials are needed to assess the safety and efficacy of senotherapeutic approaches, optimize treatment regimens and develop more individualized and standardized treatment strategies.