Senotherapy for chronic lung disease.

Abstract

Chronic respiratory diseases are an enormous burden on healthcare and the third ranked cause of death globally. There is now compelling evidence that acceleration of lung aging and associated cellular senescence is a key driving mechanism of several chronic lung diseases, particularly chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Senescent cells, arising from oxidative stress and unrepaired damage, can accumulate in the lung and develop a senescence-associated secretory phenotype, spreading senescence and resulting in disease progression. In addition, there is a reduction in normally protective antiaging molecules, such as sirtuins, in the lungs. The role of cellular senescence in chronic lung disease has driven interest in senotherapy that targets senescent cells as a novel approach to treating respiratory diseases, and includes repurposing of existing drugs or developing new therapies. Senomorphics, which prevent the development of senescence and inhibit senescence-associated secretory phenotype mediators, include inhibitors of phosphoinositide-3-kinase-mechanistic target of rapamycin signaling, novel antioxidants, and sirtuin activators. Senolytics remove senescent cells by inducing apoptosis and include inhibitors of antiapoptotic proteins, such as B-cell lymphoma-extra large, inhibitors of forkhead box O-4-p53 interaction, heat shock protein 90 inhibitors, and cardiac glycosides. Senotherapies have been effective in animal models of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, and several clinical trials are currently underway. The safety of these treatments after long-term administration requires further study, but this could potentially to be a promising approach to treating chronic lung diseases. SIGNIFICANCE STATEMENT: Cellular senescence induced by oxidative stress is a key driving mechanism in chronic lung diseases, such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis and may account for disease progression. Senotherapies, including senomorphics that inhibit senescent cells and senolytics that eliminate them, are promising therapeutic approaches to these common diseases, either with repurposed drugs or several new drugs that are in development.