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Here, researchers discuss what is known of the role of senescent cells, and the chronic inflammation that they create, in the aging of the lung. The first human trials of senolytic therapies to selectively destroy senescent cells were aimed at reversal of idiopathic pulmonary fibrosis. There is a good evidence for the growing presence of senescent cells to disrupt tissue maintenance and produce fibrosis as a result, the deposition of excessive, scar-like collagen structures that harm tissue function. There is a little that can be done to reverse fibrotic disease in the clinic, but animal studies showing improvement following clearance of senescent cells have given some hope for progress on this front.
Cellular senescence, a coordinated cellular response to stress characterized by permanent cell cycle exit and the development of an elaborate secretory profile, is intricately linked with aging. It is well-appreciated that the number of senescent cells increases with age, and the removal of senescent cells through various mechanisms has been shown to improve both healthspan and median lifespan in mice. The senescent cell secretory profile, commonly referred to as the senescence-associated secretory phenotype (SASP), is considered one of the major mechanisms by which senescent cells impact their resident tissues. The SASP – which frequently encompasses cytokines, chemokines, and growth factors – is thought to mediate its effects through multiple mechanisms, including direct action on tissue-resident stem cells and immune cell recruitment.
The human lung has an elaborate epithelial structure to accomplish its numerous functions, which include mucus production and clearance, antimicrobial defense, surfactant production, and the facilitation of gas exchange. Maintenance and repair of the epithelium requires proper functioning of airway epithelial stem cells. These stem cells are both supported by and responsive to signals from their niche cells, which usually include, but are not limited to fibroblasts, endothelial, and resident immune cells. Emerging data have demonstrated that cells of the lung stem cell niche can express cytokines and growth factors that overlap with SASP factors, and that these secreted factors can alter stem cell behavior, thus offering a potential mechanism through which the aging niche impacts stem cell function.
Here we explore the mechanisms by which senescent cells develop in the aging lung, and how these cells contribute to both physiologic aging and aging-associated lung diseases. We give particular attention to mechanisms by which senescent cells interact with the lung stem cell niche, and how senescent cell interaction with the immune system can modulate not only tissue immune cell composition but also immune cell function. Finally, we explore the potential contribution of senescence to the pathogenesis of some of the most common age-related diseases in the lung, highlighting the therapeutic implications of unraveling the intersection between senescence and inflammation in the aging lung.