Cellular senescence in the lung across the age spectrum

Abstract

Cellular senescence results in cell cycle arrest with secretion of cytokines, chemokines, growth factors, and remodeling proteins (senescence-associated secretory phenotype; SASP) that have autocrine and paracrine effects on the tissue microenvironment. SASP can promote remodeling, inflammation, infectious susceptibility, angiogenesis, and proliferation, while hindering tissue repair and regeneration. While the role of senescence and the contributions of senescent cells are increasingly recognized in the context of aging and a variety of disease states, relatively less is known regarding the portfolio and influences of senescent cells in normal lung growth and aging per se or in the induction or progression of lung diseases across the age spectrum such as bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, or pulmonary fibrosis. In this review, we introduce concepts of cellular senescence, the mechanisms involved in the induction of senescence, and the SASP portfolio that are relevant to lung cells, presenting the potential contribution of senescent cells and SASP to inflammation, hypercontractility, and remodeling/fibrosis: aspects critical to a range of lung diseases. The potential to blunt lung disease by targeting senescent cells using a novel class of drugs (senolytics) is discussed. Potential areas for future research on cellular senescence in the lung are identified.

Keywords: aging; airway; alveoli; bronchi; senolytic.

Fig. 1.

Cellular senescence and the senescence-associated secretory phenotype (SASP): naive cells can be exposed to a number endogenous or exogenous stimuli that initiate an intracellular signaling cascade that induces senescence. Factors such as DNA damage from radiation, chemotherapy etc., aging-associated telomere shortening, oncogenic signals, and the influence of inflammation, reactive oxygen species (ROS), and/or mitochondrial dysfunction can all serve as triggers. Here, it is possible, indeed likely, that interplay between these factors is temporally involved. Senescent cells do not proliferate, but they are also resistant to apoptosis and autophagy and are thus long-living. Senescent cells secrete cytokines, chemokines, matrix-modulating factors (e.g., matrix metalloproteinases, MMPs), and growth factors that can have paracrine influences on surrounding naive cells to promote inflammation, mitochondrial dysfunction, and other disease-promoting pathways.

Fig. 2.

Throughout the lifespan, including during embryonic development, endogenous and exogenous factors can lead to structural and functional dysfunction of lung cells, promoting disease. Here, senescent cells and senescence-associated secretory phenotype (SASP) could play a role at each life stage, sometimes as part of normal developmental processes or in response to insults. Senescence/SASP in pregnancy can lead to premature birth, which in itself is a risk factor for diseases such as asthma. Interventions such as supplemental oxygen and mechanical ventilation in the context of prematurity place the infant at further risk for asthma and bronchopulmonary dysplasia. Environmental exposures such as allergens, pollution, and tobacco smoke from birth onwards and certainly throughout life contribute to asthma, chronic obstructive pulmonary disease (COPD), and fibrosis. Here, senescent cells may play variable roles that are not yet entirely clear. Finally, senescent cells could contribute to normal aging-associated changes in the lung, as well as to aging-associated diseases such as COPD and fibrosis (and even asthma). MMPs, matrix metalloproteinases.