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.

Fig. 1

Accelerated lung aging in chronic lung diseases. Lung function reaches a peak at around 25 years and then slowly declines with increasing age, but this does not cause symptoms in normal individuals. The lungs of the very elderly show features of senile emphysema, similar to the pathology of COPD. Patients with COPD have accelerated decline in lung function leading to symptoms when FEV₁ reaches ∼50% of normal. Accelerated lung aging may be due to loss of endogenous anti-aging molecules, leading to the accumulation of senescent cells in the lung. Cellular senesce is also a feature of other chronic lung diseases.

Fig. 2

Mechanisms of cellular senescence. Cell division leads to progressive shortening of the telomeres which eventually leads to the activation of the DDR which activates p53, leading to activation of the cyclin kinase inhibitor p21^CIP1 , which induces cell cycle arrest by inhibiting CDK2 (replicative senescence). Oxidative stress, from cigarette smoke, air pollution, or activated inflammatory cells, may also cause telomere DNA damage and also activates p16^INK4a (stress-related senescence), which inhibits CDK4/6 to cause cell cycle arrest. Senescent cells are larger and flatter, and stain positively for SA-β-gal and lipofuscin. Senescent cells show activation of NF-κB, p38 MAPK, and JAK, resulting in the secretion of multiple inflammatory proteins known as the SASP, which includes inflammatory cytokines, chemokines, proteins, and growth factors. The SASP induces further senescence. The SASP also leads to structural changes, including local fibrosis and tissue destruction in chronic lung diseases. EVs from senescent cells also induce further senescence, contributing to lung disease progression.

Fig. 3

Cellular senescence in COPD. Cigarette smoke, indoor and outdoor air pollution, and chronic inflammation increase oxidative stress to induce senescence of small airway epithelial cells that drive further inflammation because of SASP mediators. Senescent cells also release EVs, which may be taken up by other epithelial cells, by small airway fibroblasts to induce peribronchial fibrosis, and by AT2 cells to result in emphysema, thus resulting in disease progression. In addition, SASP mediators and EVs reach the systemic circulation and may induce senescence in other organs, resulting in the age-related comorbidities commonly seen in patients with COPD.

Fig. 4

Comorbidities of COPD. Spread of EVs containing microRNAs released from senescent cells in the lung reach the systemic circulation and induce senescence in distant organs, resulting in accelerated age-related skeletal muscle wasting, and cardiovascular, metabolic and bone disease, which are common comorbidities of patients with COPD.

Fig. 5

Reduced sirtuins in chronic lung disease. Oxidative stress inactivates PTEN, which has cysteine (Cys) residues at its catalytic site, resulting in the activation of PI3K and mTORC1. This activates microRNA-34a, which inhibits sirtuin-1 and sirtuin-6 in parallel. Reduced sirtuin-1 leads to cellular senescence and mitochondrial dysfunction. Reduction of sirtuin-1 and sirtuin-6 leads to secretion of the SASP, which spreads senescence leading to disease progression. Reduction in sirtuin-1 and sirtuin 6 leads to reduced antioxidant genes FOXO3a and Nrf2, which further increases oxidative stress to accelerate the aging process.

Fig. 6

Senomorphic drugs for chronic lung disease. ROS inhibit PTEN, resulting in activation of PI3K and then mTORC1, which is inhibited by AMPK. mTOR activation reduces sirtuin-1, resulting in cellular senescence and mitochondrial dysfunction, which lead to release of mROS. Senescent cells release inflammatory proteins known the SASP. These pathways can be inhibited at several points as shown in the boxes. The drugs in red have already been tested in clinical studies.

Fig. 7

Senolytic therapies. Senolytics drive the senescent cell in cell cycle arrest toward apoptosis and subsequent clearance from the tissue by efferocytosis. Senolytic therapies include inhibitors of the antiapoptotic Bcl family and inhibitors of p53, and several other classes of drug.