Cellular Senescence in Lung Disease

Today's open access paper is a review of what is known of the role of cellular senescence in lung disease. With the development of senolytic therapies that can selectively destroy senescent cells, all conditions in which senescent cells contribute meaningfully to pathology may soon be effectively treated. Senescent cells accumulate with age in all tissues, and while never a sizable fraction of all cells, even a comparatively small number of senescent cells can cause chronic inflammation and tissue dysfunction. They secrete a mix of inflammatory signals, growth factors, and other molecules that has a sizable effect on the behavior of surrounding cells. In the short term, this behavior is a necessary part of wound healing and cancer suppression, among other activities, but when sustained over the long term, this contributes to the degeneration and diseases of aging.

Taken in the broader context of medical research as a whole, senescence is still poorly mapped, and its role in all too many conditions is not explored in any detail. There is only so much research funding, and only so many research teams. The hundreds of age-related conditions and scores of different tissues in the body are being explored with some sense of prioritization, but a great deal of work remains to be accomplished. The lung in an organ for which the role of cellular senescence in disease been more extensively investigated in recent years, largely because senescent cells are implicated in fibrosis, and fibrotic lung diseases have no truly effective treatments at this time. One of the first human trials of a senolytic therapy targeted idiopathic pulmonary fibrosis, and further, some very interesting animal studies have examined the more general decline of lung function with age, and its reversal through senolytic therapy.

Cellular Senescence in the Lung: The Central Role of Senescent Epithelial Cells

It is thought that cellular senescence contributes to developmental processes including promoting remodeling, inflammation, infectious susceptibility, and angiogenesis as well as fundamental processes, such as wound healing and tissue regeneration. Herein, senescent cells which fulfilled their action are removed from the interfered tissue via infiltrating immune cells. However, if senescent cells persist, these cells might foster age- and disease-associated physiological dysfunction particularly through their progressively changing secretory profile. With this respect, cellular senescence is now considered an important driving force for the development of chronic lung pathologies, particularly chronic inflammation observed in lungs of aging patients and of patients suffering from asthma, chronic obstructive pulmonary disease, or pulmonary fibrosis. The accumulation of senescent cells in lungs has disadvantageous consequences. Understanding the mechanisms driving induction of cellular senescence as well as the mechanisms mediating pathology-promoting effects of senescence may offer new treatment strategies for chronic lung diseases.

Age-related changes in lung morphology include enlargement of small airways and a decreased alveolar surface tension, finally leading to a compliant distensible lung. Furthermore, senescent cells with increased senescence-associated secretory phenotype (SASP) secretion accumulate with age in adult lungs; these cells exert autocrine and paracrine effects resulting in increased inflammation, induced stem cell dysfunction, and/or senescence of neighboring cells. Most importantly, the age-related increase in senescent lung cells, together with 'immune senescence', namely the lack of inflammatory cells to respond to SASP, result in an ineffective or slowed clearance of senescent cells, a progressively altered local environment, and subsequently tissue aging or development of age-related diseases.

Considerable in vitro and preclinical in vivo data support a deleterious impact of senescence on vascular endothelial cells finally resulting in the failure of the endothelium to perform its normal, physiologic functions. It has been demonstrated that chronic clearance of senescent cells with senolytic drugs (e.g., dasatinib or quercetin), that selectively induce death of senescent cells or genetic clearance of p16-expressing endothelial cells, improves vascular phenotypes.

Repetitive injury, especially to the pulmonary epithelium, is considered a central factor in the development of various lung diseases. Herein, the senescence of the respiratory epithelium is regarded as a central process for the initiation and progression of related lung diseases, particularly in pulmonary fibrosis and experimental lung fibrosis models. Human lung tissues from lung fibrosis (idiopathic pulmonary fibrosis, IPF) patients were shown to harbor numerous senescent epithelial cells as revealed by prominent SA-β-gal and p16 staining. IPF related epithelial senescence was closely associated with the SASP factors IL-1β, IL-6, IL-8 and TNF-α, which were already correlated with pulmonary fibrogenesis. Therefore, the current hypothesis is that alveolar epithelial injury imposed on senescent epithelial cells leads to aberrant wound healing and the secretion of high levels of growth factors and chemokines that foster the activation of adjacent cells, including endothelial cells and fibroblasts, and fibrogensis.

In a preclinical model of radiation-induced pneumopathy, clearance of senescent cells with a senolytic drug (ABT-263) efficiently reduced senescent cells and reversed pulmonary fibrosis. This, of course, would even limit the diminishing epithelial regenerative capacity, as well as associated SASP-mediated effects on adjacent lung cells as a central aspect in the development of lung injury. Therefore, targeting particularly senescent lung epithelial cells was suggested as a promising option for pulmonary fibrosis. Moreover, treatment of irradiated mice with ABT-263 almost completely reversed pulmonary fibrosis, even when the initiation of ABT-263 treatment was delayed until fibrosis was established. This means that unlike other known radiation protectants and mitigators, which were usually needed to be applied before or shortly after radiotherapy, senolytic drugs such as ABT-263 have the potential to be used as an effective, novel treatment of radiation-induced side complications such as inflammation and fibrosis, even after the lung injury develops into a progressive disease.

Comments

I'm planning to try dasatinib + quercetin for my chronic sinusitis. I have some dasatinib on order from alibaba.

Posted by: european bob at May 21st, 2020 1:39 AM

@european

Are you that desperate to try it? Dasatinib is quite poisonous. And given that we have second generation Senolytics in the pipeline like OISIN and pro drugs it might be wiser to wait a few years.

In the mean time, if you have appetite for risk, you can try fisetin and fasting (say 2 days dry + 2 days water fast , laxative on day 0, break the fast with fresh juices on day 1 , gradually introduce more food like veggies on day 2, plain yogurt on day 3, bread, nuts, cheese on day 4 and try to eat healthy for a couple weeks more. You can start slowly and have one day (24h) of dry fast just to test the waters. Dry fast while sounding more extreme is easier than the water one since you don't have the food cravings)

This fasting protocol gives me more subjectively perceivable benefits than 3-4 grams of of fisetin and quercetin ( F+Q are on the scale of placebo for my body.)

Posted by: Cuberat at May 21st, 2020 8:04 AM

@cube rat - already tried both fisetin and fasting with no effect (5 day water fasts, 4 of them). Also tried azithromycin to no effect.

I'm hoping that chronic sinusitis resistant to steroids is driven by senescent cells like steroid resistant asthma seems to be.

I am desperate, sinusitis is destroying my life.

Posted by: european bob at May 21st, 2020 9:27 AM

@european
since you already have experienced water fasts, try 2-3 dry fast. Usually it suppresses, at least temporarily, various inflammations

Posted by: cuberat at May 21st, 2020 11:48 AM

Does anyone know if ABT-263 or other senolytic drugs have any effectiveness against NON radiation-induced pulmonary fibrosis?

Posted by: rod at May 24th, 2020 5:23 PM

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