A Mechanism by which Cellular Senescence Drives Pulmonary Fibrosis

The lingering senescent cells that accumulate with age are an important contributing cause of degenerative aging. If nothing else, their secretions generate a significant fraction of the chronic inflammation of aging, disrupting tissue function and immune function. Chronic inflammation is in turn well known to accelerate all of the most common age-related conditions. Fibrosis is a consequence of dysfunctional tissue maintenance and regeneration, in which scar-like deposits form, degrading tissue function. There is good evidence for fibrotic diseases, such as those of the lung, kidney, and heart, to be driven in large part by the presence of senescent cells. This is good news for patients, as while there is little that can be done to treat these conditions in the practice of medicine at the present time, senolytic therapies to clear senescent cells may well help to turn back fibrosis.

Accumulation of senescent cells is associated with the progression of pulmonary fibrosis but mechanisms accounting for this linkage are not well understood. To explore this issue, we investigated whether a class of biologically active profibrotic lipids, the leukotrienes (LT), is part of the senescence-associated secretory phenotype. The analysis of conditioned medium (CM) lipid extracts and gene expression of LT biosynthesis enzymes revealed that senescent cells secreted LT regardless of the origin of the cells or the modality of senescence induction.

The synthesis of LT was biphasic and followed by anti-fibrotic prostaglandin (PG) secretion. The LT-rich CM of senescent lung fibroblasts induced pro-fibrotic signaling in naïve fibroblasts, which were abrogated by inhibitors of ALOX5, the principal enzyme in LT biosynthesis. The bleomycin-induced expression of genes encoding LT and PG synthases, level of cysteinyl leukotriene in the bronchoalveolar lavage, and overall fibrosis were reduced upon senescent cells removal either in a genetic mouse model or after senolytic treatment. Quantification of ALOX5+cells in lung explants obtained from idiopathic pulmonary fibrosis (IPF) patients indicated that half of these cells were also senescent (p16Ink4a+). Unlike human fibroblasts from unused donor lungs made senescent by irradiation, senescent IPF fibroblasts secreted LTs but failed to synthesize PGs.

This study demonstrates for the first time that senescent cells secrete functional LTs, significantly contributing to the LTs pool known to cause or exacerbate idiopathic pulmonary fibrosis.

Link: https://doi.org/10.1172/jci.insight.130056


Jose Rodrigues:

The interviewer asks reasonable questions (e.g. "senolytics have been shown to increase median lifespan and healthspan in murine models. Given that senescent cells are a common mechanism in both mice and humans and are a proposed secondary cause of aging, it doesn't seem unreasonable to think the results in humans would be similar. Why would removing senescent cells be significantly different in humans than it is in mice?") and Michael Fossel gives total BS answers (e.g. "I don't see any credible data that supports the contention that 'senolytics have been shown to increase median lifespan and healthspan in murine models.'"-this constitutes his entire response to the question above!). He cites a textbook he wrote in 2004, which was published well before we acquired meaningful data on senolytics. All of his positive arguments against the efficacy of senolytics seem to be based on armchair analogies. I cannot understand how someone can look at the data accumulated over the past decade on senolytics in mice and come to the conclusion that senolytics are harmful. Maybe they don't extend maximum lifespan, but there is not a shred of evidence that eliminating senolytic cells has long-term negative consequences.

Posted by: gheme at November 18th, 2019 3:43 PM

Hi gheme. Thank you for your response

Posted by: Jose Rodrigues at November 19th, 2019 8:03 AM
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