Research into cellular senescence as a cause of aging and age-related disease has expanded greatly these past few years. Several companies are developing approaches to safely remove these unwanted cells. Very compelling evidence has emerged for the role of senescent cells in aging; a number of research teams have demonstrated reversal of specific measures of aging in various tissues, with one study reporting extended life spans in normal mice in which senescent cells were cleared. The evidence to date is particular interesting in the case of lung conditions, especially those in which inflammation and fibrosis are prominent features. Removing senescent cells from aged mice has been shown to improve lung tissue function and elasticity. Further, senescent cells and their ability to generate inflammation have been strongly implicated in the pathology of fibrotic, inflammatory lung conditions such as idiopathic pulmonary fibrosis.
Senescent cells accumulate with age, a small lingering remnant population of the vast number of cells that every day become senescent and then self-destruct or are destroyed by the immune system. Tissues have a two-tier hierarchy of cells: the vast majority of somatic cells that can only divide a limited number of times before becoming senescent, and the small number of stem cells that can self-renew themselves over the course of a lifetime, and which act as a source of new somatic cells. In most tissues the somatic cell population turns over consistently on a timescale of days to weeks depending on tissue type: countless senescent cells are created as this happens. Near all are quickly destroyed in one way or another, but the very few that fail to achieve that goal become a significant cause of aging over the years.
Senescent cells secrete a potent mix of signals that spurs inflammation, degrades tissue structures, and makes nearby cells more likely to become senescent themselves, among other effects. The signals relate to the normal short-term roles for the senescent cells: to assist in wound healing; to rouse the immune system to clear senescent cells; to halt tissue construction in embryonic development; to suppress the risk of cancer by ensuring that the most at-risk cells become senescent. But left to continue this program for the long-term, and in increasing numbers, the result is age-related disease and failure of tissue function.
The presence of senescent cells appears to be one of the important contributing causes of the dysfunction in regeneration that occurs with aging. Fibrosis is a part of this, in essence a failure to correctly repair and restore tissue structures that involves the formation of scar-like deposits that disrupt normal tissue function. It is at least partially driven by rising levels of inflammation, and a signaling environment that upsets the normal relationship between the immune system and tissue-resident cells. Senescent cells are the most obvious culprit, and a range of studies like the one noted here present evidence in support of the role of cellular senescence in driving fibrosis and fibrotic disease. As the number of senolytic treatments capable of clearing senescent cells increases, and these treatments become more reliable and well-characterized, expect to see more and better studies on this topic in the years ahead. Human trials of senolytics to reverse fibrosis should not be more than a few years distant at this point.
Pulmonary fibrosis causes the patient's lung tissue to scar, resulting in progressive pulmonary function deterioration. In particular, the surface of the alveoli (called the alveolar epithelium) is often affected. If the disease's origin is unknown, the condition is called idiopathic pulmonary fibrosis, or IPF for short. "The treatment options for IPF have been few and far between. We are therefore attempting to understand how the disease comes about so that we can facilitate targeted treatment." In the current work, researchers have now succeeded in solving another piece of the puzzle. "In both the experimental model and in the lungs of IPF patients, we were able to show that some cells in the alveolar epithelium have markers for senescence. Because the occurrence of IPF increases with age, this was already suspected. We have now succeeded in proving this hypothesis."
Senescence impairs lung function in two ways: It prevents lung cells from dividing when they need to be replaced. And senescent cells secrete mediators that further promote fibrosis. Since this effect also plays a role in cancer, the scientists were able to access an already existing group of medicines, the so-called senolytic drugs that selectively kill off senescent cells. In order to test possible treatment strategies, the scientists placed the affected cells into a three-dimensional cell culture and examined the drugs's effect ex vivo. "We observed that this caused a decline in the quantity of secreted mediators and additionally a reduction in the mass of connective tissue proteins, which are greatly increased in the disease." Altogether, the study shows that senescence in the cells of the alveolar epithelium can contribute to the development and worsening of IPF.
The incidence of idiopathic pulmonary fibrosis (IPF) increases with age and accumulating evidence strongly suggests ageing as a crucial contributor to IPF initiation and progression. In support of ageing as one proposed driver of disease pathogenesis, normal and accelerated-aged mice are more susceptible to experimentally induced fibrosis. A landmark paper in 2013 described nine hallmarks of ageing, and importantly, all nine hallmarks have been found to contribute to IPF pathogenesis, albeit to a variable degree. Cellular senescence, representing one of these hallmarks, is characterised by stable cell cycle arrest accompanied by secretion of mediators, including pro-inflammatory cytokines and metalloproteinases, collectively termed the "senescence-associated secretory phenotype" (SASP). While the detrimental effects of senescence are thought to be a result of stem or progenitor cell depletion or of the SASP components, senescence has also been described to be beneficial in tumour suppression and wound healing.
In the lung, as in other organs, the number of senescent cells increases with age and cellular senescence has been linked to the pathogenesis of chronic lung diseases such as chronic obstructive pulmonary disease or IPF. The contribution of senescent cells to disease onset and progression remain unclear. Some studies have suggested a link between increased senescence and fibrotic burden, while others report that attenuation of lung fibrosis correlates with lung fibroblast senescence. In addition to lung fibroblasts, evidence has emerged that alveolar epithelial cells can become senescent in IPF. However, lung epithelial cell senescence and its potential pathogenic role in IPF remains largely unexplored. Here, we aimed to investigate whether senescence of this cell population is detrimental or beneficial to lung repair. We utilised senolytic drugs on fibrotic lung epithelial cells in vitro and ex vivo in three-dimensional lung tissue cultures and demonstrated that senolytic treatment attenuates fibrotic mediator expression, while stabilising epithelial cell marker expression and function. These findings suggest that senescence contributes to development of lung fibrosis and that treatment of pulmonary fibrosis with senolytic drugs might be beneficial.