Fight Aging!

Senescent cells accumulate in tissues throughout the body with age. The produce inflammatory sections that actively maintain a disrupted state of tissue maintenance, structure, and function. Targeted removal of senescent cells has produced rejuvenation in mice, reversal of measures of aging and the progression of numerous age-related conditions. One of the ways in which tissue is affected by senescent cells is the development of fibrosis, a malfunction of tissue maintenance that leads to the inappropriate deposition of scar-like structures and consequent loss of function. This occurs in numerous organs with age, notably the heart, kidneys, liver, and lungs.

One of the first conditions to show improvement as a result of treatments producing senescent cell clearance was idiopathic pulmonary fibrosis. Human trials have shown initially promising results, and are presently ongoing. In today's open access paper, the authors discuss in some detail the role of cellular senescence in the development of lung fibrosis, a pathology with no good, established treatment options at the present time. The prospect of a viable therapy for this and other forms of fibrosis based on targeted destruction of senescent cells is encouraging a great deal of interest and activity in the research community.

Cellular Senescence in Lung Fibrosis

Fibrosis and wound healing are essentially interwoven processes, driven by a cascade of injury, inflammation, fibroblast proliferation and migration, matrix deposition and remodelling. Pathological fibrogenesis that occurs in many diverse organs and diseases is a dynamic process involving complex interactions between epithelial cells, fibroblasts, immune cells (macrophages, T-cells), and/or endothelial injuries.

As a response to lung injury, many interrelated wound-healing pathways are activated in order to facilitate the repair, turnover, and adaptation of lung tissue. However, although their aetiology and causative mechanisms varies, the different fibrotic lung diseases all fail to properly eliminate inciting factors, leading to continued tissue damaging with an abnormal and exaggerated accumulation of extracellular matrix (ECM) components and collagen deposition. Another hallmark of lung fibrosis is that older individuals display impaired ability to restore tissue homeostasis, heal wounds and resolve fibrosis, resulting in tissue scarring and irreversible organ damage

The number of senescent cells gradually increases with age, and the presence of senescent cells is a common finding in age-related pathologies. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. Our understanding of the biology of senescence in an evolutionary context has led us to think about cellular senescence as an essential mechanism of antagonistic pleiotropy. This concept encompasses processes that are meant to be beneficial to the health of young organisms (as a strong tumour-suppressor mechanism, or integrating physiologically programmed mechanisms during development), but also can demonstrate deleterious effects in older organisms, most likely by promoting chronic inflammation and fibrosis that leads to both degenerative and hyper-plastic pathologies.

Antagonistic pleiotropy is key to understanding many aspects of lung fibrosis, especially the relationship between aging, cellular senescence, and lung fibrosis. In the lung, there is a relatively straightforward relationship to several environmental factors, such as tobacco smoke, air pollutants, environmental antigens, or infections, so the setting in which cellular senescence develops is fraught with dangerous stressors, including DNA damage and telomere attrition, oncogenic signalling activation, epigenomic stress, redox imbalance, or mitochondrial biogenesis dysfunction. This attribute might also explain the vulnerability of the lung to increases in senescence-inducing conditions that promote the loss of architectural integrity and elasticity, and subsequent pulmonary function impairment.