Our research team is conducting research on "senescent cells," which accumulate in each organ with aging. The Research Team for Functional Biogerontology, with which I am affiliated, seeks to clarify how senescent cells influence disease, and develop treatments for diseases that currently have no fundamental treatment. Accordingly, I will discuss chronic obstructive pulmonary disease (COPD), while also introducing our research details.
Ø What are senescent cells?
When the cells that constitute our bodies experience irreparable damage (e.g., DNA damage, oxidative stress), tumor suppressor proteins are activated, which leads to a state of cellular senescence. Cells that have undergone cellular senescence are called "senescent cells," and these cells begin to develop several features that are not observed in normal cells, such as the irreversible cessation of cell division.
Cellular senescence has both beneficial and harmful effects on our bodies. A beneficial aspect of cellular senescence is that it prevents the proliferation of dangerous cells that pose a risk of cancer while functioning as an extremely important cancer suppression mechanism for the body. However, senescent cells are known to accumulate in many tissues with aging and affect surrounding cells by secreting various physiologically active substances. Such secretory phenomena have harmful effects on the body and promote tissue senescence and chronic diseases.
Studies conducted on animals have revealed that the removal of senescent cells (senolysis; Fig. 1) restores function in multiple tissues and has an effect in preventing the onset and progression of diseases. Our laboratory has reported the restoration of respiratory function when senolysis is conducted on aged mice with reduced lung function[1] and the suppression of emphysema and metastatic lung cancer through the combination of pathological models with senolysis.[2-4] Recently, considering this background, senescent cells have been receiving attention as a therapeutic target for diseases.
Ø Increasing number of COPD patients with aging
COPD (chronic obstructive pulmonary disease) is a leading cause of death worldwide. The latest data from the WHO (World Health Organization) reveals that it is the third leading cause of death worldwide. In the United States, the number of new patients is 200 per 10,000 people under the age of 45; and 1,200 per 10,000 people aged 65 years or older. In Japan, it is estimated that 8.6% of people aged 40 years or older, or approximately 5.3 million people, suffer from the disease.[5,6] COPD is a disease that increases with aging, and the increase in the number of patients worldwide is related to the increase in the elderly population. Smoking is the chief cause of COPD, and 15-20% of smokers develop COPD.[7] However, in Japan, awareness regarding COPD remained at less than 30% in a 2017 survey. Moreover, public awareness activities aimed at raising awareness and promoting smoking cessation have been conducted in Tokyo.[8]
Ø Current status and issues of COPD treatment
COPD is an inflammatory disease of the lungs caused by the long-term inhalation of harmful substances such as tobacco smoke, including chronic bronchitis and emphysema as the primary conditions (Fig. 2). In chronic bronchitis, breathing becomes difficult as inflammation of the bronchi causes coughing, production of phlegm, and narrowing of the bronchi. In emphysema, the small sacs that compose the lungs (alveoli) are destroyed, which reduces the ability to absorb oxygen and expel carbon dioxide. These conditions cause symptoms such as shortness of breath and difficulty in breathing while moving, in addition to chronic coughing and phlegm.
COPD treatments include symptomatic and exercise treatment, and lifestyle guidance based on the cessation of smoking. For chronic bronchitis, drugs that suppress bronchial inflammation and dilate the bronchi are used to alleviate symptoms. However, no treatment currently exists for emphysema that can restore alveoli that have already been destroyed.
Ø Can the lungs regenerate?
Some organs, such as the liver, have a high regenerative capacity, and experiments on animals have revealed that even if 70% of the liver is removed, the weight and function of the liver recover within about a week. However, the lungs have been recognized as organs with poor regenerative capacity. However, a phenomenon known as "compensatory growth" occurs in the lungs, where lung regeneration with an increase in the number of alveoli occurs in children who have undergone lung transplant surgery and adults who have had part of their lungs removed.[9,10] Recent studies have revealed that patients with pneumonia owing to the novel coronavirus infection, even in severe cases, exhibited an almost complete restoration of the structure and function of the lungs,[11] revealing that lungs have regenerative capacity.
Our team is conducting research on the effect of senescent cells on the regeneration of lung tissues. The lung tissues of mice from which senescent cells have been removed exhibited enhanced proliferation of progenitor cells that form alveoli, suggesting that substances secreted by senescent cells may suppress the repair and regeneration of alveoli. Our team is currently studying the mechanism by which senescent cells suppress the repair and regeneration of alveoli and influence conditions such as emphysema.
Ø Conclusion
Studies have revealed that senescent cells play a crucial role in COPD, a disease in which the number of patients increases with aging. Our laboratory has previously reported that senescent cells worsen the condition of emphysema by promoting inflammation. Current research has revealed that "inhibition of lung regeneration" is a new mechanism by which senescent cells worsen the disease. In the future, to develop innovative treatments for COPD, our team will seek to clarify in detail the effects of senescent cells on disease.
１．Hashimoto, M. et al. Elimination of p19ARF-expressing cells enhances pulmonary function in mice. JCI Insight 1, e87732, doi:10.1172/jci.insight.87732 (2016).
２．Mikawa, R. et al. Elimination of p19(ARF) -expressing cells protects against pulmonary emphysema in mice. Aging Cell 17, e12827, doi:10.1111/acel.12827 (2018).
３．Mikawa, R. et al. p19Arf Exacerbates Cigarette Smoke-Induced Pulmonary Dysfunction. Biomolecules 10, 462, doi: 10.3390/biom10030462 (2018).
４．Kawaguchi, K. et al. Cellular senescence promotes cancer metastasis by enhancing soluble E-cadherin production. iScience 24, 103022, doi: 10.1016/j.isci.2021.103022 (2021).
５．Meiners, S., Eickelberg, O. & Konigshoff, M. Hallmarks of the ageing lung. The European respiratory journal 45, 807-827, doi:10.1183/09031936.00186914 (2015).
６．Fukuchi, Y. et al. COPD in Japan: the Nippon COPD Epidemiology study. Respirology 9, 458-465, doi:10.1111/j.1440-1843.2004.00637.x (2004).
７．Cigarette smoking and health. American thoracic society. American journal of respiratory and critical care medicine 153, 861-5 (1996).
８．Tokyo Metropolitan Government Bureau of Public Health: https://www.hokeniryo.metro.tokyo.lg.jp/kensui/copd/index.html
９．Toyooka S., Sano Y., Yamane M., et al. Long-term follow-up of living-donor single lobe transplantation for idiopathic pulmonary arterial hypertension in a child. J Thorac Cardiovasc Surg 135, 451-452, doi:10.1016/j.jtcvs.2007.10.010 (2008).
10．Butler J.P., Loring S.H., Patz S., et al. Evidence for adult lung growth in humans. N Engl J Med 367, 244-247, doi:10.1056/NEJMoa1203983 (2012).
11．Bailey J., Lavelle B., Miller J., et al. Multidisciplinary Center Care for Long COVID Syndrome-A Retrospective Cohort Study. Am J Med, doi:10.1016/j.amjmed.2023.05.002 (2023).
