Removing Senescent Cells: Extending the Human Age Span

Aging is a universal process, yet the science behind how and why aging occurs is still relatively mysterious. However, during the past few decades, modern aging research has progressed dramatically. The first key finding in aging science was that calorie restriction can extend the average and maximum lifespan of many organisms. Today, the discovery of the relationship between senescent cells and the rate of aging comes forward as the latest breakthrough in the field, as animal studies have proposed that destroying senescent cells can slow down age-related physical decline and enhance overall health.

Cellular senescence is characterized by the state of cell cycle arrest where cell division is halted and cells become resistant to growth-promoting stimuli and apoptosis. It is a multifaceted process that occurs throughout one’s lifespan. As humans age, the number of senescent cells increases as cells are more likely to encounter potentially oncogenic events such as non-telomeric DNA damage and non-genotoxic stress. When these stimuli are applied to mitotic cells, the cells cease proliferation, becoming senescent, and depending on the age of the cells, develop apoptosis resistance (Powell, A., 2019). Usually, when cells experience unfavorable stress, they would self-destruct through apoptosis and are removed by the immune system (a natural safety mechanism that prevents the cancer growth in the body). However, as the immune system weakens with age, senescent cells begin to accumulate in the body. Senescent cells produce the senescence-associated secretory phenotype (SASP), a double-edged gene expression that contributes to wound healing and embryonic development yet promotes inflammation and tumor progression (Coppé, J., Desprez, P., 2010).

Overall, SASP stimulates cell motility, migration and invasion. Normally, senescent cells serve as a potential defense mechanism against tumor growth, but as these cells build up, the excess of SASP promotes tumor progression. This conflicting process can be explained by the antagonistic pleiotropy hypothesis, which proposed that the combined effect of pleiotropic genes that contribute to aging can have a beneficial effect in the youth but adverse effects later in life (Coppé, J., Desprez, P., 2010). The SASP secretes proinflammatory cytokines, chemokines, and extracellular matrix proteases, which impacts the surrounding microenvironment, promoting senescence in neighboring cells. A study done on mice showed that transplanting even a small number of senescent cells around the knee joints of young mice caused an age-related osteoarthritis-like condition, showing how effective the secreted SASP can be on surrounding cells (Xu, 2016). The accumulation of senescent cells leads to inflammation and damage to surrounding tissue, and has been implicated in the progression of age-related diseases such as Alzheimer’s and cardiovascular syndromes, as well as the decline of organismal function over time.

Figure 1. Cellular senescence generates a pro-tumorigenic microenvironment. Cellular senescence can be caused by various stimuli that lead to the accumulation of senescent cells as tissues age. The senescence-associated secretory phenotype (SASP) induces extracellular matrix remodeling and inflammation, which generates a pro-tumorigenic microenvironment

With this newfound knowledge on senescent cells, recent research has been focused on how to reduce the senescent cell burden to improve the health and life span of organisms. The correlation between senescent cells and age-related pathologies such as cancer, neurodegeneration, and cardiovascular diseases serve as a compelling motivator to conduct research in this field. So far, research has shown that senescent cells can be cleared genetically in animal models, and pharmacologically in animals and humans. Specifically, a new class of drugs called “senolytics” has been developed to treat inflammation and improve tissue function through the destruction of senescent cells (Kirkland, J., & Tchkonia, T., 2020). UT Health San Antonio researchers along with the Mayo Clinic and the Wake Forest School of Medicine were the first to conduct and publish research on the treatment of human patients using senolytics in early 2019. In previous animal studies, senolytics were observed to selectively clear senescent cells in mice that model idiopathic pulmonary fibrosis (IPF), a chronic, irreversible disease affecting the lungs. In this first human pilot study, 14 adults diagnosed with IPF were given two senolytics, dasatinib and quercetin, to be taken by mouth for three weeks, three consecutive days each week. Rigorous symptom questionnaires and physical function evaluations were administered, and biological assays of senescence proteins secreted by senescent cells were conducted. The results were preliminary, but encouraging. The most consistent improvement following the senolytic therapy was in the participants’ mobility, a promising finding as until now no drug therapies have ever been shown to stabilize or increase an IPF patient’s walking distance. Although this result should be handled with caution as the study was relatively small, the results are encouraging in the field of senescent cell research. (Justice, J. N., 2019) Another study was the first to show that the clearance of senescent cells improves aspects of vascular aging and chronic hypercholesterolemia, which implies that senolytics can be used to potentially reduce morbidity from cardiovascular diseases. (Tamara Tchkonia, P., 2018) Recently, there has been progress made in treating atherosclerosis using senolytics. (Zimmer, K., 2020)

Figure 2. In preclinical studies, the clearance of senescent cells using senolytics have shown to improve physical function and extend the health and lifespan of affected cells

As recent research on aging shows, it seems increasingly clear that senescent cells play a vital role in the pathogenesis of age-associated disorder. Using senolytic therapy to target senescent cells has therefore emerged as a promising strategy to treat diseases that impact millions around the world, a potential that would have transformative effects on modern geriatric medicine.

Edited by Rhea Tumminkatti

Placed by Vivian Huang

References

Coppé, J., Desprez, P., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: The dark side of tumor suppression. Retrieved October 12, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166495/

Justice, J. N. (2019). Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. Retrieved 2020, from https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(18)30629-7/fulltext

Kirkland, J., & Tchkonia, T. (2020, July 19). Senolytic drugs: From discovery to translation. Retrieved October 12, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395/

Powell, A. (2019, April 01). Anti-aging research: ‘Prime time for an impact on the globe’. Retrieved September 27, 2020, from https://news.harvard.edu/gazette/story/2019/03/anti-aging-research-prime-time-for-an-impact-on-the-globe/

Tamara Tchkonia, P. (2018, October 02). Emerging Therapeutic Strategies for Aging, Cell Senescence, and Chronic Disease. Retrieved September 27, 2020, from https://jamanetwork.com/journals/jama/article-abstract/2703113

Van Deursen, J. (2014, May 22). The role of senescent cells in ageing. Retrieved September 27, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214092/

Zainabadi K. (2018). A brief history of modern aging research. Experimental gerontology, 104, 35–42. https://doi.org/10.1016/j.exger.2018.01.018

Zimmer, K. (2020). Can Destroying Senescent Cells Treat Age-Related Disease? Retrieved September 27, 2020, from https://www.the-scientist.com/features/can-destroying-senescent-cells-treat-age-related-disease–67136

Image Citations

Ellison-Hughes, Georgina. “Senolytics: an Emerging Therapeutic for the Prevention and Treatment of Cardiovascular Disease.” Senolytics: an Emerging Therapeutic for the Prevention and Treatment, 2019, www.medthority.com/news/news-trends/senolytics–an-emerging-therapeutic-for-the-prevention-and-treatment-of-cardiovascular-disease/. 

Schosserer, Markus, et al. The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy. 6 Nov. 2017, www.frontiersin.org/articles/10.3389/fonc.2017.00278/full.

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