Why we Age: Cellular Senescence

The Hallmarks of Aging [1] describes dysfunctional senescent cells, which promote chronic inflammation, support the onset of various age-related diseases, and encourage other nearby healthy cells to become senescent too.  This is thought to be one of the reasons we age and therefore, targeting these cells has become a priority of the rejuvenation biotechnology industry.

What are senescent cells?

As you age, increasing numbers of your cells enter into a state known as senescence. These cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful chemical signals that encourage nearby healthy cells to enter the same senescent state. Their presence causes many problems: they reduce tissue repair, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related diseases.

Worn out or badly damaged cells normally destroy themselves via a programmed cell death called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of old and damaged cells escape this process and begin to accumulate in all the tissues of the body. By the time people reach old age, significant numbers of these death resistant cells have built up, causing chronic inflammation and damage to surrounding cells and tissue. These senescent cells are a key process in the progression of aging [1-2].

Cells become senescent due to various reasons including replicative senescence where telomere shortening or telomere dysfunction halts further cell division. Other causes are excessive mitogenic signaling, or DNA damage, which can  also trigger senescence and is characterized by stable growth arrest.

Even though they only make up a small number of total cells in the body, they secrete a cocktail of pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which, together, form the senescence-associated secretory phenotype, or SASP. The SASP is thought to significantly contribute to aging [3] and cancer [4]; thus, targeting these harmful cells and removing them has been suggested as a potential solution to this problem.

Taking out the trash

Researchers first tested the idea of targeting senescent cells to selectively induce apoptosis by engineering special mice that were designed to react to a chemical cue; when they encountered this chemical, it triggered the cells to enter apoptosis and die [5]. The health and lifespan of the mice were improved by the removal of these death resistant cells, and this started the search for drugs and therapies that could achieve the same result without the need to engineer the test subject.

Researchers discovered that these express higher levels of pro-survival genes, which make them highly resistant to apoptosis [6]. The search was on to find drugs that could target these cells, and it was not long before the first drugs which targeted these “death-resistant” cells were discovered. This new class of drugs became known as senolytics [7].

Follow-up studies showed that removing just thirty percent of the cells was enough to slow down age-related decline and ill health in mice [8-10]. This serves to strengthen the case for therapeutically removing senescent cells as a potential way to address some age-related diseases. Vascular aging appears to be at least partially driven by the presence of these cells, and their removal improves vascular health [11]. There is also data suggesting they are also implicated in atherosclerosis [12], type 2 diabetes [13], skin aging [14], and osteoarthritis [15].

Conclusion

The therapeutic removal using a senolytic agent or blocking the SASP of senescent cells to delay or prevent age-related diseases is a very promising area of medicine, so much so that a number of companies are developing senolytic therapies, some of which are now in human trials to see if the results observed in mice translate to humans.

Some researchers suggest there may be other ways to deal with senescent cells, such as rejuvenating the immune system so it clears them out or more recently, modulating the SASP using signaling pathways such as KDM4 so that its harmful effects are mitigated [16]. KDM4 targeting is a potential new therapeutic path to manipulate senescence and reduce its contribution to age-related diseases, including cancer.

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446.

[3] Freund, A., Orjalo, A. V., Desprez, P. Y., & Campisi, J. (2010). Inflammatory networks during cellular senescence: causes and consequences. Trends in molecular medicine, 16(5), 238-246.

[4] Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual review of pathology, 5, 99.

[5] Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., … & van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236.

[6] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’Hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.

[7] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’Hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.

[8] Tchkonia, T., Zhu, Y., Van Deursen, J., Campisi, J., & Kirkland, J. L. (2013). Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. The Journal of clinical investigation, 123(3), 966-972.

[9] Zhu, Y., Armstrong, J. L., Tchkonia, T., & Kirkland, J. L. (2014). Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Current Opinion in Clinical Nutrition & Metabolic Care, 17(4), 324-328.

[10] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’Hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.

[11] Roos, C. M., Zhang, B., Palmer, A. K., Ogrodnik, M. B., Pirtskhalava, T., Thalji, N. M., … & Zhu, Y. (2016). Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging cell.

[12] Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., & van Deursen, J. M. (2016). Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science, 354(6311), 472-477.

[13] Palmer, A. K., Tchkonia, T., LeBrasseur, N. K., Chini, E. N., Xu, M., & Kirkland, J. L. (2015). Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes, 64(7), 2289-2298.

[14] Velarde, M. C., & Demaria, M. (2016). Targeting Senescent Cells: Possible Implications for Delaying Skin Aging: A Mini-Review. Gerontology.

[15] Xu, M., Bradley, E. W., Weivoda, M. M., Hwang, S. M., Pirtskhalava, T., Decklever, T., … & Lowe, V. (2016). Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glw154.

[16] Zhang, B., Long, Q., Wu, S., Song, S., Xu, Q., Han, L., … & Sun, Y. (2020). KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype. bioRxiv.