This is part of our ongoing series of articles that discuss the Hallmarks of Aging. Published in 2013, the paper divides aging into distinct categories (“hallmarks”) of damage to explain how the aging process works and how it causes age-related diseases. Today, we will be looking at the hallmark of cellular senescence.
What are senescent cells?
As you age, increasing numbers of your cells enter into a state known as senescence. Senescent 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.
Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of senescent 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 senescent cells have built up, causing chronic inflammation and damage to surrounding cells and tissue. These senescent cells are one of the hallmarks of aging and a key process in the progression of aging [1, 2].
Senescent cells only make up a small number of total cells in the body, but they secrete 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 senescent 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 by engineering special mice that were designed to react to a chemical cue; when they encountered this chemical, it triggered the senescent cells to die [5]. The health and lifespan of the mice were improved by the removal of these senescent 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 senescent cells 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 senescent 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 senescent cells, and their removal improves vascular health [11]. Senescent cells are also implicated in atherosclerosis [12], type 2 diabetes [13], skin aging [14], and osteoarthritis [15].
Conclusion
The therapeutic removal 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. There is every reason to be optimistic, as senescent cells are a common and fundamental mechanism in both species, but only time will tell.
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] Lluc Mosteiro, Cristina Pantoja, Noelia Alcazar et al. (2016) Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science, 354(6315).
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