As your body ages, increasing amounts of your cells enter into a state of senescence. Senescent cells do not divide or support the tissue they are a part of, but instead emit a range of potentially harmful chemical signals, which encourage other nearby cells to also enter the same senescent state.

Their presence causes many problems: they degrade tissue function, increase levels of chronic inflammation, and can even eventually raise the risk of cancer.

Senescent cells and aging

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 these senescent cells escape this process and build up.

By the time people reach old age, significant numbers of these senescent cells have accumulated in the body and 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].

A new class of drugs known as senolytics focuses on the destruction of these stubborn “death-resistant” cells from the body, in order to reduce inflammation and improve tissue function. What follows is a short primer into some of the research that proposes to remove some of these senescent cells to promote healthy longevity.

A brief history of senolytics

The health and lifespan of mice have been demonstrated to improve by the removal of senescent cells using a transgenic suicide gene[3], and additional experiments showed that the same could be achieved using small molecules.

Senescent cells comprise 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 resulting SASP is thought to significantly contribute to aging[4] and cancer[5], and thus senolytics and the removal of SASP are a potential strategy for promoting health and longevity.

 

It was discovered through transcript analysis that senescent cells have increased expression of pro-survival genes, consistent with their resistance to apoptosis[6]. Drugs targeting these pro-survival factors selectively killed senescent cells. Two such drugs were Dasatinib and Quercetin, which were both able to remove senescent cells but were better in differing tissue types.

However, it was discovered that a combination of the two drugs formed a synergy that was significantly more effective at removing some senescent cell types[7].

In other studies, removing only thirty percent of senescent cells was sufficient to slow down age-related decline. These results suggest the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating the diseases of aging and promoting healthy longevity[8][9][10].

Further confirming the potential of senolytics to treat age-related disease, a recent study demonstrated the benefits of senolytics for certain aspects of vascular aging[11]. This was the first study to show that clearance of senescent cells improves aspects of vascular aging and chronic hypercholesterolemia, and could be a viable therapeutic to reduce morbidity and mortality from cardiovascular diseases.

Even more recently progress has been made treating atherosclerosis using senolytics to address the “foam cells” that contribute to this disease[12]. There has also been progress in ways to treat type-2 diabetes using senescent cell removal[13]. Senolytics also have potential for slowing skin aging[14] and treating osteoarthritis[15].

Senescent cells however are not all bad, and evidence shows that they play a role in cellular reprogramming[16] and wound healing. Like all things in biology, it is therefore clearly a question of balance: too much clearance of senescent cells would be bad for wound healing and cellular reprogramming, but too many senescent cells lead to damage[17][18].

Therefore, the key to developing effective senolytic therapies that combat the diseases of aging is the creation of even more accurate biomarkers to measure senescent cell numbers in tissue[19], combined with effective delivery methods for the selective removal of senescent cells.

Conclusion

There are now several companies involved in researching and developing senolytic therapies, and with Unity Biotechnology moving to clinical trials in 2017 and others close behind, it seems likely that senescent cell clearing will be the first rejuvenation therapy in the repair approach to aging to arrive. 

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. 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.

  4. 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.

  5. 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.

  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).

  17. Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., … & Hoeijmakers, J. H. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733.

  18. Tominaga, K. (2015). The emerging role of senescent cells in tissue homeostasis and pathophysiology. Pathobiology of Aging & Age-Related Diseases, 5.

  19. Matjusaitis, M., Chin, G., Sarnoski, E. A., & Stolzing, A. (2016). Biomarkers to identify and isolate senescent cells. Ageing research reviews, 29, 1-12.

     
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