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Today, we have a guest article from Dr. Marion Tible, a scientist, and author over at the aging research-focused blog Long Long Life. What follows is an introduction to the senescent cell-clearing therapies known as senolytics, these therapies are poised to enter human trials and if successful could revolutionize how we treat age-related diseases.

What are senolytics?

Discovered in 2015 by a team from Mayo Clinic and the Scripps Research Institute in the United States, senolytics are a growing trend in the anti-aging community. They are very promising drugs in the fight against cellular senescence, a hallmark of aging.

In our bodies, we have stem cells that are capable of replacing cells that die every day. During aging, these stem cells can stop dividing and differentiating, becoming senescent and compromising our ability to replace the cells that die. In parallel, a similar phenomenon occurs in non-stem cells, compounding the problem and overloading our immune cleaning systems [1]. When senescent cells are too numerous, they accumulate and secrete proinflammatory factors that promote the development of age-related diseases [2].

Thanks to bioinformatics tools, several dozen potential treatments for cellular senescence have been identified. Some of them have already been tested on animals, with remarkable results. In mice genetically modified for the expression of caspase 8, supplementation with one class of senolytic has been shown to decrease the number of senescent cells by up to 30%, thereby prolonging their lifespan [3]. After this success, researchers sought to increase the apoptosis of senescent cells, thus helping the immune system to get rid of them. This approach has allowed the identification of several new drugs and drug combinations, and their administration has led to better heart function, decreased osteoporosis and increased lifespan [4].

Drugs classified as senolytic

The very first publication reporting senolytics studied quercetin (a flavonoid) and dasatinib (Sprycel) [4]. These two treatments allowed the reduction of senescence markers in both in vitro and in vivo studies. In a more recent study by the same team, navitoclax, an anti-cancer treatment, was identified as a senolytic [5]. Also by the same team, Fisetin, Piperlongumine, and BCl-2 inhibitors were reported to have a specific effect on senescence [6]. Right now, it is too soon to establish a proper posology for humans, as the testing has only been done on murine models, and incorrect doses of some senolytic drugs have strong side effects.

Senolytics for which diseases?

Cellular senescence does not affect all organs equally, and the cardiovascular system is especially vulnerable to it. During aging, pathologies such as atherosclerosis, heart attacks, and arterial stiffening can appear, and cellular senescence has a prominent role in these diseases. Treatment with senolytics appears to reduce arterial calcification in hypercholesterolemic mice [7], thus reducing the risk of atherosclerosis. In another study, regulation of specific signaling pathways by senolytics led to a targeted apoptosis of cancer cells [8]. Treatments are in development for many other conditions, including neurodegenerative diseases, sarcopenia, metabolic diseases, and osteoporosis.

Conclusion

By targeting specifically important processes and reducing cellular senescence, senolytics are very promising tools in anti-aging research. Although the decrease rarely exceeds 15-30% of the total pool of senescent cells, this reduction seems sufficient to induce drastic changes in age-related pathologies. If this therapy can be translated to humans, it will potentially offer another way to improve our lifespan and prevent age-related diseases.

If you enjoyed this article, you should check out Marion’s recent article, Senolytics: the war on senescence is on!, over at Long Long Life.

Literature

[1] Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW, Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007; 445(7128):656-60

[2] JP de Magalhães, JF Passos, Stress, cell senescence and organismal ageing, Mechanisms of Ageing and Development, 2018;170:2-9

[3] Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM, Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders, Nature, 2011; 479(7372):232-6

[4] Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644-658

[5] Zhu Y, Tchkonia T, Fuhrmann‐Stroissnigg H, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors. Aging Cell. 2016;15(3):428-435

[6] Zhu Y, Doornebal EJ, Pirtskhalava T, et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY). 2017;9(3):955-963

[7] Roos CM, Zhang B, Palmer AK, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell. 2016;15(5):973-977

[8] Ståhl S, Kaminskyy VO, Efazat G, Hyrslova Vaculova A, Rodriguez-Nieto S, Moshfegh A, Lewensohn R, Viktorsson K, Zhivotovsky B, Inhibition of Ephrin B3-mediated survival signaling contributes to increased cell death response of non-small cell lung carcinoma cells after combined treatment with ionizing radiation and PKC 412. Cell Death Dis. 2013;4:e454

About the author

Marion Tible

Marion has a PhD in cellular biology and physiopathology. Formerly a researcher in thematics varying from cardiology to neurodegenerative diseases, she is now part of the Long Long Life team and is involved in scientific writing and anti-aging research.
  1. September 4, 2019

    So when will human trials begin.

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