Senolytic

A senolytic (from the words "senescence" and "lytic" - destroying) is among the class of small molecules under basic research to determine if they can selectively induce death of senescent cells.[1] In basic research, senescence is a potential tumor suppressive mechanism[2] and possible factor that accelerates the aging process.[3] The goal of those working to develop senolytic agents is to delay, prevent, alleviate, or reverse age-related diseases.[4]

Research

Research and possible agents

Multiple possible senolytic agents are under investigation.[5] Certain anti-cancer agents may in low doses decelerate aging and age-related diseases.[6] Targeting cancer prevention pathways with anti-cancer agents may confer longevity effects by offering protection from metabolic pathologies during aging, independently of effects on cancer.[7]

Navitoclax, also known as ABT-263, was originally studied as an anti-cancer drug.[8] It is under basic research as a possible inhibitor of the anti-apoptotic proteins BCL-2, BCL-w, and BCL-xL. Navitoclax may have senolytic properties against some cell types (e.g., human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts and murine embryonic fibroblasts (MEFs), but not all (e.g., human primary preadipocytes).[9] In laboratory studies, oral administration of Navitoclax to either sublethally irradiated or normally aged mice reduced senescent cells, including bone marrow hematopoietic stem cells and muscle stem cells.[10] It has toxic side effects, including thrombocytopenia and lymphopenia.[11][12]

See also

References

  1. ↑ Childs BG, Durik M, Baker DJ, van Deursen JM (2015). "Cellular senescence in aging and age-related disease: from mechanisms to therapy". Nature Medicine. 21 (12): 1424–35. PMC 4748967 Freely accessible. PMID 26646499. doi:10.1038/nm.4000. Retrieved 2015-12-27.
  2. ↑ Campisi J (2013). "Aging, cellular senescence, and cancer". Annual Review of Physiology. 75: 685–705. PMC 4166529 Freely accessible. PMID 23140366. doi:10.1146/annurev-physiol-030212-183653. Retrieved 2016-02-07. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyper-plastic pathologies, most likely by promoting chronic inflammation.
  3. ↑ van Deursen JM (2014). "The role of senescent cells in ageing". Nature. 509 (7501): 439–46. PMC 4214092 Freely accessible. PMID 24848057. doi:10.1038/nature13193. Retrieved 2015-12-27.
  4. ↑ Kirkland JL, Tchkonia T (2015). "Clinical strategies and animal models for developing senolytic agents". Experimental Gerontology. 68: 19–25. PMID 25446976. doi:10.1016/j.exger.2014.10.012. Retrieved 2015-12-28.
  5. ↑ Dominick Burton (2017). Killing ‘zombie’ cells to improve health in old age. The Conversation. Academic rigour, journalistic flair
  6. ↑ Blagosklonny MV (2013). "Selective anti-cancer agents as anti-aging drugs". Cancer Biology & Therapy. 14 (12): 1092–7. PMC 3912031 Freely accessible. PMID 24345884. doi:10.4161/cbt.27350. Retrieved 2015-12-27.
  7. ↑ Slack C, Alic N, Partridge L (2015). "Could cancer drugs provide ammunition against ageing?". Cell Cycle (Georgetown, Tex.). PMID 26587873. doi:10.1080/15384101.2015.1118905. Retrieved 2015-12-27.
  8. ↑ Shoemaker AR, Mitten MJ, Adickes J, Ackler S, Refici M, Ferguson D, Oleksijew A, O'Connor JM, Wang B, Frost DJ, Bauch J, Marsh K, Tahir SK, Yang X, Tse C, Fesik SW, Rosenberg SH, Elmore SW (2008). "Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models". Clinical Cancer Research. 14 (11): 3268–77. PMID 18519752. doi:10.1158/1078-0432.CCR-07-4622. Retrieved 2015-12-30.
  9. ↑ Zhu, Yi; Tchkonia, T; Fuhrmann-Stroissnigg, H; Dai, HM; Ling, YY; Stout, MB; Pirtskhalava, T; Giorgadze, N; Johnson, KO; Giles, CB; Wren, JD; Niedernhofer, LJ; Robbins, PD; Kirkland, JL (2015). "Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl-2 Family of Anti-Apoptotic Factors". Aging Cell. PMID 26711051. doi:10.1111/acel.12445.
  10. ↑ Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D (2015). "Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice". Nature Medicine. 22: 78–83. PMC 4762215 Freely accessible. PMID 26657143. doi:10.1038/nm.4010. Retrieved 2015-12-23.
  11. ↑ Wilson WH, O'Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP, Tulpule A, Dunleavy K, Xiong H, Chiu YL, Cui Y, Busman T, Elmore SW, Rosenberg SH, Krivoshik AP, Enschede SH, Humerickhouse RA (2010). "Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity". The Lancet. Oncology. 11 (12): 1149–59. PMC 3025495 Freely accessible. PMID 21094089. doi:10.1016/S1470-2045(10)70261-8. Retrieved 2015-12-30.
  12. ↑ Kaefer A, Yang J, Noertersheuser P, Mensing S, Humerickhouse R, Awni W, Xiong H (2014). "Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia". Cancer Chemotherapy and Pharmacology. 74 (3): 593–602. PMID 25053389. doi:10.1007/s00280-014-2530-9. Retrieved 2015-12-30. Thrombocytopenia is a primary dose-limiting toxicity of navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies.
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