Senolytic

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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] The goal of those working to develop senolytic agents is to delay, prevent, alleviate, or reverse age-related diseases.[2]

Research[edit]

Research and possible agents[edit]

Multiple possible senolytic agents are under investigation. Certain anti-cancer agents may in low doses decelerate aging and age-related diseases.[3] 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.[4]

Navitoclax, also known as ABT-263, was originally studied as an anti-cancer drug.[5] 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).[6] 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.[7] It has toxic side effects, including thrombocytopenia and lymphopenia.[8][9]

See also[edit]

References[edit]

  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. doi:10.1038/nm.4000. PMC 4748967Freely accessible. PMID 26646499. Retrieved 2015-12-27. 
  2. ^ Kirkland JL, Tchkonia T (2015). "Clinical strategies and animal models for developing senolytic agents". Experimental Gerontology. 68: 19–25. doi:10.1016/j.exger.2014.10.012. PMC 4412760Freely accessible. PMID 25446976. Retrieved 2015-12-28. 
  3. ^ Blagosklonny MV (2013). "Selective anti-cancer agents as anti-aging drugs". Cancer Biology & Therapy. 14 (12): 1092–7. doi:10.4161/cbt.27350. PMC 3912031Freely accessible. PMID 24345884. Retrieved 2015-12-27. 
  4. ^ Slack C, Alic N, Partridge L (2015). "Could cancer drugs provide ammunition against ageing?". Cell Cycle (Georgetown, Tex.). doi:10.1080/15384101.2015.1118905. PMC 4825846Freely accessible. PMID 26587873. Retrieved 2015-12-27. 
  5. ^ 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. doi:10.1158/1078-0432.CCR-07-4622. PMID 18519752. Retrieved 2015-12-30. 
  6. ^ 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. doi:10.1111/acel.12445. PMID 26711051. 
  7. ^ 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. doi:10.1038/nm.4010. PMC 4762215Freely accessible. PMID 26657143. Retrieved 2015-12-23. 
  8. ^ 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. doi:10.1016/S1470-2045(10)70261-8. PMC 3025495Freely accessible. PMID 21094089. Retrieved 2015-12-30. 
  9. ^ 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. doi:10.1007/s00280-014-2530-9. PMID 25053389. Retrieved 2015-12-30. 

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