返老药
反老药（Senolytic）是一类受到基础科学研究以确定其是否能选择性地杀死衰老细胞并增进人体健康的小分子物质；[1]这类研究的目标是找出或开发能延缓、阻止、纾解甚至逆转老化相关疾病的药物。[2][3]与此类研究相关的一个概念是“冻龄”（senostatic），其意为抑制老化。
研究
[编辑]目前对返老药的研究处于初步阶段，其中一些已经进入人体试验阶段的早期。[4]目前多数潜在的返老药，其原本的目的是用作抗癌药物，像是用于化疗的药物达沙替尼以及实验性的小分子药物那维托克（Navitoclax，ABT-263）等是其中的例子。[5][6]
潜在的反老药
[编辑]- 和FOXO4相关的胜肽。FOXO4可和p53结合以促进细胞衰老（cell senescence），[7]和FOXO4有竞争效应的胜肽可借由将p53屏除于细胞核之外而成为返老药。[7]
- Bcl-2蛋白家族抑制剂，Bcl-2蛋白家族是一类会阻止细胞凋亡的蛋白质。[8]
- 七型泛素特异性加工蛋白酶（USP7，英文全名Ubiquitin-specific processing protease 7）抑制剂。[9]
- 达沙替尼和槲皮素的混合物。[8][10]
- 漆黄素[11]
- 那维托克（Navitoclax）[12]
- 荜拔酰胺（Piperlongumine）[13]
- 阿奇霉素和罗红霉素[14]
- SSK1（衰老细胞特异性杀手物质1号，senescence-specific killing compound 1）：一种借由溶酶体中的β-半乳糖苷酶来驱动的吉西他滨（一种细胞毒性的化疗药物）前驱药物。[15]
临床试验
[编辑]尽管目前只有少数的返老药进入临床测试的阶段，但一项人体初步临床试验显示，达沙替尼和槲皮素的混合物在患有糖尿病肾脏病变的人类患者中，确会降低部分组织当中衰老细胞的数量。[10]
参见
[编辑]参考资料
[编辑]- ^ Childs, Bennett G; Durik, Matej; Baker, Darren J; van Deursen, Jan M. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nature Medicine. 8 December 2015, 21 (12): 1424–1435. PMC 4748967
. PMID 26646499. doi:10.1038/nm.4000.
- ^ Kirkland, James L.; Tchkonia, Tamara. Clinical strategies and animal models for developing senolytic agents. Experimental Gerontology. August 2015, 68: 19–25. PMC 4412760 . PMID 25446976. doi:10.1016/j.exger.2014.10.012.
- ^ van Deursen, Jan M. Senolytic therapies for healthy longevity. Science. 16 May 2019, 364 (6441): 636–637. Bibcode:2019Sci...364..636V. PMC 6816502 . PMID 31097655. doi:10.1126/science.aaw1299.
- ^ Baumann, Kim. Rejuvenating senolytics. Nature Reviews Molecular Cell Biology. 27 July 2018, 19 (9): 543. PMID 30054558. doi:10.1038/s41580-018-0047-5.
- ^ Blagosklonny, Mikhail V. Selective anti-cancer agents as anti-aging drugs. Cancer Biology & Therapy. 28 October 2014, 14 (12): 1092–1097. PMC 3912031 . PMID 24345884. doi:10.4161/cbt.27350.
- ^ Slack, Cathy; Alic, Nazif; Partridge, Linda. Could cancer drugs provide ammunition against aging?. Cell Cycle. 6 January 2016, 15 (2): 153–155. PMC 4825846 . PMID 26587873. doi:10.1080/15384101.2015.1118905.
- ^ 7.0 7.1 Baar, Marjolein P.; Brandt, Renata M.C.; Putavet, Diana A.; Klein, Julian D.D.; Derks, Kasper W.J.; Bourgeois, Benjamin R.M.; Stryeck, Sarah; Rijksen, Yvonne; van Willigenburg, Hester; Feijtel, Danny A.; van der Pluijm, Ingrid; Essers, Jeroen; van Cappellen, Wiggert A.; van IJcken, Wilfred F.; Houtsmuller, Adriaan B.; Pothof, Joris; de Bruin, Ron W.F.; Madl, Tobias; Hoeijmakers, Jan H.J.; Campisi, Judith; de Keizer, Peter L.J. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. March 2017, 169 (1): 132–147.e16. PMC 5556182 . PMID 28340339. doi:10.1016/j.cell.2017.02.031.
- ^ 8.0 8.1 Hernandez-Segura, Alejandra; Nehme, Jamil; Demaria, Marco. Hallmarks of Cellular Senescence (PDF). Trends in Cell Biology. June 2018, 28 (6): 436–453 [2020-07-05]. PMID 29477613. doi:10.1016/j.tcb.2018.02.001. （原始内容存档 (PDF)于2020-01-13）.
- ^ He, Yonghan; Li, Wen; Lv, Dongwen; Zhang, Xin; Zhang, Xuan; Ortiz, Yuma T.; Budamagunta, Vivekananda; Campisi, Judith; Zheng, Guangrong; Zhou, Daohong. Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity. Aging Cell. 16 February 2020, 19 (3): e13117. PMC 7059172 . PMID 32064756. doi:10.1111/acel.13117.
- ^ 10.0 10.1 Hickson, LaTonya J.; Langhi Prata, Larissa G.P.; Bobart, Shane A.; Evans, Tamara K.; Giorgadze, Nino; Hashmi, Shahrukh K.; Herrmann, Sandra M.; Jensen, Michael D.; Jia, Qingyi; Jordan, Kyra L.; Kellogg, Todd A.; Khosla, Sundeep; Koerber, Daniel M.; Lagnado, Anthony B.; Lawson, Donna K.; LeBrasseur, Nathan K.; Lerman, Lilach O.; McDonald, Kathleen M.; McKenzie, Travis J.; Passos, João F.; Pignolo, Robert J.; Pirtskhalava, Tamar; Saadiq, Ishran M.; Schaefer, Kalli K.; Textor, Stephen C.; Victorelli, Stella G.; Volkman, Tammie L.; Xue, Ailing; Wentworth, Mark A.; Wissler Gerdes, Erin O.; Zhu, Yi; Tchkonia, Tamara; Kirkland, James L. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. September 2019, 47: 446–456. PMC 6796530 . PMID 31542391. doi:10.1016/j.ebiom.2019.08.069.
- ^ Yousefzadeh, Matthew J.; Zhu, Yi; McGowan, Sara J.; Angelini, Luise; Fuhrmann-Stroissnigg, Heike; Xu, Ming; Ling, Yuan Yuan; Melos, Kendra I.; Pirtskhalava, Tamar; Inman, Christina L.; McGuckian, Collin; Wade, Erin A.; Kato, Jonathon I.; Grassi, Diego; Wentworth, Mark; Burd, Christin E.; Arriaga, Edgar A.; Ladiges, Warren L.; Tchkonia, Tamara; Kirkland, James L.; Robbins, Paul D.; Niedernhofer, Laura J. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. October 2018, 36: 18–28. PMC 6197652 . PMID 30279143. doi:10.1016/j.ebiom.2018.09.015.
- ^ Shoemaker, Alex R.; Mitten, Michael J.; Adickes, Jessica; Ackler, Scott; Refici, Marion; Ferguson, Debra; Oleksijew, Anatol; O'Connor, Jacqueline M.; Wang, Baole; Frost, David J.; Bauch, Joy; Marsh, Kennan; Tahir, Steven K.; Yang, Xiufen; Tse, Christin; Fesik, Stephen W.; Rosenberg, Saul H.; Elmore, Steven W. Activity of the Bcl-2 Family Inhibitor ABT-263 in a Panel of Small Cell Lung Cancer Xenograft Models. Clinical Cancer Research. 1 June 2008, 14 (11): 3268–3277. PMID 18519752. doi:10.1158/1078-0432.CCR-07-4622.
- ^ Wang, Yingying; Chang, Jianhui; Liu, Xingui; Zhang, Xuan; Zhang, Suping; Zhang, Xin; Zhou, Daohong; Zheng, Guangrong. Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging. 19 November 2016, 8 (11): 2915–2926. PMC 5191878 . PMID 27913811. doi:10.18632/aging.101100.
- ^ Ozsvari, Bela; Nuttall, John R.; Sotgia, Federica; Lisanti, Michael P. Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging. 14 November 2018, 10 (11): 3294–3307. PMC 6286845 . PMID 30428454. doi:10.18632/aging.101633.
- ^ Cai, Yusheng; Zhou, Huanhuan; Zhu, Yinhua; Sun, Qi; Ji, Yin; Xue, Anqi; Wang, Yuting; Chen, Wenhan; Yu, Xiaojie; Wang, Longteng; Chen, Han; Li, Cheng; Luo, Tuoping; Deng, Hongkui. Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell Research. 27 April 2020: 1–16. PMC 7184167 . PMID 32341413. doi:10.1038/s41422-020-0314-9.
