返老藥

反老藥（Senolytic）是一類受到基礎科學研究以確定其是否能選擇性地殺死衰老細胞並增進人體健康的小分子物質；^[1]這類研究的目標是找出或開發能延緩、阻止、紓解甚至逆轉老化相關疾病的藥物。^[2]^[3]與此類研究相關的一個概念是「凍齡」（senostatic），其意為抑制老化。

研究

目前對返老藥的研究處於初步階段，其中一些已經進入人體試驗階段的早期。^[4]目前多數潛在的返老藥，其原本的目的是用作抗癌藥物，像是用於化療的藥物達沙替尼以及實驗性的小分子藥物那維托克（Navitoclax，ABT-263）等是其中的例子。^[5]^[6]

潛在的反老藥

和FOXO4相關的胜肽。FOXO4可和p53結合以促進細胞衰老（cell senescence），^[7]和FOXO4有競爭效應的胜肽可藉由將p53屏除於細胞核之外而成為返老藥。^[7]
Bcl-2蛋白家族抑制劑，Bcl-2蛋白家族是一類會阻止細胞凋亡的蛋白質。^[8]
七型泛素特異性加工蛋白酶（USP7，英文全名Ubiquitin-specific processing protease 7）抑制劑。^[9]
達沙替尼和槲皮素的混合物。^[8]^[10]
漆黃素^[11]
那維托克（Navitoclax）^[12]
蓽拔醯胺（Piperlongumine）^[13]
阿奇黴素和羅紅黴素^[14]
SSK1（衰老細胞特異性殺手物質1號，senescence-specific killing compound 1）：一種藉由溶酶體中的β-半乳糖苷酶來驅動的吉西他濱（一種細胞毒性的化療藥物）前驅藥物。^[15]

臨床試驗

盡管目前只有少數的返老藥進入臨床測試的階段，但一項人體初步臨床試驗顯示，達沙替尼和槲皮素的混合物在患有糖尿病腎臟病變的人類患者中，確會降低部分組織當中衰老細胞的數量。^[10]

參見

自噬
老化防護（Geroprotector）
維奈托克（Venetoclax）
抗衰老治療（Senotherapy）

參考資料

[1]
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.
[2]
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.
[3]
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.
[4]
Baumann, Kim. Rejuvenating senolytics. Nature Reviews Molecular Cell Biology. 27 July 2018, 19 (9): 543. PMID 30054558. doi:10.1038/s41580-018-0047-5.
[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.
[6]
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]
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]
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. （原始內容存檔 (PDF)於2020-01-13）.
[9]
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]
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.
[11]
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.
[12]
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.
[13]
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.
[14]
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.
[15]
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.

外部連結

Killing 『zombie’ cells to improve health in old age. The Conversation, Dominick Burton, Aston University, 17 March 2017 （頁面存檔備份，存於網際網路檔案館）

Can Destroying Senescent Cells Treat Age-Related Disease? The Scientist, Katarina Zimmer, 1 March, 2020 （頁面存檔備份，存於網際網路檔案館）

[pmid26646499-1] [1]
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.

[pmid25446976-2] [2]
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.

[3] [3]
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.

[4] [4]
Baumann, Kim. Rejuvenating senolytics. Nature Reviews Molecular Cell Biology. 27 July 2018, 19 (9): 543. PMID 30054558. doi:10.1038/s41580-018-0047-5.

[pmid24345884-5] [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.

[pmid26587873-6] [6]
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.

[pmid28340339-7] [7]
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.

[pmid29477613-8] [8]
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. （原始內容存檔 (PDF)於2020-01-13）.

[pmid32064756-9] [9]
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.

[pmid31542391-10] [10]
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.

[pmid30279143-11] [11]
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.

[pmid18519752-12] [12]
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.

[13] [13]
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.

[14] [14]
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.

[15] [15]
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.

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