Senotherapeutics

from Wikipedia, the free encyclopedia

Senotherapeutic agents are substances that are being researched as possible means of combating cell aging in a targeted manner. Senescence is an altered cell condition that is associated with aging and age-related diseases. The name is derived from the intention of the proposed drug to treat old age. So far there are no approved drugs and no evidence of an age-inhibiting effect. In 2018, the US company Unity Biotechnology recruited test subjects for a first clinical study to test UBX0101, a potential senotherapeutic agent for patients with osteoarthritis.

Various substances with different points of attack are seen as potential senotherapeutic agents:

  • Geroprotectors (in the narrower sense): means / strategies that prevent or reverse the aging process by blocking or preventing triggers of cellular senescence, such as: B. DNA damage , oxidative stress, proteotoxic stress , telomere shortening (this can be reversed , for example, by telomerase activators).
  • SASP inhibitors: agents that interfere with the production of the proinflammatory senescence-associated secretion phenotype (SASP), including:
    1. Glucocorticoids as potent suppressors of selected components of the SASP.
    2. Statins like simvastatin, which can reduce the expression of proinflammatory cytokines (IL-6, IL-8 and MCP-1).
    3. JAK1 / 2 inhibitors such as ruxolitinib .
    4. NF-κB and p38 inhibitors.
    5. IL-1α blockers.
    6. Mitochondrial degradation mechanisms in impaired mitophagy .
  • Senolytics - small molecules that specifically induce cell death in aging cells. They target cell survival mechanisms, in particular anti-apoptotic mechanisms.
  • Senomorphics - small molecules that suppress senescent cell properties without killing the cell.
  • Gene therapy - changing the genetic information in cells of an organism in order to increase their resistance to aging and diseases of the elderly and to extend the life of the organism, for example through telomerase gene therapy, which causes telomere lengthening on the chromosomes of the cells.

See also

Individual evidence

  1. ↑ a b BG Childs, M Durik, DJ Baker, JM van Deursen: Cellular senescence in aging and age-related disease: from mechanisms to therapy . In: Nature Medicine , 21, No. 12, 2015, pp. 1424–1435, PMID 26646499 doi: 10.1038 / nm.4000 , PMC 4748967 (free full text)
  2. ↑ ClinicalTrials.gov of the US National Library of Medicine.Retrieved December 7, 2018.
  3. ↑ Juhi Misra, Sindhu T. Mohanty, Sanjeev Madan, James A. Fernandes, F. Hal Ebetino, R. Graham G. Russell, Ilaria Bellantuono: Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function . In: Stem Cells . tape 34 , 2015, p. 756-767 , doi : 10.1002 / stem.2255 , PMID 26679354 , PMC 4832316 (free full text).
  4. ↑ a b Shiqin Xiong, Nikolay Patrushev, Farshad Forouzandeh, Lula Hilenski, R. Wayne Alexander: PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases . In: Cell Reports . tape 12 , no. 9 , 2015, p. 1391-9 , doi : 10.1016 / j.celrep.2015.07.047 , PMID 26299964 .
  5. ↑ Wahlestedt, M., Pronk, CJ, & Bryder, D. (2015). Concise Review: Hematopoietic Stem Cell Aging and the Prospects for Rejuvenation. Stem cells translational medicine, 4 (2), 186-194.
  6. ↑ Tobias Eisenberg, Heide Knauer, Alexandra Schauer, Sabrina Büttner, Christoph Ruckenstuhl, Didac Carmona-Gutierrez, Julia Ring, Sabrina Schroeder, Christoph Magnes, Lucia Antonacci, Heike Fussi, Luiza Deszcz, Regina Hartl, Elisabeth Schraml, Alfredo Criollo, Evgenia Megalou , Daniela Weiskopf, Peter Laun, Gino Heeren, Michael Breitenbach, Beatrix Grubeck-Loebenstein, Eva Herker, Birthe Fahrenkrog, Kai-Uwe Fröhlich, Frank Sinner, Nektarios Tavernarakis, Nadege Minois, Guido Kroemer, Frank Madeo: Induction of autophagy by spermidine promotes longevity . In: Nature Cell Biology . tape 11 , no. 11 , 2009, p. 1305-14 , doi : 10.1038 / ncb1975 , PMID 19801973 .
  7. ↑ Harrison Pride, Zhen Yu, Bharath Sunchu, Jillian Mochnick, Alexander Coles, Yiqiang Zhang, Rochelle Buffenstein, Peter J. Hornsby, Steven N. Austad, Viviana I. Pérez: Long-lived species have improved proteostasis compared to phylogenetically-related shorter -lived species . In: Biochemical and Biophysical Research Communications . tape 457 , no. 4 , 2015, p. 669-75 , doi : 10.1016 / j.bbrc.2015.01.046 , PMID 25615820 .
  8. ↑ EH Blackburn, ES Epel, J. Lin: human telomere biology: A contributory and interactive factor in aging, disease risks, and protection . In: Science . tape 350 , no. 6265 , 2015, p. 1193-8 , doi : 10.1126 / science.aab3389 , PMID 26785477 .
  9. ^ HO Byun, YK Lee, JM Kim, G. Yoon: From cell senescence to age-related diseases: Differential mechanisms of action of senescence-associated secretory phenotypes . In: BMB reports . tape 48 , no. 10 , 2015, p. 549-58 , doi : 10.5483 / bmbrep.2015.48.10.122 , PMID 26129674 , PMC 4911181 (free full text).
  10. ↑ Andrew RJ Young, Masashi Narita: SASP reflects senescence . In: EMBO Reports . tape 10 , no. 3 , 2009, p. 228–30 , doi : 10.1038 / embor.2009.22 , PMID 19218920 , PMC 2658552 (free full text).
  11. ↑ Remi-Martin Laberge, Lili Zhou, Melissa R. Sarantos, Francis Rodier, Adam Freund, Peter LJ De Keizer, Su Liu, Marco Demaria, Yu-Sheng Cong, Pankaj Kapahi, Pierre-Yves Desprez, Robert E. Hughes, Judith Campisi: Glucocorticoids suppress selected components of the senescence-associated secretory phenotype . In: Aging Cell . tape 11 , no. 4 , 2012, p. 569-78 , doi : 10.1111 / j.1474-9726.2012.00818.x , PMID 22404905 , PMC 3387333 (free full text).
  12. ↑ Su Liu, Harpreet Uppa, Marco Demaria, Pierre-Yves Desprez, Judith Campisi, Pankaj Kapahi: Simvastatin Suppresses breast cancer cell proliferation induced by senescent cells . In: Scientific Reports . tape 5 , 2015, p. 17895 , doi : 10.1038 / srep17895 , PMID 26658759 , PMC 4677323 (free full text).
  13. ↑ Ming Xu, Tamara Tchkonia, Husheng Ding, Mikolaj Ogrodnik, Ellen R. Lubbers, Tamar Pirtskhalava, Thomas A. White, Kurt O. Johnson, Michael B. Stout, Vojtech Mezera, Nino Giorgadze, Michael D. Jensen, Nathan K. Lebrasseur, James L. Kirkland: JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age . In: Proceedings of the National Academy of Sciences . tape 112 , no. 46 , 2015, p. E6301 , doi : 10.1073 / pnas.1515386112 , PMID 26578790 , PMC 4655580 (free full text).
  14. ↑ Ming Xu, Allyson K. Palmer, Husheng Ding, Megan M. Weivoda, Tamar Pirtskhalava, Thomas A. White, Anna Sepe, Kurt O. Johnson, Michael B. Stout, Nino Giorgadze, Michael D. Jensen, Nathan K. Lebrasseur , Tamar Tchkonia, James L. Kirkland: Targeting senescent cells enhances adipogenesis and metabolic function in old age . In: eLife . tape 4 , 2015, doi : 10.7554 / eLife.12997 , PMID 26687007 , PMC 4758946 (free full text).
  15. ↑ DH Kang: Senotherapy for attenuation of cellular senescence in aging and organ implantation . In: Industrial & Engineering Chemistry Research . 2017, doi : 10.1016 / j.jiec.2017.08.053 .
  16. ↑ C. Correia-Melo, FD Marques, R. Anderson, G. Hewitt, R. Hewitt, J. Cole, BM Carroll, S. Miwa, J. Birch, A. Merz, MD Rushton, M. Charles, D. Jurk, SW Tait, R. Czapiewski, L. Greaves, G. Nelson, M. Bohlooly-Y, S. Rodriguez-Cuenca, A. Vidal-Puig, D. Mann, G. Saretzki, G. Quarato, DR Green, PD Adams, T. von Zglinicki, VI Korolchuk, JF Passos: Mitochondria are required for pro-aging features of the senescent phenotype . In: The EMBO Journal . tape 35 , 2016, p. 724-42 , doi : 10.15252 / embj.201592862 , PMID 26848154 ( embopress.org [accessed February 6, 2016]).
  17. ↑ Yi Zhu, Tamara Tchkonia, Heike Fuhrmann-Stroissnigg, HM Dai, Yuan Yuan Ling, Michael B. Stout, Tamar Pirtskhalava, Nino Giorgadze, KO Johnson, CB Giles, Jonathan D. Wren, Laura J. Niedernhofer, Paul D. Robbins , James L. Kirkland ,: Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl-2 Family of Anti-Apoptotic Factors . In: Aging Cell . 2015, doi : 10.1111 / acel.12445 , PMID 26711051 .
  18. ↑ Yi Zhu, Tamara Tchkonia, Tamar Pirtskhalava, Adam Gower, Husheng Ding, Nino Giorgadze, Allyson K. Palmer, Yuji Ikeno, Gene Borden, Marc Lenburg, Steven P. O'Hara, Nicholas F. LaRusso, Jordan D. Miller, Carolyn M. Roos, Grace C. Verzosa, Nathan K. LeBrasseur, Jonathan D. Wren, Joshua N. Farr, Sundeep Khosla, Michael B. Stout, Sara J. McGowan, Heike Fuhrmann-Stroissnigg, Aditi U. Gurkar, Jing Zhao , Debora Colangelo, Akaitz Dorronsoro, Yuan Yuan Ling, Amira S. Barghouthy, Diana C. Navarro, Tokio Sano, Paul D. Robbins, Laura J. Niedernhofer, James L. Kirkland: The Achilles' Heel of Senescent Cells: From Transcriptome to Senolytic Drugs . In: Aging Cell . tape 14 , no. 4 , 2015, p. 644-58 , doi : 10.1111 / acel.12344 , PMID 25754370 , PMC 4531078 (free full text) - ( wiley.com [accessed March 1, 2015]).
  19. ↑ Heike Fuhrmann-Stroissnigg, Yuan Yuan Ling, Jing Zhao, Sara J. McGowan, Yi Zhu, Robert W. Brooks, Diego Grassi, Siobhan Q. Gregg, Jennifer L. Stripay: Identification of HSP90 inhibitors as a novel class of senolytics . In: Nature Communications . tape 8 , no. 1 , September 4, 2017, ISSN  2041-1723 , doi : 10.1038 / s41467-017-00314-z (English, nature.com ).
  20. ↑ Jeffrey W. Hofmann, Xiaoai Zhao, Marco De Cecco, Abigail L. Peterson, Luca Pagliaroli, Jayameenakshi Manivannan, Gene B. Hubbard, Yuji Ikeno, Yongqing Zhang, Bin Feng, Xiaxi Li, Thomas Serre, Wenbo Qi, Holly Van Remmen , Richard A. Miller, Kevin G. Bath, Rafael De Cabo, Haiyan Xu, Nicola Neretti, John M. Sedivy: Reduced Expression of MYC Increases Longevity and Enhances Healthspan . In: Cell . tape 160 , no. 3 , 2015, p. 477-88 , doi : 10.1016 / j.cell.2014.12.016 , PMID 25619689 , PMC 4624921 (free full text).