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词条 Senotherapy
释义

  1. Types

  2. References

  3. Further reading

Senotherapy is an early-stage basic research field for development of possible therapeutic agents and strategies to specifically target cellular senescence,[1] an altered cell state associated with ageing and age-related diseases. The name derives from intent of the proposed anti-aging drug to halt "senescence".[1] As of 2017, much of the research remains preliminary and there are no drugs approved for this purpose.

Types

Senotherapeutics include:

  • Geroprotectors – agents/strategies which prevent or reverse the senescent state by preventing triggers of cellular senescence, such as DNA damage,[2][3][4] oxidative stress,[5] proteotoxic stress,[6] telomere shortening [7] (i.e. telomerase activators).
  • SASP inhibitors – agents interfering with pro-inflammatory senescence‐associated secretory phenotype (SASP)[8][9] production, including:
  • #Glucocorticoids as potent suppressors of selected components of the SASP[10]
  • #Statins such as simvastatin, that can reduce the expression of pro-inflammatory cytokines (IL-6, IL-8, and MCP-1)[11]
  • #JAK1/2 inhibitors such as ruxolitinib[12][13]
  • #NF-κB and p38 inhibitors
  • #IL-1α blockers
  • # Mitochondrial depleters in the case of impaired mitophagy[14]
  • Senolytics – small molecules that specifically induce cell death in senescent cells,[15][16] targeting survival pathways and anti-apoptotic mechanisms, antibodies and antibody-mediated drug delivery medications.
  • Senomorphics – small molecules that suppress senescent phenotypes without cell killing[17]
  • Gene therapy strategies – edit the genes of the cells of an organism in order to increase their resistance to aging, senile diseases and to prolong the life of the organism[3][18]

References

1. ^1 {{cite journal | vauthors = Childs BG, Durik M, Baker DJ, van Deursen JM | title = Cellular senescence in aging and age-related disease: from mechanisms to therapy | journal = Nature Medicine | volume = 21 | issue = 12 | pages = 1424–35 | year = 2015 | pmid = 26646499 | pmc = 4748967 | doi = 10.1038/nm.4000 }}
2. ^{{Cite journal|doi=10.1002/stem.2255|title=Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function|journal=Stem Cells|pages=756–767|year=2015|last1=Misra|first1=Juhi|last2=Mohanty|first2=Sindhu T.|last3=Madan|first3=Sanjeev|last4=Fernandes|first4=James A.|last5=Hal Ebetino|first5=F.|last6=Russell|first6=R. Graham G.|last7=Bellantuono|first7=Ilaria|volume=34|issue=3|pmid=26679354|pmc=4832316}}
3. ^1 {{Cite journal|doi=10.1016/j.celrep.2015.07.047|pmid=26299964|pmc=4549794|title=PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases|journal=Cell Reports|volume=12|issue=9|pages=1391–9|year=2015|last1=Xiong|first1=Shiqin|last2=Patrushev|first2=Nikolay|last3=Forouzandeh|first3=Farshad|last4=Hilenski|first4=Lula|last5=Alexander|first5=R. Wayne}}
4. ^Wahlestedt, M., Pronk, C. J., & Bryder, D. (2015). Concise Review: Hematopoietic Stem Cell Aging and the Prospects for Rejuvenation. Stem cells translational medicine, 4(2), 186-194.
5. ^{{Cite journal|doi=10.1038/ncb1975|pmid=19801973|title=Induction of autophagy by spermidine promotes longevity|journal=Nature Cell Biology|volume=11|issue=11|pages=1305–14|year=2009|last1=Eisenberg|first1=Tobias|last2=Knauer|first2=Heide|last3=Schauer|first3=Alexandra|last4=Büttner|first4=Sabrina|last5=Ruckenstuhl|first5=Christoph|last6=Carmona-Gutierrez|first6=Didac|last7=Ring|first7=Julia|last8=Schroeder|first8=Sabrina|last9=Magnes|first9=Christoph|last10=Antonacci|first10=Lucia|last11=Fussi|first11=Heike|last12=Deszcz|first12=Luiza|last13=Hartl|first13=Regina|last14=Schraml|first14=Elisabeth|last15=Criollo|first15=Alfredo|last16=Megalou|first16=Evgenia|last17=Weiskopf|first17=Daniela|last18=Laun|first18=Peter|last19=Heeren|first19=Gino|last20=Breitenbach|first20=Michael|last21=Grubeck-Loebenstein|first21=Beatrix|last22=Herker|first22=Eva|last23=Fahrenkrog|first23=Birthe|last24=Fröhlich|first24=Kai-Uwe|last25=Sinner|first25=Frank|last26=Tavernarakis|first26=Nektarios|last27=Minois|first27=Nadege|last28=Kroemer|first28=Guido|last29=Madeo|first29=Frank}}
6. ^{{Cite journal|doi=10.1016/j.bbrc.2015.01.046|pmid=25615820|title=Long-lived species have improved proteostasis compared to phylogenetically-related shorter-lived species|journal=Biochemical and Biophysical Research Communications|volume=457|issue=4|pages=669–75|year=2015|last1=Pride|first1=Harrison|last2=Yu|first2=Zhen|last3=Sunchu|first3=Bharath|last4=Mochnick|first4=Jillian|last5=Coles|first5=Alexander|last6=Zhang|first6=Yiqiang|last7=Buffenstein|first7=Rochelle|last8=Hornsby|first8=Peter J.|last9=Austad|first9=Steven N.|last10=Pérez|first10=Viviana I.}}
7. ^{{Cite journal|doi=10.1126/science.aab3389|pmid=26785477|title=Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection|journal=Science|volume=350|issue=6265|pages=1193–8|year=2015|last1=Blackburn|first1=E. H.|last2=Epel|first2=E. S.|last3=Lin|first3=J.}}
8. ^{{cite journal|pmid=26129674|year=2015|author1=Byun|first1=H. O.|title=From cell senescence to age-related diseases: Differential mechanisms of action of senescence-associated secretory phenotypes|journal=BMB Reports|volume=48|issue=10|pages=549–58|last2=Lee|first2=Y. K.|last3=Kim|first3=J. M.|last4=Yoon|first4=G|doi=10.5483/bmbrep.2015.48.10.122|pmc=4911181}}
9. ^{{Cite journal|doi=10.1038/embor.2009.22|pmid=19218920|title=SASP reflects senescence|journal=EMBO Reports|volume=10|issue=3|pages=228–30|year=2009|last1=Young|first1=Andrew R J|last2=Narita|first2=Masashi|pmc=2658552}}
10. ^{{Cite journal|doi=10.1111/j.1474-9726.2012.00818.x|pmid=22404905|title=Glucocorticoids suppress selected components of the senescence-associated secretory phenotype|journal=Aging Cell|volume=11|issue=4|pages=569–78|year=2012|last1=Laberge|first1=Remi-Martin|last2=Zhou|first2=Lili|last3=Sarantos|first3=Melissa R.|last4=Rodier|first4=Francis|last5=Freund|first5=Adam|last6=De Keizer|first6=Peter L. J.|last7=Liu|first7=Su|last8=Demaria|first8=Marco|last9=Cong|first9=Yu-Sheng|last10=Kapahi|first10=Pankaj|last11=Desprez|first11=Pierre-Yves|last12=Hughes|first12=Robert E.|last13=Campisi|first13=Judith|pmc=3387333}}
11. ^{{Cite journal|doi=10.1038/srep17895|pmid=26658759|pmc=4677323|title=Simvastatin suppresses breast cancer cell proliferation induced by senescent cells|journal=Scientific Reports|volume=5|pages=17895|year=2015|last1=Liu|first1=Su|last2=Uppal|first2=Harpreet|last3=Demaria|first3=Marco|last4=Desprez|first4=Pierre-Yves|last5=Campisi|first5=Judith|last6=Kapahi|first6=Pankaj}}
12. ^{{Cite journal|doi=10.1073/pnas.1515386112|title=JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age|journal=Proceedings of the National Academy of Sciences|volume=112|issue=46|pages=E6301–10|year=2015|last1=Xu|first1=Ming|last2=Tchkonia|first2=Tamara|last3=Ding|first3=Husheng|last4=Ogrodnik|first4=Mikolaj|last5=Lubbers|first5=Ellen R.|last6=Pirtskhalava|first6=Tamar|last7=White|first7=Thomas A.|last8=Johnson|first8=Kurt O.|last9=Stout|first9=Michael B.|last10=Mezera|first10=Vojtech|last11=Giorgadze|first11=Nino|last12=Jensen|first12=Michael D.|last13=Lebrasseur|first13=Nathan K.|last14=Kirkland|first14=James L.|pmid=26578790|pmc=4655580}}
13. ^{{Cite journal|doi=10.7554/eLife.12997|title=Targeting senescent cells enhances adipogenesis and metabolic function in old age|journal=eLife|volume=4|pages=e12997|year=2015|last1=Xu|first1=Ming|last2=Palmer|first2=Allyson K|last3=Ding|first3=Husheng|last4=Weivoda|first4=Megan M|last5=Pirtskhalava|first5=Tamar|last6=White|first6=Thomas A|last7=Sepe|first7=Anna|last8=Johnson|first8=Kurt O|last9=Stout|first9=Michael B|last10=Giorgadze|first10=Nino|last11=Jensen|first11=Michael D|last12=Lebrasseur|first12=Nathan K|last13=Tchkonia|first13=Tamar|last14=Kirkland|first14=James L|pmid=26687007|pmc=4758946}}
14. ^{{cite journal | vauthors = Correia-Melo C, Marques FD, Anderson R, Hewitt G, Hewitt R, Cole J, Carroll BM, Miwa S, Birch J, Merz A, Rushton MD, Charles M, Jurk D, Tait SW, Czapiewski R, Greaves L, Nelson G, Bohlooly-Y M, Rodriguez-Cuenca S, Vidal-Puig A, Mann D, Saretzki G, Quarato G, Green DR, Adams PD, von Zglinicki T, Korolchuk VI, Passos JF | title = Mitochondria are required for pro-ageing features of the senescent phenotype | journal = The EMBO Journal | volume = 35| issue = 7| pages = 724–42| year = 2016 | pmid = 26848154 | pmc = 4818766 | doi = 10.15252/embj.201592862 | url = http://emboj.embopress.org/content/early/2016/02/02/embj.201592862 | accessdate = 2016-02-06 | quote = 60% of the SASP genes which are significantly different between proliferating and senescent were reversed upon mitochondrial depletion, whereas only 5% were exacerbated}}
15. ^{{cite journal|last1=Zhu|first1=Yi|last2=Tchkonia|first2=T|last3=Fuhrmann-Stroissnigg|first3=H|last4=Dai|first4=HM|last5=Ling|first5=YY|last6=Stout|first6=MB|last7=Pirtskhalava|first7=T|last8=Giorgadze|first8=N|last9=Johnson|first9=KO|last10=Giles|first10=CB|last11=Wren|first11=JD|last12=Niedernhofer|first12=LJ|last13=Robbins|first13=PD|last14=Kirkland|first14=JL|title=Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl-2 Family of Anti-Apoptotic Factors|journal=Aging Cell|volume=15|issue=3|pages=428–35|date=2015|pmid=26711051|pmc=4854923|doi=10.1111/acel.12445}}
16. ^{{cite journal |first1=Yi |last1= Zhu|first2=Tamara |last2= Tchkonia|first3=Tamar |last3= Pirtskhalava|first4=Adam |last4= Gower|first5=Husheng |last5= Ding|first6=Nino |last6= Giorgadze|first7=Allyson K. |last7= Palmer|first8=Yuji |last8= Ikeno |first9=Gene |last9= Borden|first10=Marc |last10= Lenburg|first11=Steven P. |last11= O'Hara|first12=Nicholas F. |last12= LaRusso|first13=Jordan D. |last13= Miller|first14=Carolyn M. |last14= Roos|first15=Grace C. |last15= Verzosa|first16=Nathan K. |last16= LeBrasseur|first17=Jonathan D. |last17= Wren|first18=Joshua N. |last18= Farr|first19=Sundeep |last19= Khosla|first20=Michael B. |last20= Stout|first21=Sara J. |last21= McGowan|first22=Heike |last22= Fuhrmann-Stroissnigg|first23=Aditi U. |last23= Gurkar|first24=Jing |last24= Zhao|first25=Debora |last25= Colangelo|first26=Akaitz |last26= Dorronsoro|first27=Yuan Yuan |last27= Ling|first28=Amira S. |last28= Barghouthy|first29=Diana C. |last29= Navarro|first30=Tokio |last30= Sano|first31=Paul D. |last31= Robbins|first32=Laura J. |last32= Niedernhofer|first33=James L. |last33= Kirkland |title=The Achilles' Heel of Senescent Cells: From Transcriptome to Senolytic Drugs |journal=Aging Cell |volume= 14|issue= 4|pages= 644–58|year=2015 |doi=10.1111/acel.12344 |pmid= 25754370|pmc=4531078}}
17. ^{{Cite journal|last=Fuhrmann-Stroissnigg|first=Heike|last2=Ling|first2=Yuan Yuan|last3=Zhao|first3=Jing|last4=McGowan|first4=Sara J.|last5=Zhu|first5=Yi|last6=Brooks|first6=Robert W.|last7=Grassi|first7=Diego|last8=Gregg|first8=Siobhan Q.|last9=Stripay|first9=Jennifer L.|date=2017-09-04|title=Identification of HSP90 inhibitors as a novel class of senolytics|journal=Nature Communications|language=En|volume=8|issue=1|pages=422|doi=10.1038/s41467-017-00314-z|pmid=28871086|pmc=5583353|issn=2041-1723}}
18. ^{{Cite journal|doi=10.1016/j.cell.2014.12.016|pmid=25619689|title=Reduced Expression of MYC Increases Longevity and Enhances Healthspan|journal=Cell|volume=160|issue=3|pages=477–88|year=2015|last1=Hofmann|first1=Jeffrey W.|last2=Zhao|first2=Xiaoai|last3=De Cecco|first3=Marco|last4=Peterson|first4=Abigail L.|last5=Pagliaroli|first5=Luca|last6=Manivannan|first6=Jayameenakshi|last7=Hubbard|first7=Gene B.|last8=Ikeno|first8=Yuji|last9=Zhang|first9=Yongqing|last10=Feng|first10=Bin|last11=Li|first11=Xiaxi|last12=Serre|first12=Thomas|last13=Qi|first13=Wenbo|last14=Van Remmen|first14=Holly|last15=Miller|first15=Richard A.|last16=Bath|first16=Kevin G.|last17=De Cabo|first17=Rafael|last18=Xu|first18=Haiyan|last19=Neretti|first19=Nicola|last20=Sedivy|first20=John M.|pmc=4624921}}

Further reading

  • {{cite book | vauthors = Kirkland JL, Tchkonia T | title = The Way Forward: Translation | journal = Advances in Geroscience | pages = 593–622 | year = 2016 | doi = 10.1007/978-3-319-23246-1_19 | publisher = Springer International Publishing| isbn = 978-3-319-23245-4 }}
  • {{cite journal | vauthors = Soto-Gamez A, Demaria M | title = Therapeutic interventions for aging: the case of cellular senescence | journal = Drug Discovery Today | volume = 22 | issue = 5 | pages = 786–795| year = 2017 | doi = 10.1016/j.drudis.2017.01.004 | pmid = 28111332 | isbn = }}
  • {{cite journal | vauthors = Niedernhofer LJ, Robbins PD | title = Senotherapeutics for healthy ageing | journal = Nature Reviews Drug Discovery

| volume = 17 | issue = 5 | pages = 377| year = 2018 | doi = 10.1038/nrd.2018.44 | pmid = 29651106 | isbn = }}

2 : Anti-aging substances|Senescence
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