Senotherapy
From Wikipedia the free encyclopedia
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 2019, much of the research remains preliminary and there are no drugs approved for this purpose.
Types[edit]
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,[17] antibodies and antibody-mediated drug delivery medications. Unlike SASP inhibitors, senolytics can be effective by intermittent rather than continuous application.[18]
- Senomorphics – small molecules that suppress senescent phenotypes without cell killing[19]
- 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][20]
See also[edit]
References[edit]
- ^ a b Childs BG, Durik M, Baker DJ, van Deursen JM (December 2015). "Cellular senescence in aging and age-related disease: from mechanisms to therapy". Nature Medicine. 21 (12): 1424–1435. doi:10.1038/nm.4000. PMC 4748967. PMID 26646499.
- ^ Misra J, Mohanty ST, Madan S, Fernandes JA, Hal Ebetino F, Russell RG, Bellantuono I (March 2016). "Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function". Stem Cells. 34 (3): 756–767. doi:10.1002/stem.2255. PMC 4832316. PMID 26679354.
- ^ a b Xiong S, Patrushev N, Forouzandeh F, Hilenski L, Alexander RW (September 2015). "PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases". Cell Reports. 12 (9): 1391–1399. doi:10.1016/j.celrep.2015.07.047. PMC 4549794. PMID 26299964.
- ^ 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.
- ^ Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C, Carmona-Gutierrez D, et al. (November 2009). "Induction of autophagy by spermidine promotes longevity". Nature Cell Biology. 11 (11): 1305–1314. doi:10.1038/ncb1975. PMID 19801973. S2CID 3126330.
- ^ Pride H, Yu Z, Sunchu B, Mochnick J, Coles A, Zhang Y, et al. (February 2015). "Long-lived species have improved proteostasis compared to phylogenetically-related shorter-lived species". Biochemical and Biophysical Research Communications. 457 (4): 669–675. doi:10.1016/j.bbrc.2015.01.046. PMID 25615820.
- ^ Blackburn EH, Epel ES, Lin J (December 2015). "Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection". Science. 350 (6265): 1193–1198. Bibcode:2015Sci...350.1193B. doi:10.1126/science.aab3389. PMID 26785477.
- ^ Byun HO, Lee YK, Kim JM, Yoon G (October 2015). "From cell senescence to age-related diseases: differential mechanisms of action of senescence-associated secretory phenotypes". BMB Reports. 48 (10): 549–558. doi:10.5483/bmbrep.2015.48.10.122. PMC 4911181. PMID 26129674.
- ^ Young AR, Narita M (March 2009). "SASP reflects senescence". EMBO Reports. 10 (3): 228–230. doi:10.1038/embor.2009.22. PMC 2658552. PMID 19218920.
- ^ Laberge RM, Zhou L, Sarantos MR, Rodier F, Freund A, de Keizer PL, et al. (August 2012). "Glucocorticoids suppress selected components of the senescence-associated secretory phenotype". Aging Cell. 11 (4): 569–578. doi:10.1111/j.1474-9726.2012.00818.x. PMC 3387333. PMID 22404905.
- ^ Liu S, Uppal H, Demaria M, Desprez PY, Campisi J, Kapahi P (December 2015). "Simvastatin suppresses breast cancer cell proliferation induced by senescent cells". Scientific Reports. 5: 17895. Bibcode:2015NatSR...517895L. doi:10.1038/srep17895. PMC 4677323. PMID 26658759.
- ^ Xu M, Tchkonia T, Ding H, Ogrodnik M, Lubbers ER, Pirtskhalava T, et al. (November 2015). "JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age". Proceedings of the National Academy of Sciences of the United States of America. 112 (46): E6301–E6310. Bibcode:2015PNAS..112E6301X. doi:10.1073/pnas.1515386112. PMC 4655580. PMID 26578790.
- ^ Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, et al. (December 2015). "Targeting senescent cells enhances adipogenesis and metabolic function in old age". eLife. 4: e12997. doi:10.7554/eLife.12997. PMC 4758946. PMID 26687007.
- ^ Correia-Melo C, Marques FD, Anderson R, Hewitt G, Hewitt R, Cole J, et al. (April 2016). "Mitochondria are required for pro-ageing features of the senescent phenotype". The EMBO Journal. 35 (7): 724–742. doi:10.15252/embj.201592862. PMC 4818766. PMID 26848154.
60% of the SASP genes which are significantly different between proliferating and senescent were reversed upon mitochondrial depletion, whereas only 5% were exacerbated
- ^ Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, et al. (June 2016). "Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors". Aging Cell. 15 (3): 428–435. doi:10.1111/acel.12445. PMC 4854923. PMID 26711051.
- ^ Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. (August 2015). "The Achilles' heel of senescent cells: from transcriptome to senolytic drugs". Aging Cell. 14 (4): 644–658. doi:10.1111/acel.12344. PMC 4531078. PMID 25754370.
- ^ Soto-Gamez A, Quax WJ, Demaria M (July 2019). "Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions". Journal of Molecular Biology. 431 (15): 2629–2643. doi:10.1016/j.jmb.2019.05.036. PMID 31153901. S2CID 173993854.
- ^ Khosla S, Farr JN, Tchkonia T, Kirkland JL (May 2020). "The role of cellular senescence in ageing and endocrine disease". Nature Reviews. Endocrinology. 16 (5): 263–275. doi:10.1038/s41574-020-0335-y. PMC 7227781. PMID 32161396.
- ^ Fuhrmann-Stroissnigg H, Ling YY, Zhao J, McGowan SJ, Zhu Y, Brooks RW, et al. (September 2017). "Identification of HSP90 inhibitors as a novel class of senolytics". Nature Communications. 8 (1): 422. Bibcode:2017NatCo...8..422F. doi:10.1038/s41467-017-00314-z. PMC 5583353. PMID 28871086.
- ^ Hofmann JW, Zhao X, De Cecco M, Peterson AL, Pagliaroli L, Manivannan J, et al. (January 2015). "Reduced expression of MYC increases longevity and enhances healthspan". Cell. 160 (3): 477–488. doi:10.1016/j.cell.2014.12.016. PMC 4624921. PMID 25619689.
Further reading[edit]
- Kirkland JL, Tchkonia T (2016). "The Way Forward: Translation". Advances in Geroscience. Springer International Publishing. pp. 593–622. doi:10.1007/978-3-319-23246-1_19. ISBN 978-3-319-23245-4.
- Soto-Gamez A, Demaria M (May 2017). "Therapeutic interventions for aging: the case of cellular senescence". Drug Discovery Today. 22 (5): 786–795. doi:10.1016/j.drudis.2017.01.004. PMID 28111332.
- Niedernhofer LJ, Robbins PD (May 2018). "Senotherapeutics for healthy ageing". Nature Reviews. Drug Discovery. 17 (5): 377. doi:10.1038/nrd.2018.44. PMID 29651106.
- Liu JK (May 2022). "Antiaging agents: safe interventions to slow aging and healthy life span extension". Natural Products and Bioprospecting. 12 (1): 18. doi:10.1007/s13659-022-00339-y. PMC 9086005. PMID 35534591.
- Zhang L, Pitcher LE, Prahalad V, Niedernhofer LJ, Robbins PD (January 2022). "Targeting cellular senescence with senotherapeutics: senolytics and senomorphics". The FEBS Journal. 290 (5): 1362–1383. doi:10.1111/febs.16350. PMID 35015337. S2CID 245900209.