Quantifying Pharmacologic Suppression of Cellular Senescence: Prevention of Cellular Hypertrophy Versus Preservation of Proliferative Potential

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2010 Feb 17

PMID 20157583

Citations 55

Authors

Zoya N Demidenko

Mikhail V Blagosklonny

Affiliations

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Abstract

Development of agents that suppress aging (aging suppressants) requires quantification of cellular senescence. Cellular senescence in vitro is characterized by a large cell morphology and permanent loss of proliferative potential. When HT-1080 cells were arrested by p21, they continued to grow exponentially in size and became hypertrophic with a 15-fold increase in the protein content per cell. These changes were mirrored by accumulation of GFP (driven by CMV promoter) per cell, which also served as a marker of cellular hypertrophy. Preservation of proliferative potential (competence) was measured by an increase in live cell number, when p21 was switched off. While modestly decreasing hypertrophy in p21-arresrted cells, rapamycin considerably preserved competence, converting senescence into quiescence. Preservation of proliferative potential (competence) correlated with inhibition of S6 phosphorylation by rapamycin. When p21 was switched off, competent cells, by resuming proliferation, became progressively less hypertrophic. Preservation of proliferative potential is a sensitive and quantitative measure of suppression of mTOR-driven senescence.

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References

Blagosklonny M . Aging, stem cells, and mammalian target of rapamycin: a prospect of pharmacologic rejuvenation of aging stem cells. Rejuvenation Res. 2008; 11(4):801-8. DOI: 10.1089/rej.2008.0722. View

Chang B, Broude E, Fang J, Kalinichenko T, Abdryashitov R, Poole J . p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene. 2000; 19(17):2165-70. DOI: 10.1038/sj.onc.1203573. View

Blagosklonny M . Validation of anti-aging drugs by treating age-related diseases. Aging (Albany NY). 2010; 1(3):281-8. PMC: 2806014. DOI: 10.18632/aging.100034. View

Demidenko Z, Blagosklonny M . Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle. 2008; 7(21):3355-61. DOI: 10.4161/cc.7.21.6919. View

Serrano M, Blasco M . Putting the stress on senescence. Curr Opin Cell Biol. 2001; 13(6):748-53. DOI: 10.1016/s0955-0674(00)00278-7. View

Bhaumik D, Scott G, Schokrpur S, Patil C, Orjalo A, Rodier F . MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging (Albany NY). 2010; 1(4):402-11. PMC: 2818025. DOI: 10.18632/aging.100042. View

Kuilman T, Michaloglou C, Vredeveld L, Douma S, van Doorn R, Desmet C . Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008; 133(6):1019-31. DOI: 10.1016/j.cell.2008.03.039. View

Broude E, Swift M, Vivo C, Chang B, Davis B, Kalurupalle S . p21(Waf1/Cip1/Sdi1) mediates retinoblastoma protein degradation. Oncogene. 2007; 26(48):6954-8. DOI: 10.1038/sj.onc.1210516. View

Blagosklonny M . Aging-suppressants: cellular senescence (hyperactivation) and its pharmacologic deceleration. Cell Cycle. 2009; 8(12):1883-7. DOI: 10.4161/cc.8.12.8815. View

10.

Blagosklonny M . Prevention of cancer by inhibiting aging. Cancer Biol Ther. 2008; 7(10):1520-4. DOI: 10.4161/cbt.7.10.6663. View

11.

Acosta J, OLoghlen A, Banito A, Raguz S, Gil J . Control of senescence by CXCR2 and its ligands. Cell Cycle. 2008; 7(19):2956-9. DOI: 10.4161/cc.7.19.6780. View

12.

Rodier F, Coppe J, Patil C, Hoeijmakers W, Munoz D, Raza S . Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009; 11(8):973-9. PMC: 2743561. DOI: 10.1038/ncb1909. View

13.

Coppe J, Kauser K, Campisi J, Beausejour C . Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem. 2006; 281(40):29568-74. DOI: 10.1074/jbc.M603307200. View

14.

Efeyan A, Ortega-Molina A, Velasco-Miguel S, Herranz D, Vassilev L, Serrano M . Induction of p53-dependent senescence by the MDM2 antagonist nutlin-3a in mouse cells of fibroblast origin. Cancer Res. 2007; 67(15):7350-7. DOI: 10.1158/0008-5472.CAN-07-0200. View

15.

Ruggero D, Montanaro L, Ma L, Xu W, Londei P, Cordon-Cardo C . The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med. 2004; 10(5):484-6. DOI: 10.1038/nm1042. View

16.

Blagosklonny M . An anti-aging drug today: from senescence-promoting genes to anti-aging pill. Drug Discov Today. 2007; 12(5-6):218-24. DOI: 10.1016/j.drudis.2007.01.004. View

17.

Kandel E, Chang B, Schott B, Shtil A, Gudkov A, Roninson I . Applications of green fluorescent protein as a marker of retroviral vectors. Somat Cell Mol Genet. 1998; 23(5):325-40. DOI: 10.1007/BF02674280. View

18.

Campisi J . Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005; 120(4):513-22. DOI: 10.1016/j.cell.2005.02.003. View

19.

Shay J, Roninson I . Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene. 2004; 23(16):2919-33. DOI: 10.1038/sj.onc.1207518. View

20.

Pospelova T, Demidenko Z, Bukreeva E, Pospelov V, Gudkov A, Blagosklonny M . Pseudo-DNA damage response in senescent cells. Cell Cycle. 2009; 8(24):4112-8. PMC: 4970747. DOI: 10.4161/cc.8.24.10215. View