Abstract
Cellular senescence, which is characterized by permanent proliferation arrest, has become an important target for the amelioration of various human diseases. The activity of senescent cells is mainly related to the senescence-associated secretory phenotype (SASP). The SASP can cause chronic inflammation in local tissues and organs through autocrine and paracrine mechanisms, and a series of factors secreted by senescent cells can deteriorate the cellular microenvironment, promoting tumor formation and exacerbating aging-related diseases. Therefore, avoiding the promotion of cancer is an urgent problem. In recent years, increased attention has been given to the mechanistic study of microRNAs in senescence. As important posttranscriptional regulators, microRNAs possess unique tissue-specific expression in senescence. MicroRNAs can regulate the SASP by regulating proteins in the senescence signaling pathway, the reverse transcriptase activity of telomerase, the generation of reactive oxygen species and oxidative damage to mitochondria. Numerous studies have confirmed that removing senescent cells does not cause significant side effects, which also opens the door to the development of treatment modalities against senescent cells. Herein, this review discusses the double-edged sword of cellular senescence in tumors and aging-related diseases and emphasizes the roles of microRNAs in regulating the SASP, especially the potential of microRNAs to be used as therapeutic targets to inhibit senescence, giving rise to novel therapeutic approaches for the treatment of aging-associated diseases.
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References
Acosta JC, Banito A, Wuestefeld T et al (2013) A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15:978–990. https://doi.org/10.1038/ncb2784
Adamczyk A, Pastille E, Kehrmann J et al (2021) GPR15 facilitates recruitment of regulatory T cells to promote colorectal cancer. Cancer Res 81:2970–2982. https://doi.org/10.1158/0008-5472
Astrike-Davis EM, Coryell P, Loeser RF (2022) Targeting cellular senescence as a novel treatment for osteoarthritis. Curr Opin Pharmacol 64:102213. https://doi.org/10.1016/j.coph.2022.102213
Bao X, Wang Z, Jia Q et al (2021) HIF-1α-mediated miR-623 regulates apoptosis and inflammatory responses of nucleus pulposus induced by oxidative stress via targeting TXNIP. Oxid Med Cell Longev 2021:6389568. https://doi.org/10.1155/2021/6389568
Bhaumik D, Scott GK, Schokrpur S et al (2009) (2009) MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging (albany NY) 1(4):402–411
Bilsland AE, Revie J, Keith WN (2013) MicroRNA and senescence: the senectome, integration and distributed control. Crit Rev Oncog 18:373–390
Birner P, Egger G, Merkel O et al (2015) JunB and PTEN in prostate cancer: ‘loss is nothing else than change.’ Cell Death Differ 22:522–523. https://doi.org/10.1038/cdd.2014.232
Bonifacio LN, Jarstfer MB (2010) MiRNA profile associated with replicative senescence, extended cell culture, and ectopic telomerase expression in human foreskin fibroblasts. PLoS ONE 5:e12519. https://doi.org/10.1371/journal.pone.0012519
Budzinska M, Owczarz M, Pawlik-Pachucka E et al (2016) miR-96, miR-145 and miR-9 expression increases, and IGF-1R and FOXO1 expression decreases in peripheral blood mononuclear cells of aging humans. BMC Geriatr 16:200. https://doi.org/10.1186/s12877-016-0379-y
Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120:513–522. https://doi.org/10.1016/j.cell.2005.02.003
Chen F, Long Q, Fu D et al (2018) Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance. Nat Commun 9:4315. https://doi.org/10.1038/s41467-018-06860-4
Chibaya L, Snyder J, Ruscetti M (2022) Senescence and the tumor-immune landscape: implications for cancer immunotherapy. Semin Cancer Biol. https://doi.org/10.1016/j.semcancer.2022.02.005
Childs BG, Baker DJ, Wijshake T et al (2016) Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354:472–477. https://doi.org/10.1126/science.aaf6659
Collado M, Gil J, Efeyan A et al (2005) Tumour biology: senescence in premalignant tumours. Nature 436:642. https://doi.org/10.1038/436642a
Coppe JP, Patil CK, Rodier F et al (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868. https://doi.org/10.1371/journal.pbio.0060301
Cuollo L, Antonangeli F, Santoni A, Soriani A (2020) The senescence-associated secretory phenotype (SASP) in the challenging future of cancer therapy and age-related diseases. Biology (basel) 9:485. https://doi.org/10.3390/biology9120485
Da Silva-Álvarez S, Guerra-Varela J, Sobrido-Cameán D et al (2020) Cell senescence contributes to tissue regeneration in zebrafish. Aging Cell 19:e13052. https://doi.org/10.1111/acel.13052
Demaria M, Ohtani N, Youssef SA et al (2014) An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 31:722–733. https://doi.org/10.1016/j.devcel.2014.11.012
Deng L, Ren R, Liu Z et al (2019) Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis. Nat Commun 10:3329. https://doi.org/10.1038/s41467-019-10831-8
Dhomen N, Reis-Filho JS, da Rocha DS et al (2009) Oncogenic braf induces melanocyte senescence and melanoma in mice. Cancer Cell 15:294–303. https://doi.org/10.1016/j.ccr.2009.02.022
DuPont JJ, McCurley A, Davel AP et al (2016) Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging. JCI Insight 1:e88942. https://doi.org/10.1172/jci.insight.88942
Ewald JA, Jarrard DF (2012) Decreased skp2 expression is necessary but not sufficient for therapy-induced senescence in prostate cancer. Transl Oncol 5:278–287. https://doi.org/10.1593/tlo.12181
Fane M, Weeraratna AT (2020) How the ageing microenvironment influences tumour progression. Nat Rev Cancer 20:89–106. https://doi.org/10.1038/s41568-019-0222-9
Farr JN, Xu M, Weivoda MM et al (2017) Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 23:1072–1079. https://doi.org/10.1038/nm.4385
Fitsiou E, Soto-Gamez A, Demaria M (2022) Biological functions of therapy-induced senescence in cancer. Semin Cancer Biol 81:5–13. https://doi.org/10.1016/j.semcancer.2021.03.021
Foley NH, O’Neill LA (2012) miR-107: a toll-like receptor-regulated miRNA dysregulated in obesity and type II diabetes. J Leukoc Biol 92:521–527. https://doi.org/10.1189/jlb.0312160
Gaudet AD, Fonken LK, Watkins LR et al (2018) MicroRNAs: roles in regulating neuroinflammation. Neuroscientist 24:221–245. https://doi.org/10.1177/1073858417721150
Gaudet AD, Fonken LK, Ayala MT et al (2021) Aging and miR-155 in mice influence survival and neuropathic pain after spinal cord injury. Brain Behav Immun 97:365–370. https://doi.org/10.1016/j.bbi.2021.07.003
Georgilis A, Klotz S, Hanley CJ et al (2018) PTBP1-mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells. Cancer Cell 34:85-102.e9
Gorgoulis V, Adams PD, Alimonti A et al (2019) Cellular senescence: defining a path forward. Cell 179:813–827. https://doi.org/10.1016/j.cell.2019.10.005
Goulet CR, Champagne A, Bernard G et al (2019) Cancer-associated fibroblasts induce epithelial-mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling. BMC Cancer 19:137. https://doi.org/10.1186/s12885-019-5353-6
Guerrero A, De Strooper B, Arancibia-Cárcamo IL (2021) Cellular senescence at the crossroads of inflammation and Alzheimer’s disease. Trends Neurosci 44:714–727. https://doi.org/10.1016/j.tins.2021.06.007
Hao Y, Zhou Q, Ma J, Zhao Y, Wang S (2016) miR-146a is upregulated during retinal pigment epithelium (RPE)/choroid aging in mice and represses IL-6 and VEGF-a expression in RPE cells. J Clin Exp Ophthalmol 7:562. https://doi.org/10.4172/2155-9570.1000562
Hou J, Cui C, Kim S et al (2018) Ginsenoside F1 suppresses astrocytic senescence-associated secretory phenotype. Chem Biol Interact 283:75–83. https://doi.org/10.1016/j.cbi.2018.02.002
Islam MR, Kaurani L, Berulava T et al (2021) A microRNA signature that correlates with cognition and is a target against cognitive decline. EMBO Mol Med. https://doi.org/10.15252/emmm.202013659
Ito T, Yagi S, Yamakuchi M (2010) MicroRNA-34a regulation of endothelial senescence. Biochem Biophys Res Commun 398:735–740. https://doi.org/10.1016/j.bbrc.2010.07.012
Jeon OH, Kim C, Laberge RM et al (2017) Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 23:775–781. https://doi.org/10.1038/nm.4324
Jin HM, Kim TJ, Choi JH et al (2014) MicroRNA-155 as a proinflammatory regulator via SHIP-1 down-regulation in acute gouty arthritis. Arthritis Res Ther 16:R88. https://doi.org/10.1186/ar4531
Justice JN, Nambiar AM, Tchkonia T et al (2019) Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40:554–563. https://doi.org/10.1016/j.ebiom.2018.12.052
Kabir TD, Leigh RJ, Tasena H et al (2016) A miR-335/COX-2/PTEN axis regulates the secretory phenotype of senescent cancer-associated fibroblasts. Aging (albany NY) 8:1608–1635
Kang D, Shin J, Cho Y et al (2019) Stress-activated miR-204 governs senescent phenotypes of chondrocytes to promote osteoarthritis development. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aar6659
Kim TH, Kim JY, Bae J et al (2021) Korean red ginseng prevents endothelial senescence by downregulating the HO-1/NF-κB/miRNA-155-5p/eNOS pathway. J Ginseng Res 45:344–353. https://doi.org/10.1016/j.jgr.2020.08.002
Krichevsky AM, Sonntag KC, Isacson O et al (2006) Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 24:857–864. https://doi.org/10.1634/stemcells.2005-0441
Krizhanovsky V, Yon M, Dickins RA et al (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134:657–667. https://doi.org/10.1016/j.cell.2008.06.049
Lee C-T, Risom T, Strauss WM (2007) Evolutionary conservation of microRNA regulatory circuits: an examination of microRNA gene complexity and conserved microRNA-target interactions through metazoan phylogeny. DNA Cell Biol 26:209–218. https://doi.org/10.1089/dna.2006.0545
Leu JD, Wang CY, Lo CC et al (2021) Involvement of c-Myc in low dose radiation-induced senescence enhanced migration and invasion of unirradiated cancer cells. Aging (albany NY). https://doi.org/10.18632/aging.203527
Li R, Zhang X, Tian X et al (2017) Triptolide inhibits tumor growth by induction of cellular senescence. Oncol Rep 37:442–448. https://doi.org/10.3892/or.2016.5258
Li Y, Zhao H, Huang X et al (2018) Embryonic senescent cells re-enter cell cycle and contribute to tissues after birth. Cell Res 28:775–778. https://doi.org/10.1038/s41422-018-0050-6
Liu D, Hornsby PJ (2007) Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res 67:3117–3126. https://doi.org/10.1158/0008-5472.CAN-06-3452
Lu J, Li S, Li X et al (2021) Declined miR-181a-5p expression is associated with impaired natural killer cell development and function with aging. Aging Cell 20:e13353. https://doi.org/10.1111/acel.13353
Meyer K, Hodwin B, Ramanujam D et al (2016) Essential role for premature senescence of myofibroblasts in myocardial fibrosis. J Am Coll Cardiol 67:2018–2028. https://doi.org/10.1016/j.jacc.2016.02.047
Migdalska-Sęk M, Góralska K, Jabłoński S et al (2020) Evaluation of the relationship between the IL-17A gene expression level and regulatory miRNA-9 in relation to tumor progression in patients with non-small cell lung cancer: a pilot study. Mol Biol Rep 47:583–592. https://doi.org/10.1007/s11033-019-05164-0
Milczarek M (2020) The premature senescence in breast cancer treatment strategy. Cancers (basel) 12:1815. https://doi.org/10.3390/cancers12071815
Milczarek M, Wiktorska K, Mielczarek L et al (2018) Autophagic cell death and premature senescence: new mechanism of 5-fluorouracil and sulforaphane synergistic anticancer effect in MDA-MB-231 triple negative breast cancer cell line. Food Chem Toxicol 111:1–8. https://doi.org/10.1016/j.fct.2017.10.056
Min HK, Kapoor A, Fuchs M et al (2012) Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab 15:665–674. https://doi.org/10.1016/j.cmet.2012.04.004
Mongiardi MP, Radice G, Piras M et al (2019) Axitinib exposure triggers endothelial cells senescence through ROS accumulation and ATM activation. Oncogene 38:5413–5424. https://doi.org/10.1038/s41388-019-0798-2
Moreno-Guerrero SS, Ramírez-Pacheco A, Rocha-Ramírez LM et al (2021) Association of genetic polymorphisms and serum levels of IL-6 and IL-8 with the prognosis in children with neuroblastoma. Cancers (basel) 13:529. https://doi.org/10.3390/cancers13030529
Muñoz-Espín D, Cañamero M, Maraver A et al (2013) Programmed cell senescence during mammalian embryonic development. Cell 155:1104–1118. https://doi.org/10.1016/j.cell.2013.10.019
Nacarelli T, Fukumoto T, Zundell JA et al (2020) NAMPT inhibition suppresses cancer stem-like cells associated with therapy-induced senescence in ovarian cancer. Cancer Res 80:890–900. https://doi.org/10.1158/0008-5472
Nagai N, Kudo Y, Aki D et al (2021) Immunomodulation by inflammation during liver and gastrointestinal tumorigenesis and aging. Int J Mol Sci 22:2238. https://doi.org/10.3390/ijms22052238
Navarro F, Lieberman J (2015) miR-34 and p53: new insights into a complex functional relationship. PLoS ONE 10:e0132767. https://doi.org/10.1371/journal.pone.0132767
Naylor RM, Baker DJ, van Deursen JM (2013) Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin Pharmacol Ther 93:105–116. https://doi.org/10.1038/clpt.2012.193
Nelson PT, Wang WX (2010) MiR-107 is reduced in Alzheimer’s disease brain neocortex: validation study. J Alzheimers Dis 21:75–79. https://doi.org/10.3233/JAD-2010-091603
NorenHooten N, Abdelmohsen K, Gorospe M et al (2010) microRNA expression patterns reveal differential expression of target genes with age. PLoS ONE 5:e10724. https://doi.org/10.1371/journal.pone.0010724
Oubaha M, Miloudi K, Dejda A et al (2016) Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aaf9440
Ovadya Y, Krizhanovsk V (2014) Senescent cells: SASP ected drivers of age-related pathologies. Biogerontology 15:627–642. https://doi.org/10.1007/s10522-014-9529-9
Owczarz M, Budzinska M, Domaszewska-Szostek A et al (2017) miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans. Exp Biol Med (maywood) 242:1453–1461. https://doi.org/10.1177/1535370217720884
Panda S, Isbatan A, Adami GR (2008) Modification of the ATM/ATR directed DNA damage response state with aging and long after hepatocyte senescence induction in vivo. Mech Ageing Dev 129:332–340. https://doi.org/10.1016/j.mad.2008.02.014
Piegari E, Cozzolino A, Ciuffreda LP et al (2020) Cardioprotective effects of miR-34a silencing in a rat model of doxorubicin toxicity. Sci Rep 10:12250. https://doi.org/10.1038/s41598-020-69038-3
Prattichizzo F, De Nigris V, La Sala L et al (2016) “Inflammaging” as a druggable target: a senescence-associated secretory phenotype-centered view of type 2 diabetes. Oxid Med Cell Longev 2016:1810327. https://doi.org/10.1155/2016/1810327
Qi F, Jiang X, Tong T et al (2020) MiR-204 inhibits inflammation and cell apoptosis in retinopathy rats with diabetic retinopathy by regulating Bcl-2 and SIRT1 expressions. Eur Rev Med Pharmacol Sci. https://doi.org/10.26355/eurrev_202006_21631
Raucci A, Vinci MC (2020) miR-34a: a promising target for inflammaging and age-related diseases. Int J Mol Sci 21:8293. https://doi.org/10.3390/ijms21218293
Roger L, Tomas F, Gire V (2021) Mechanisms and regulation of cellular senescence. Int J Mol Sci 22:13173. https://doi.org/10.3390/ijms222313173
Salminen A, Kauppinen A, Kai K (2012) Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal 24:835–845. https://doi.org/10.1016/j.cellsig.2011.12.006
Salminen A, Kauppinen A, Kaarniranta K (2018) Myeloid-derived suppressor cells (MDSC): an important partner in cellular/tissue senescence. Biogerontology 19:325–339. https://doi.org/10.1007/s10522-018-9762-8
Sanguinete MMM, Oliveira PH, Martins-Filho A et al (2017) Serum IL-6 and IL-8 correlate with prognostic factors in ovarian cancer. Immunol Invest 46:677–688. https://doi.org/10.1080/08820139.2017.1360342
Santoro R, Blandino G (2010) p53: the pivot between cell cycle arrest and senescence. Cell Cycle 9:4262–4263. https://doi.org/10.4161/cc.9.21.13853
Sapochnik M, Fuertes M, Arzt E (2017) Programmed cell senescence: role of IL-6 in the pituitary. J Mol Endocrinol 58:R241–R253. https://doi.org/10.1530/JME-17-0026
Shen M, Dong C, Ruan X et al (2019) Chemotherapy-induced extracellular vesicle miRNAs promote breast cancer stemness by targeting ONECUT2. Cancer Res 79:3608–3621. https://doi.org/10.1158/0008-5472.CAN-18-4055
Slabáková E, Culig Z, Remšík J et al (2017) Alternative mechanisms of miR-34a regulation in cancer. Cell Death Dis 8:e3100. https://doi.org/10.1038/cddis.2017.495
Storer M, Mas A, Robert-Moreno A et al (2013) Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155:1119–1130. https://doi.org/10.1016/j.cell.2013.10.041
Tabasso AFS, Jones DJL, Jones GDD et al (2019) Radiotherapy-Induced senescence and its effects on responses to treatment. Clin Oncol (r Coll Radiol) 31:283–289. https://doi.org/10.1016/j.clon.2019.02.003
Van Deursen JM (2019) Senolytic therapies for healthy longevity. Science 364:636–637. https://doi.org/10.1126/science.aaw1299
Wan Y, McDaniel K, Wu N et al (2017) Regulation of cellular senescence by miR-34a in alcoholic liver injury. Am J Pathol 187:2788–2798. https://doi.org/10.1016/j.ajpath.2017.08.027
Xiao D, Gao HX (2019) Mechanism of miR-107-targeting of regulator of G-protein signaling 4 in hepatocellular carcinoma. Oncol Lett 18:5145–5154. https://doi.org/10.3892/ol.2019.10857
Xu S, Wu W, Huang H et al (2019) The p53/miRNAs/Ccna2 pathway serves as a novel regulator of cellular senescence: complement of the canonical p53/p21 pathway. Aging Cell 18:e12918. https://doi.org/10.1111/acel.12918
Yamada H, Suzuki K, Ichino N et al (2013) Associations between circulating micro-RNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin Chim Acta 424:99–103. https://doi.org/10.1016/j.cca.2013.05.021
Yasuda T, Koiwa M, Yonemura A et al (2021) Inflammation-driven senescence-associated secretory phenotype in cancer-associated fibroblasts enhances peritoneal dissemination. Cell Rep 34:108779. https://doi.org/10.1016/j.celrep.2021.108779
Ye L, Wang F, Wu H et al (2021) Functions and targets of miR-335 in cancer. Onco Targets Ther 14:3335–3349. https://doi.org/10.2147/OTT.S305098
Yu S, Wang X, Geng P et al (2017) Melatonin regulates PARP1 to control the senescence-associated secretory phenotype (SASP) in human fetal lung fibroblast cells. J Pineal Res. https://doi.org/10.1111/jpi.12405
Zhang H, Qi M, Li S et al (2012) microRNA-9 targets matrix metalloproteinase 14 to inhibit invasion, metastasis, and angiogenesis of neuroblastoma cells. Mol Cancer Ther 11:1454–1466. https://doi.org/10.1158/1535-7163
Zhang J, Jia J, Zhao L et al (2016) Down-regulation of microRNA-9 leads to activation of IL-6/Jak/STAT3 pathway through directly targeting IL-6 in HeLa cell. Mol Carcinog 55:732–742. https://doi.org/10.1002/mc.22317
Zhang LM, Zhang J, Zhang Y et al (2019a) Interleukin-18 promotes fibroblast senescence in pulmonary fibrosis through down-regulating Klotho expression. Biomed Pharmacother 113:108756. https://doi.org/10.1016/j.biopha.2019.108756
Zhang P, Yang X, Wang L et al (2019b) Overexpressing miR335 inhibits DU145 cell proliferation by targeting early growth response 3 in prostate cancer. Int J Oncol 54:1981–1994. https://doi.org/10.3892/ijo.2019.4778
Zhao Y, Wu Z, Chanal M et al (2020) Oncogene-induced senescence limits the progression of pancreatic neoplasia through production of activin A. Cancer Res 80:3359–3371. https://doi.org/10.1158/0008-5472
Zhong H, Zhou Z, Guo L et al (2021) The miR-623/CXCL12 axis inhibits LPS-induced nucleus pulposus cell apoptosis and senescence. Mech Ageing Dev 194:111417. https://doi.org/10.1016/j.mad.2020.111417
Zhu J, Yang S, Qi Y et al (2022) Stem cell-homing hydrogel-based miR-29b-5p delivery promotes cartilage regeneration by suppressing senescence in an osteoarthritis rat model. Sci Adv. https://doi.org/10.1126/sciadv.abk0011
Zuccolo E, Badi I, Scavello F et al (2020) The microRNA-34a-Induced senescence-associated secretory phenotype (SASP) favors vascular smooth muscle cells calcification. Int J Mol Sci 21:4454. https://doi.org/10.3390/ijms21124454
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Wang, Z., Gao, J. & Xu, C. Tackling cellular senescence by targeting miRNAs. Biogerontology 23, 387–400 (2022). https://doi.org/10.1007/s10522-022-09972-z
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DOI: https://doi.org/10.1007/s10522-022-09972-z