The roles of MTOR and miRNAs in endothelial cell senescence
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REVIEW ARTICLE
The roles of MTOR and miRNAs in endothelial cell senescence Eng-Soon Khor . Pooi-Fong Wong
Received: 21 January 2020 / Accepted: 30 March 2020 Ó Springer Nature B.V. 2020
Abstract Accumulation of senescent cells in vascular endothelium is known to contribute to vascular aging and increases the risk of developing cardiovascular diseases. The involvement of classical pathways such as p53/p21 and p16/pRB in cellular senescence are well described but there are emerging evidence supporting the increasingly important role of mammalian target of rapamycin (MTOR) as driver of cellular senescence via these pathways or other effector molecules. MicroRNAs (miRNAs) are a highly conserved group of small non-coding RNAs (18–25 nucleotides), instrumental in modulating the expression of target genes associated with various biological and cellular processes including cellular senescence. The inhibition of MTOR activity is predominantly linked to cellular senescence blunting and prolonged lifespan in model organisms. To date, known miRNAs regulating MTOR in endothelial cell senescence remain limited. Herein, this review discusses the roles of MTOR and MTOR-associated miRNAs in regulating endothelial cell senescence, including the crosstalk between MTOR Complex 1 (MTORC1) and cell cycle pathways and the emerging role of MTORC2 in cellular senescence. New insights on how MTOR and miRNAs coordinate underlying molecular mechanisms of endothelial senescence will E.-S. Khor P.-F. Wong (&) Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia e-mail: [email protected]
provide deeper understanding and clarity to the complexity of the regulation of cellular senescence. Keywords Endothelium MicroRNAs MTOR Senescence Vascular aging
Introduction Cellular senescence, also known as replicative senescence is defined as the state of irreversible cell cycle arrest in response to a diverse range of triggers and stressors such as telomere dysfunction, activated oncogenes, oxidative stress and DNA damage which permanently restrict cell proliferation or doubling (Burton and Krizhanovsky 2014; Fridlyanskaya et al. 2015; Hayflick 1965). It is therefore a cellular antiproliferative program that is vital for the control of defective cells which otherwise cause deleterious consequences. Cellular senescence plays important roles in wound healing (Demaria et al. 2014; Telgenhoff and Shroot 2005), embryonic development (Munoz-Espin et al. 2013), tumour suppression (Ohtani et al. 2009) and organismal aging (Campisi and Robert 2014). Morphologically, senescent cells are enlarged, flattened, vacuolated and exhibit high granularity with increased senescence-associated betagalactosidase (SA-b-gal) activity and DNA damage foci.
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Biogerontology
Senescent cells also acquire the senescence-associated secretory phenotype (SASP), characterised by the release of soluble mediators via autocrine or paracrine signalling which affect the surrounding ti
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