Journal of Aging Research 3 Canonical miRNA miRNA encoding gene 7mG Drosha AAAAA DGCR8 pri-miRNA Mirtron Exon Exon Spliceosome Exon Exon Cytoplasm Exportin 5-RanGTP pre-miRNA TRBP Dicer TRBP Dicer AGO2 RISC complex Nucleus TRBP Dicer AGO2 AGO2 Translational repression TRBP Dicer Target mRNA cleavage AAAA AAAA mRNA Figure 1: miRNA biogenesis. In the nucleus, canonical miRNAs are processed by the endoribonuclease, Drosha, in partnership with DGCR8. In contrast, mirtrons are processed by the spliceosome. The pre-miRNA is then exported from the nucleus into the cytoplasm by Exportin-5, and it is processed into a mature miRNA by Dicer. After RISC incorporation, mature miRNAs inhibit translation or promote degradation of their target mRNA transcripts depending on the degree of complementarity between the 3 -UTR of the target mRNA and the seed region of the miRNA. pathways. p53 provokes growth arrest, in part by inducing the expression of p21Cip1, which is a cyclin-dependent kinase (CDK) inhibitor that suppresses the phosphorylation and, hence, the inactivation of pRB [32, 33]. In addition, senescence signals that engage the p16INK4A-pRB pathway generally do so by inducing the expression of p16INK4A, which is another CDK inhibitor that prevents pRB phosphorylation and inactivation [32]. In this regard, the loss of tumor suppressors that function downstream of oncogenes, such as p53, impair senescence and allow progression to malignant stages providing a link between tumor suppression and the induction of senescence by p16INK4A, p19ARF, and p53 [30]. In general, oncogenes that elicit a senescence response often converge on the activation of p53 and/or pRB. However, RAF-induced senescence independent of both p53 and pRB has been reported in human cells [34]. Importantly, several groups have shown that benign tumors contain senescent cells and that these cells fully disappear in the corresponding malignant areas of the patients. Senescent cells are found in premalignant lesions in mice and humans, and they are absent in their corresponding malignant stages, which suggests a role for senescence as a barrier to tumor progression [35, 36]. In addition, senescent cells are relatively rare in young organisms, but their number increases with age. Consistent with a role in aging, senescent cells accumulate with age in many rodent, primate, and human tissues [37, 38]. Moreover, they are found at sites of age-related pathology including degenerative disorders, such as osteoarthritis and atherosclerosis [37], in addition to hyperproliferative lesions, such as benign prostatic hyperpla- sia [39]. Several miRNAs have been reported to be diﬀerentially expressed in senescent cells when compared to primary cells, providing a role for miRNAs in senescence (Figure 2, Table 1). Recently, it has been reported that miR-34a overex- pression during senescence can be p53 dependent and p53 independent [40–44]. p53 activates transcription of a set of genes, which induces cell cycle arrest, senescence, or apopto- sis. Moreover, p53 also regulates the expression of miR-34a because genes in the family of miR-34 genes contain p53- binding sites in their promoters, which are conserved among humans and rodents. In turn, miR-34a increases the activity of p53 by means of reducing expression of sirtuin 1 (SIRT1), which interacts with p53 and deacetylates the Lys382 residue