4 Journal of Aging Research Oncogenic stress Oncogen overexpression MEK, RAS, BRAF, PI3K, E2F. . . Loss tumour suppressor upstream oncogen: PTEN, VHL, NFI. . . Telomeric erosion Oxidative stress miR-34a (upregulated) MYC SIRT1 miR-217 (upregulated) SIRT1 INK4A/AR p19 p53 p21 Senescence Cell cycle arrest β-Gal (+) p16 pRB Bmi-1 Cyclin D1 miR-128a (upregulated) miR-449a (upregulated) B-Myb miR-29; miR-30 (upregulated) HuR miR-519 (upregulated) Figure 2: Role of miRNAs in senescence. Cellular senescence is triggered by several factors including telomeric erosion, oncogenic stress, oxidative stress, and miRNA modulation. The following miRNAs are key regulatory miRNAs modulating senescence: miR-128a, miR-449a, miR-29, miR-30, miR-519, miR-217, and miR-34a. of p53 in a NAD+-dependent manner, thereby decreasing p53-mediated transcriptional activation and reducing the expression levels of downstream proteins, such as p21Cip1. Therefore, overexpression of miR-34a decreases SIRT1 expression, allowing an increase in p53 acetylation and p53 activity and thus mediating the senescence response [43, 45]. On the other hand, several studies have shown that miR- 34a causes senescence in a p53-independent manner. miR- 34a induces senescence and suppression of cell proliferation through downregulation of the E2F pathway in human colon cancer cells p53 (+/+) leading to the upregulation of the p53/p21Cip1 pathway, but also in human colon cancer cells p53 (−/−) [42]. In addition, another study has reported a strong upregulation of miR-34a during B-RAF-induced senescence independent of p53. In this case, miR-34a is transcriptionally upregulated by ELK1, which is a member of the ETS oncogene family and has previously been implicated in cellular senescence. Moreover, miR-34a is upregulated after activation of the B-RAF oncogene. Finally, miR-34a provokes senescence through repression of v-myc myelocy- tomatosis viral oncogene homolog (Myc) [44]. Importantly, miR-34a, which is a tumor suppressor in the miR-34 family, is downregulated in pancreatic cancer cells, neuroblastomas, colon cancer cells, and lung cancer cells [40–42, 46]. The expression levels of miR-29 and miR-30 increase during cellular senescence in a Rb-dependent manner. More- over, these microRNAs directly repress v-myb myeloblastosis viral oncogene homolog (avian)-like 2 (B-Myb) by binding Table 1: Novel miRNAs involved in senescence. miRNA miRNA function hsa-miR-29/30 Oncomir/Tumour suppressor hsa-miR-34a Tumour suppressor hsa-miR-519 Tumour suppressor hsa-miR-449a Tumour suppressor hsa-miR-128a Tumour suppressor hsa-miR-217 Tumour suppressor hsa-miR-372/373 Oncomir hsa-miR-17-5p Oncomir hsa-miR-130b Oncomir hsa-miR-15b/25/141 Oncomir mmu-miR-20a Tumour suppressor mmu-miR-290 Tumour suppressor Reference [47–51] [40–44] [52] [53, 54] [55–57] [58, 59] [60–63] [60, 64–69] [60, 70] [71–74] [75] [76] to its 3 -UTR acting in conjunction with Rb-E2F complexes at the B-Myb promoter to mediate repression of B-Myb expression during Rb activation resulting in senescence [47]. miR-29 is downregulated in mantle cell lymphomas [48], and the overexpression of miR-29 is suppressed during tumorigenicity in lung cancer cells [49]. Moreover, miR-29 is upregulated in indolent human B-cell chronic lymphocytic leukemia (B-CLL) when compared to aggressive B-CLL and normal CD19+ B-cells, suggesting that miR-29 can function as an oncogene and contribute to the pathogenesis