Small non-coding microRNAs are believed to be involved in the mechanism

Small non-coding microRNAs are believed to be involved in the mechanism of aging but nothing is known around the impact of microRNAs in the progeroid disorder Werner syndrome (WS). that biological pathways involving WRN and miR-124 are conserved in the aging process across different species. homologue (hereafter referred as [17]. The gene codes for the ATP-dependent 3C5 DNA helicase capable of unwinding a variety of DNA structures [18]. Notably, it has been shown that this RNAi knockdown of the gene shortens the life span, increases sensitivity to DNA damage, and accelerates aging phenotypes [17]. Recent discoveries in the fields of development, cancer, and aging have indicated that small non-coding RNAs play a major role in alterations associated with these biological processes. An important class of non-coding RNAs that has been studied in the context of aging are the microRNAs (miRNAs) [19-23]. The miRNAs are short RNAs (~22nt) that regulate post-transcriptional gene expression via base pairing to partially complementary sites mainly found in the 3 UTRs of messenger RNAs (mRNAs). miRNAs down regulate protein expression by inhibiting mRNA translation and/or mRNA stability [20]. Individual miRNAs can modulate multiple mRNA targets, and individual mRNAs can be regulated by multiple, distinct miRNAs [20]. Very few studies using rodent tissues have been performed to elucidate the role of miRNAs in aging [24-27], often with contradictory results [28, 29]. In this study, we report the differential expression of several miRNAs in the livers of young (three months old) mice compared to age-matched wild type animals. Among them, one conserved miRNA in animals (miR-124) was down regulated in both the liver of mice and in whole wrn-1 mutants. Deletion of mir-124 in C. elegans resulted in a decrease in life span, an increase in reactive oxygen species (ROS) production, a decrease in ATP levels, and an increase in the aging marker lipofuscin. All these phenotypes could be reversed in mir-124 mutation strains after vitamin C treatment. These results implicate a role for U2AF35 the conserved miR-124 in aging in mice show differential expression of miR-375 CCT128930 and miR-124 We have previously shown that in mice, the liver is the first tissue to show morphological changes compared to age-matched wild type animals [16, 30]. Interestingly, the liver undergoes substantial modifications in structure and function in old age including include alterations in liver mass, blood flow, and sinusoidal cell morphology [31]. These changes are associated with significant impairment of many hepatic metabolic and detoxification activities, with implications for systemic aging and age-related disease. We therefore focused our study around the hepatic tissue as the liver plays a pivotal role in whole body homeostasis through the maintenance of nutrient, drug, hormone, and metabolic processes. Total RNA from the liver of two and two wild type mice at three months of age was extracted to analyze the expression of 755 different miRNAs using the TaqMan-based Array. Although no gross hepatic morphological difference could be observed between mice and wild type mice at three months of age, the liver of mice exhibited changes in the expression of a number of miRNAs compared to wild type mice. Supplementary CCT128930 Tables S1 and S2 provide the raw data on all miRNAs. Table ?Table11 summarizes the list of differentially expressed miRNAs in the liver of mice compared to wild type mice. Table 1 List of miRNAs differentially expressed in the liver of three months old mutant compared to wild type mice with an adjusted mutant compared to wild type animals (Physique ?(Physique1A1A and Supplementary Physique S1). miR-375 was up regulated more than three-fold and miR-124 was down regulated by ten-fold in the liver of mutant mice compared to the liver of wild type animals (Physique ?(Figure1A1A). Physique 1 Expression levels of miRNAs in the liver of mice compared to wild type mice and in the whole body of wild type and worms. (A) Total RNA from four mice (at three months of age) of the indicated genotype was used for the quantitative … To determine whether miR-375 and miR-124 were also differentially CCT128930 expressed during aging, quantitative RT-PCR was performed around the liver tissues of four young (three months) and four old (21 months) wild type mice. miR-124 was significantly decreased (by five-fold) in the livers of old wild type mice compared to young wild type mice (Physique ?(Figure1B).1B). In.