ADAR
Double-stranded RNA-specific adenosine deaminase (EC 3.5.4.37) (DRADA) (136 kDa double-stranded RNA-binding protein) (p136) (Interferon-inducible protein 4) (IFI-4) (K88DSRBP) [ADAR1] [DSRAD] [G1P1] [IFI4]
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Alterations in microRNA (miRNA) processing have been previously linked to aging. Here we used the small molecule enoxacin to pharmacologically interfere with miRNA biogenesis and study how it affects aging in C. elegans. Enoxacin extended worm lifespan and promoted survival under normal and oxidative stress conditions. Enoxacin-induced longevity required the transcription factor SKN-1/Nrf2 and was blunted by the antioxidant N-acetyl-cysteine, suggesting a prooxidant-mediated mitohormetic response. The longevity effects of enoxacin were also dependent on the miRNA pathway, consistent with changes in miRNA expression elicited by the drug. Among these differentially expressed miRNAs, the widely conserved miR-34-5p was found to play an important role in enoxacin-mediated longevity. Enoxacin treatment down-regulated miR-34-5p and did not further extend lifespan of long-lived mir-34 mutants. Moreover, N-acetyl-cysteine abrogated mir-34(gk437)-induced longevity. Evidence also points to double-stranded RNA-specific adenosine deaminases (ADARs) as new targets of enoxacin since ADAR loss-of-function abrogates enoxacin-induced lifespan extension. Thus, enoxacin increases lifespan by reducing miR-34-5p levels, interfering with the redox balance and promoting healthspan.
MeSH Terms
- Animals
- Caenorhabditis elegans
- Cytochrome P-450 CYP1A2 Inhibitors
- Enoxacin
- Gene Expression Regulation
- Longevity
- MicroRNAs
- Oxidation-Reduction
- Oxidative Stress
- Topoisomerase II Inhibitors
Keywords
- ADAR
- Aging
- Enoxacin
- MicroRNA
- Mitohormesis
- miR-34
To investigate the impact of maternal aging on the molecular signature of cumulus cells. Experimental study. Research laboratory. Patients, young fertile oocyte donors (n = 40) and infertile women of advanced maternal age (40-45 years; n = 48), donated, with Institutional Review Board consent, cumulus cells during routine infertility treatment. None. Proteomic and gene expression profiles of cumulus cells. Proteomic analysis identified a total of 1,423 cumulus cell proteins. Statistical analysis revealed 110 (7.7%) proteins to be differentially expressed in relation to female aging (>1.5-fold change). Pathway annotation revealed significant involvement in metabolism (ACAT2, HSD17B4, ALDH9A1, MVK, CYP11A1, and FDFT1), oxidative phosphorylation (OP; NDUFA1, UQCRC1, MT-ATP6, ATP5I, and MT-ATP8), and post-transcriptional mechanisms (KHSRP, SFPQ, DDX46, SNRPF, ADAR, NHPL1, and U2AF2) relative to advanced maternal age. Gene expression analysis also revealed altered profiles in cumulus cells from women in their early to mid-40s. This novel study reveals that the cumulus cell molecular signature, at both the gene and protein level, is impacted by advanced maternal aging. A compromised follicular environment is evident with altered energy metabolism and post-transcriptional processes.
MeSH Terms
- Adult
- Aging
- Cells, Cultured
- Cumulus Cells
- Female
- Humans
- Maternal Age
- Middle Aged
- Oocyte Donation
- Proteome
Single nucleotide polymorphisms (SNPs) of the adenosine deaminase, RNA-specific (ADAR) gene were reported to be associated with human longevity. There are possibilities that ADAR is associated with major risk factors of atherosclerotic cardiovascular diseases (CVD), such as hypertension, diabetes, dyslipidemia, and obesity. To investigate the association between SNPs of the ADAR gene and clinical data associated with major risk factors of atherosclerotic CVD. A total of 1504 general population residents (586 males and 918 females) of two towns, Tanno-cho and Sobestu-cho, in Hokkaido, Japan. Clinical data associated with risk factors of atherosclerotic CVD were collected from these study subjects. DNA from peripheral blood and written informed consent were obtained. Three single nucleotide polymorphisms of ADARB1 and ADARB2, which were previously reported to be associated with longevity, were genotyped employing the TaqMan PCR method. The associations between SNPs in ADARB1 and ADARB2 and clinical parameters related to risk factors of atherosclerosis were analyzed. On uni- and multivariate analyses, rs2805533 in ADARB2 was significantly associated with the abdominal circumference, body mass index, serum triglyceride level, and serum adiponectin level. The subjects with the AA genotype of rs2805533 had a greater abdominal circumference, higher body mass index, higher triglyceride level, and lower adiponectin level than those with AG and GG genotypes. The SNP in ADARB2 related to longevity is associated with metabolic disorders. This finding suggests that genetic factors modulate human longevity via the regulation of metabolic factors such as abdominal obesity and lipid profiles.
MeSH Terms
- Adenosine Deaminase
- Adiponectin
- Aged
- Analysis of Variance
- Asian Continental Ancestry Group
- Biomarkers
- Female
- Humans
- Intra-Abdominal Fat
- Japan
- Longevity
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- RNA Editing
- RNA-Binding Proteins
- Risk Factors
- Triglycerides
- Waist Circumference
In this review, we describe recent advances in the field of RNA regulatory biology and relate these advances to aging science. We introduce a new term, RNA surveillance, an RNA regulatory process that is conserved in metazoans, and describe how RNA surveillance represents molecular cross-talk between two emerging RNA regulatory systems-RNA interference and RNA editing. We discuss how RNA surveillance mechanisms influence mRNA and microRNA expression and activity during lifespan. Additionally, we summarize recent data from our own laboratory linking the RNA editor, ADAR, with exceptional longevity in humans and lifespan in Caenorhabditis elegans. We present data showing that transcriptional knockdown of RNA interference restores lifespan losses in the context of RNA editing defects, further suggesting that interaction between these two systems influences lifespan. Finally, we discuss the implications of RNA surveillance for sarcopenia and muscle maintenance, as frailty is a universal feature of aging. We end with a discussion of RNA surveillance as a robust regulatory system that can change in response to environmental stressors and represents a novel axis in aging science.
MeSH Terms
- Aging
- Animals
- Caenorhabditis elegans
- Genes, Helminth
- Humans
- Longevity
- Models, Biological
- RNA Editing
- RNA Interference
- RNA Stability
- RNA, Messenger
- Sarcopenia