RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans

• Published in: PloS one Vol. 4; no. 12; p. e8210
• Main Authors: Sebastiani, Paola, Montano, Monty, Puca, Annibale, Solovieff, Nadia, Kojima, Toshio, Wang, Meng C, Melista, Efthymia, Meltzer, Micah, Fischer, Sylvia E J, Andersen, Stacy, Hartley, Stephen H, Sedgewick, Amanda, Arai, Yasumichi, Bergman, Aviv, Barzilai, Nir, Terry, Dellara F, Riva, Alberto, Anselmi, Chiara Viviani, Malovini, Alberto, Kitamoto, Aya, Sawabe, Motoji, Arai, Tomio, Gondo, Yasuyuki, Steinberg, Martin H, Hirose, Nobuyoshi, Atzmon, Gil, Ruvkun, Gary, Baldwin, Clinton T, Perls, Thomas T
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.12.2009; Public Library of Science (PLoS)
• Subjects: Adenosine; Adenosine Deaminase - genetics; Adolescent; Adult; Age; Aged; Aged, 80 and over; Aging; Algorithms; Animals; ARGONAUTE gene; Biology; Caenorhabditis elegans - genetics; Centenarians; Chromosomes, Human, Pair 10 - genetics; Deactivation; Diabetes; Drosophila; Editing; Female; Gene Frequency - genetics; Genes; Genes, Helminth - genetics; Genetic aspects; Genetics; Genetics and Genomics/Gene Function; Genetics and Genomics/Genetics of Disease; Genetics and Genomics/Nuclear Structure and Function; Genomes; Genotype; Geriatrics; Health services; Hospitals; Humans; Inactivation; Infectious diseases; Insects; Insulin; Insulin-like growth factor I; Insulin-like growth factors; Interference; Life span; Linkage Disequilibrium - genetics; Lipid metabolism; Lipoproteins; Longevity; Longevity - genetics; Machinery and equipment; Male; Medicine; Metabolism; Middle Aged; Mutation; Nematodes; Odds Ratio; Oldest old people; Oxidative stress; Physiological aspects; Polymorphism, Single Nucleotide - genetics; Principal components analysis; Public health; Replication; Reproducibility of Results; Ribonucleic acid; RNA; RNA editing; RNA Editing - genetics; RNA-Binding Proteins; RNA-mediated interference; Science; Signal transduction; Signaling; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Studies; Survival; Young Adult; New York; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0008210

The strong familiality of living to extreme ages suggests that human longevity is genetically regulated. The majority of genes found thus far to be associated with longevity primarily function in lipoprotein metabolism and insulin/IGF-1 signaling. There are likely many more genetic modifiers of human longevity that remain to be discovered. Here, we first show that 18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study of centenarians, the New England Centenarian Study. We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity. Some SNPs in ADARB2 replicate consistently in the four populations and suggest a strong effect that is independent of the different genetic backgrounds and environments. To evaluate the functional association of these genes with lifespan, we demonstrate that inactivation of their orthologues adr-1 and adr-2 in C. elegans reduces median survival by 50%. We further demonstrate that inactivation of the argonaute gene, rde-1, a critical regulator of RNA interference, completely restores lifespan to normal levels in the context of adr-1 and adr-2 loss of function. Our results suggest that RNA editors may be an important regulator of aging in humans and that, when evaluated in C. elegans, this pathway may interact with the RNA interference machinery to regulate lifespan.