title: RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America. sebas@bu.edu
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.forename: Monty
authors.initials: M
authors.lastname: Montano
authors.forename: Annibale
authors.initials: A
authors.lastname: Puca
authors.forename: Nadia
authors.initials: N
authors.lastname: Solovieff
authors.forename: Toshio
authors.initials: T
authors.lastname: Kojima
authors.forename: Meng C
authors.initials: MC
authors.lastname: Wang
authors.forename: Efthymia
authors.initials: E
authors.lastname: Melista
authors.forename: Micah
authors.initials: M
authors.lastname: Meltzer
authors.forename: Sylvia E J
authors.initials: SE
authors.lastname: Fischer
authors.forename: Stacy
authors.initials: S
authors.lastname: Andersen
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hartley
authors.forename: Amanda
authors.initials: A
authors.lastname: Sedgewick
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Arai
authors.forename: Aviv
authors.initials: A
authors.lastname: Bergman
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.forename: Dellara F
authors.initials: DF
authors.lastname: Terry
authors.forename: Alberto
authors.initials: A
authors.lastname: Riva
authors.forename: Chiara Viviani
authors.initials: CV
authors.lastname: Anselmi
authors.forename: Alberto
authors.initials: A
authors.lastname: Malovini
authors.forename: Aya
authors.initials: A
authors.lastname: Kitamoto
authors.forename: Motoji
authors.initials: M
authors.lastname: Sawabe
authors.forename: Tomio
authors.initials: T
authors.lastname: Arai
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Gondo
authors.forename: Martin H
authors.initials: MH
authors.lastname: Steinberg
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hirose
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
authors.forename: Gary
authors.initials: G
authors.lastname: Ruvkun
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Baldwin
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Perls
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D017238:Genes, Helminth / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017393:RNA Editing / Q000235:genetics*; D016601:RNA-Binding Proteins; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D016601:RNA-Binding Proteins; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase