RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans.
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.
Sebastiani
Paola
P
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America. sebas@bu.edu
Montano
Monty
M
Puca
Annibale
A
Solovieff
Nadia
N
Kojima
Toshio
T
Wang
Meng C
MC
Melista
Efthymia
E
Meltzer
Micah
M
Fischer
Sylvia E J
SE
Andersen
Stacy
S
Hartley
Stephen H
SH
Sedgewick
Amanda
A
Arai
Yasumichi
Y
Bergman
Aviv
A
Barzilai
Nir
N
Terry
Dellara F
DF
Riva
Alberto
A
Anselmi
Chiara Viviani
CV
Malovini
Alberto
A
Kitamoto
Aya
A
Sawabe
Motoji
M
Arai
Tomio
T
Gondo
Yasuyuki
Y
Steinberg
Martin H
MH
Hirose
Nobuyoshi
N
Atzmon
Gil
G
Ruvkun
Gary
G
Baldwin
Clinton T
CT
Perls
Thomas T
TT
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
D016601:RNA-Binding Proteins; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase