RNA Editing Genes Associated with Extreme Old Age in Humans and with Lifespan in C. elegans

Abstract

BackgroundThe 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.Methodology/Principal FindingsHere, 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/SignificanceOur 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.

Effects of ADARs on small RNA processing pathways in C. elegans

“…There are three known phenotypes in ADAR mutant worms: chemotaxis defects, cosuppression of transgenes in somatic cells, and a reduced lifespan (Knight and Bass 2002;Tonkin et al 2002;Sebastiani et al 2009). Interestingly, all of these phenotypes are rescued by additional mutations in RDE-1 and/or RDE-4, which are involved in processing of siRNAs, but the mechanism(s) giving rise to these phenotypes is unclear.…”

“…However, ADAR mutant C. elegans are viable but show chemotaxis defects, a reduced lifespan, and cosuppression of transgenes in somatic cells (Knight and Bass 2002;Tonkin et al 2002;Sebastiani et al 2009). While many ADAR editing sites have been identified in various animals, the only site clearly correlated with a phenotype is in mouse glutamate receptor subunit B mRNA, where codon editing results in a Q to R amino acid change required for viability (Higuchi et al 2000).…”

“…All three phenotypes of C. elegans ADAR mutants are rescued by additional mutations in RNA interference factors (Knight and Bass 2002;Tonkin et al 2002;Sebastiani et al 2009). This suggests ADARs intersect with dsRNA-mediated silencing pathways, such as those involving microRNAs (miRNAs) or small interfering RNAs that derive from endogenous genes (endo-siRNAs) (Nishikura 2006;Ohman 2007;Hundley and Bass 2010).…”

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

“…Although there is accumulating knowledge of the genetic pathways responsible for the longevity-related traits, based on studies using aging animal models (Finch and Ruvkun 2001) and works on people surviving to advanced ages, such as centenarians (Sebastiani et al 2009;Perls et al 2002), this information is still far from being complete. Thus, a genome-wide search offers advantages over candidate gene association studies because it provides a more extensive coverage of the genome and the opportunity for truly novel gene discoveries-which is entirely "agnostic" and unconstrained by existing knowledge.…”

“…However, the results for the longevity phenotype, defined as survival to age 90 and older, in the CHARGE consortium cohorts (longevity "cases", n= 1,836, and population comparison "controls", n=1,955) did not reach the genome-wide significance threshold (Newman et al 2010), similarly to Lunetta et al (2007) GWAS. Genome-wide association studies with extreme long-living individuals to date did provide only two longevity-associated genes (Sebastiani et al 2009). The question remains, however, how generalizable are these results and whether they replicate beyond the centenarian cohorts.…”