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.
Highlights
Exceptional longevity (EL) in humans, defined as living to extreme old ages such as 100 years and older, is strongly familial [1,2,3,4,5,6,7,8] and the factors that facilitate such exceptional survival have broad public health significance including a marked delay in age-related disability [9,10,11] and certain age-related diseases [12,13,14]
We further evaluate the functional significance of the RNA editing candidate genes in C. elegans lifespan studies and show that silencing orthologs of these genes reduces median survival by 50%
In a preliminary genome wide screening using pooled DNA samples from approximately 130 male centenarians and 130 younger male controls from the New England Centenarian Study (NECS) [27], we identified several single nucleotide polymorphisms (SNPs) in the RNA-editing genes ADARB1 (21q22.3), and ADARB2 (10p15.3) that were associated with extreme old age
Summary
Exceptional longevity (EL) in humans, defined as living to extreme old ages such as 100 years and older, is strongly familial [1,2,3,4,5,6,7,8] and the factors that facilitate such exceptional survival have broad public health significance including a marked delay in age-related disability [9,10,11] and certain age-related diseases [12,13,14]. In a preliminary genome wide screening using pooled DNA samples from approximately 130 male centenarians and 130 younger male controls from the NECS [27], we identified several single nucleotide polymorphisms (SNPs) in the RNA-editing genes ADARB1 (21q22.3), and ADARB2 (10p15.3) that were associated with extreme old age.
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