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

Sebastiani1*, Monty Montano2*, Annibale Puca3, Nadia Solovieff1, Toshio Kojima4, Meng C. Efthymia Melista6, Micah Meltzer2, Sylvia E. J. Fischer5, Stacy Andersen7, Stephen H. Sedgewick8, Yasumichi Arai9, Aviv Bergman10, Nir Barzilai11, Dellara F. Terry7, Alberto Viviani Anselmi3, Alberto Malovini3, Aya Kitamoto4, Motoji Sawabe13, Tomio Arai13, Martin H. Steinberg6, Nobuyoshi Hirose9, Gil Atzmon11, Gary Ruvkun5, Clinton T. T. Perls7"

1Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
2Department of Medicine Sections of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, United States of America
3Department of Genetics, IRCCS Multimedica, Milan, Italy
4Computational Systems Biology Research Group, Advanced Science Institute, RIKEN, Yokohama, Kanagawa, Japan
5Department of Genetics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts,
United States of America
6Center for Human Genetics,Boston University School of Medicine,Boston,
Massachusetts,
United States of America
7Geriatrics Section,
Department of Medicine,Boston University School of Medicine,Boston,
Massachusetts,
United States of America
8Department of Bioengineering,Boston University School of Engineering,Boston,
Massachusetts,
United States of America
9Division of Geriatric Medicine,
Department of Internal Medicine,
Keio University School of Medicine,Tokyo,
Japan
10Department of Systems & Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America
11Institute of Aging Research and Diabetes Research Center, Departments of Medicine and Genetics, Albert Einstein College of Medicine,
Bronx, New York,
United States of America
12Department of Molecular Genetics and Microbiology, University of Florida at Gainesville, Florida, United States of America
13Department of Pathology,
Tokyo Metropolitan Geriatric Hospital,Tokyo,
Japan
14Clinical Thanatology and Geriatric Behavioral Science, Graduate School of Human Sciences, Osaka University,Suita, Osaka,
Japan

Abstract:

In this study, we investigate two genes in the A to I RNA editing pathway associated with extreme old age in humans and lifespan in C.elegans. We demonstrate 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. Replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) support an association of ADARB1 and ADARB2 with longevity. Some SNPs in ADARB2 replicate consistently across the four populations suggesting a strong effect independent of different genetic backgrounds and environments. We also show that inactivation of the orthologues adr-1 and adr-2 in C. elegans reduces median survival by 50%. Further demonstrating that inactivation of the argonaute gene rde-1 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 this pathway may interact with the RNA interference machinery to regulate lifespan.

Funding:

This work was supported by National Institutes of Health grants: R01HL087681 (to M.H.S), K24AG025727 (to T.T.P), R01AR055115 (to M.M.), RO1AG027216 (to C.B.), the Italian Ministry of Research and University (to A.P. and A.M), and the following grants to G.A, A.B. and N.B.: AG-027734, AG-18728, RR-12248, DK-20541, and M01-RR12248 and a grant from the Glenn Foundation. M.C.W. is supported by a Life Sciences Research Foundation fellowship. S.E.J.F. is supported by the MGH ECOR Fund for Medical Discovery.

Competing Interests:

The authors have declared that no competing interests exist.

Introduction:

Exceptional longevity (EL) in humans, defined as living to extreme old ages such as 100 years and older, is strongly familial [18]. The factors that facilitate such exceptional survival have broad public health significance including a marked delay in age-related disability [9-11] and certain age-related diseases [12-14]. Genetically, exceptional longevity is presumed to beValidated with birth certificates (in the case of the JCS, the Basic Resident Registration Card), we further evaluated the functional significance of RNA editing candidate genes in C. elegans lifespan studies. We showed that silencing orthologs of these genes reduces median survival by 50%. Additionally, we demonstrated that lifespan is fully restored by additional knockdown of an RNA interference gene, supporting the functional role of these genes in determining lifespan and implicating a novel axis for future aging studies. Table 1 summarizes the characteristics of study subjects. 

Selection of candidate genes was based on multiple factors. Firstly, 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. ADARB1 exhibited the strongest evidence for genetic association with 5 SNPs that met genome-wide significance, with the posterior odds of allelic association being greater than 1500 [27]. The probability of these 5 SNPs simultaneously associated under the null hypothesis of no association was 10^−213 based upon a hypergeometric distribution.