RNA Editing Genes Associated with Extreme Old Age Humans and with 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

Methodology/PrincipalFindings: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/Significance: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.

Funding: ThisworkwassupportedbyNationalInstitutesofHealthgrants:R01HL087681(toM.H.S),K24AG025727(toT.T.P),R01AR055115(toM.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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

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 be a complex trait [15–19]. Several candidate gene association studies have been successful in discovering longevity-associated

Introduction

Exceptional longevity (EL) in humans, defined as living to extreme old ages such as 100 years and older, is strongly familial [1–8] and the factors that facilitate such exceptional survival

Subjects Selected for the Association Study

genes in humans. However, these variants have been mainly related to lipoprotein metabolism [20–22], FOXO proteins [23,24], and insulin/IGF-1 signaling [25] It is likely that many more genetic modifiers of human aging have yet to be discovered [25].