RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans

Paola Sebastiani, Monty Montano, Annibale Puca, Nadia Solovieff, Toshio Kojima, Meng C. Wang, Efthymia Melista, Micah Meltzer, Sylvia E J Fischer, Stacy Andersen, Stephen H. Hartley, Amanda Sedgewick, Yasumichi Arai, Aviv Bergman, Nir Barzilai, Dellara F. Terry, Alberto Riva, Chiara Viviani Anselmi, Alberto Malovini, Aya Kitamoto & 9 others Motoji Sawabe, Tomio Arai, Yasuyuki Gondo, Martin H. Steinberg, Nobuyoshi Hirose, Gil Atzmon, Gary Ruvkun, Clinton T. Baldwin, Thomas T. Perls

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

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. Methodology/Principal Findings: 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.

Original languageEnglish
Article numbere8210
JournalPLoS One
Volume4
Issue number12
DOIs
Publication statusPublished - 2009

Fingerprint

RNA Editing
RNA editing
Genes
RNA
RNA Interference
Polymorphism
Single Nucleotide Polymorphism
genes
Nucleotides
New England
RNA interference
Medical Genetics
Gene Silencing
genetic background
single nucleotide polymorphism
Insulin-Like Growth Factor I
Metabolism
inactivation
Lipoproteins
Machinery

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Sebastiani, P., Montano, M., Puca, A., Solovieff, N., Kojima, T., Wang, M. C., ... Perls, T. T. (2009). RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans. PLoS One, 4(12), [e8210]. https://doi.org/10.1371/journal.pone.0008210

RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans. / Sebastiani, Paola; Montano, Monty; Puca, Annibale; Solovieff, Nadia; Kojima, Toshio; Wang, Meng C.; Melista, Efthymia; Meltzer, Micah; Fischer, Sylvia E J; Andersen, Stacy; Hartley, Stephen H.; Sedgewick, Amanda; Arai, Yasumichi; Bergman, Aviv; Barzilai, Nir; Terry, Dellara F.; Riva, Alberto; Anselmi, Chiara Viviani; Malovini, Alberto; Kitamoto, Aya; Sawabe, Motoji; Arai, Tomio; Gondo, Yasuyuki; Steinberg, Martin H.; Hirose, Nobuyoshi; Atzmon, Gil; Ruvkun, Gary; Baldwin, Clinton T.; Perls, Thomas T.

In: PLoS One, Vol. 4, No. 12, e8210, 2009.

Research output: Contribution to journalArticle

Sebastiani, P, Montano, M, Puca, A, Solovieff, N, Kojima, T, Wang, MC, Melista, E, Meltzer, M, Fischer, SEJ, Andersen, S, Hartley, SH, Sedgewick, A, Arai, Y, Bergman, A, Barzilai, N, Terry, DF, Riva, A, Anselmi, CV, Malovini, A, Kitamoto, A, Sawabe, M, Arai, T, Gondo, Y, Steinberg, MH, Hirose, N, Atzmon, G, Ruvkun, G, Baldwin, CT & Perls, TT 2009, 'RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans', PLoS One, vol. 4, no. 12, e8210. https://doi.org/10.1371/journal.pone.0008210
Sebastiani, Paola ; Montano, Monty ; Puca, Annibale ; Solovieff, Nadia ; Kojima, Toshio ; Wang, Meng C. ; Melista, Efthymia ; Meltzer, Micah ; Fischer, Sylvia E J ; Andersen, Stacy ; Hartley, Stephen H. ; Sedgewick, Amanda ; Arai, Yasumichi ; Bergman, Aviv ; Barzilai, Nir ; Terry, Dellara F. ; Riva, Alberto ; Anselmi, Chiara Viviani ; Malovini, Alberto ; Kitamoto, Aya ; Sawabe, Motoji ; Arai, Tomio ; Gondo, Yasuyuki ; Steinberg, Martin H. ; Hirose, Nobuyoshi ; Atzmon, Gil ; Ruvkun, Gary ; Baldwin, Clinton T. ; Perls, Thomas T. / RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans. In: PLoS One. 2009 ; Vol. 4, No. 12.
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AU - Sebastiani, Paola

AU - Montano, Monty

AU - Puca, Annibale

AU - Solovieff, Nadia

AU - Kojima, Toshio

AU - Wang, Meng C.

AU - Melista, Efthymia

AU - Meltzer, Micah

AU - Fischer, Sylvia E J

AU - Andersen, Stacy

AU - Hartley, Stephen H.

AU - Sedgewick, Amanda

AU - Arai, Yasumichi

AU - Bergman, Aviv

AU - Barzilai, Nir

AU - Terry, Dellara F.

AU - Riva, Alberto

AU - Anselmi, Chiara Viviani

AU - Malovini, Alberto

AU - Kitamoto, Aya

AU - Sawabe, Motoji

AU - Arai, Tomio

AU - Gondo, Yasuyuki

AU - Steinberg, Martin H.

AU - Hirose, Nobuyoshi

AU - Atzmon, Gil

AU - Ruvkun, Gary

AU - Baldwin, Clinton T.

AU - Perls, Thomas T.

PY - 2009

Y1 - 2009

N2 - 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. Methodology/Principal Findings: 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.

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