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Variations of the angiotensin II type 1 receptor gene are associated with extreme human longevity

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Abstract

Longevity phenotype in humans results from the influence of environmental and genetic factors. Few gene polymorphisms have been identified so far with a modest effect on lifespan leaving room for the search of other players in the longevity game. It has been recently demonstrated that targeted disruption of the mouse homolog of the human angiotensin II type 1 receptor (AT1R) gene (AGTR1) translates into marked prolongation of animal lifespan (Benigni et al., J Clin Invest 119(3):524–530, 2009). Based on the above study in mice, here we sought to search for AGTR1 variations associated to reduced AT1 receptor protein levels and to prolonged lifespan in humans. AGTR1 was sequenced in 173 Italian centenarians and 376 younger controls. A novel non-synonymous mutation was detected in a centenarian. Two polymorphisms in AGTR1 promoter, rs422858 and rs275653, in complete linkage disequilibrium, were significantly associated with the ability to attain extreme old age. We then replicated the study of rs275653 in a large independent cohort of Japanese origin (598 centenarians and semi-supercentenarians, 422 younger controls) and indeed confirmed its association with exceptional old age. In combined analyses, rs275653 was associated to extreme longevity either at recessive model (P = 0.007, odds ratio (OR) 3.57) or at genotype level (P = 0.015). Significance was maintained after correcting for confounding factors. Fluorescence activated cell sorting analysis revealed that subjects homozygous for the minor allele of rs275653 had less AT1R-positive peripheral blood polymorphonuclear cells. Moreover, rs275653 was associated to lower blood pressure in centenarians. These findings highlight the role of AGTR1 as a possible candidate among longevity-enabling genes.

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Abbreviations

AT1R:

Angiotensin II type 1 receptor

AT1AR:

Angiotensin II type 1A receptor

AT1BR:

Angiotensin II type 1B receptor

AT1AR−/− :

Mouse deficient for angiotensin II type 1A receptor

AGTR1 :

Human angiotensin II type 1 receptor gene

FOXO3A:

Forkhead box O3A

ROS:

Reactive oxygen species

AngII:

Angiotensin II

NCBI:

National Center of Biotechnology Information

PBMC:

Peripheral blood mononuclear cells

PMN:

Polymorphonuclear cells

OR:

Odds ratio

FACS:

Fluorescence activated cell sorting

HW:

Hardy-Weinberg

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Acknowledgments

The generous support of Fondazione ART per la Ricerca sui Trapianti ONLUS (Milan, Italy) and of Fondazione Aiuti per la Ricerca sulle Malattie Rare, Bergamo, Italy, and of Istituto Edizioni ATLAS SpA, Bergamo, Italy is acknowledged. The authors thank the Istituto Italiano Edizioni ATLAS S.p.A for the grant for printing colour figures. The authors are indebted to Dr. Rossella Piras, recipient of a fellowship of Fondazione ART, for the invaluable help in gene sequencing and to Dr. Antonietta Chianca, Ph.D., for elrm analysis.

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Authors and Affiliations

  1. Department of Molecular Medicine, Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126, Bergamo, Italy

    Ariela Benigni & Silvia Orisio

  2. Transplant Research Center, “Chiara Cucchi De Alessandri & Gilberto Crespi”, Mario Negri Institute for Pharmacological Research, 24020, Ranica, Italy

    Marina Noris & Marta Todeschini

  3. Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”, Mario Negri Institute for Pharmacological Research, 24020, Ranica, Italy

    Paraskevas Iatropoulos

  4. Ph.D. School of Informatics, DISCo, University of Milan—Bicocca, 20126, Milan, Italy

    Davide Castaldi

  5. Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, 565-0871, Osaka, Japan

    Kei Kamide & Hiromi Rakugi

  6. Division of Geriatric Medicine, Department of Internal Medicine, Keio University School of Medicine, 160-8582, Tokyo, Japan

    Yasumichi Arai & Nobuyoshi Hirose

  7. Department of Medical Sciences, Geriatric Unit, IRCCS Ca’ Granda Foundation Maggiore Policlinico Hospital, University of Milan, 20122, Milan, Italy

    Giulia Ogliari & Daniela Mari

  8. Department of Nephrology, Nagoya University Graduate School of Medicine, 466-8550, Nagoya, Japan

    Enyu Imai

  9. Department of Clinical Thanatology and Geriatric Behavioral Science, Osaka University Graduate School of Medicine, 565-0871, Osaka, Japan

    Yasuyuki Gondo

  10. Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126, Bergamo, Italy

    Giuseppe Remuzzi

  11. Unit of Nephrology and Dialysis, Azienda Ospedaliera Ospedali Riuniti di Bergamo, 24128, Bergamo, Italy

    Giuseppe Remuzzi

Authors
  1. Ariela Benigni
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  2. Silvia Orisio
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  3. Marina Noris
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  4. Paraskevas Iatropoulos
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  5. Davide Castaldi
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  6. Kei Kamide
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  8. Yasumichi Arai
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  9. Marta Todeschini
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  10. Giulia Ogliari
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  11. Enyu Imai
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  12. Yasuyuki Gondo
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  13. Nobuyoshi Hirose
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  14. Daniela Mari
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  15. Giuseppe Remuzzi
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Corresponding author

Correspondence to Silvia Orisio.

Additional information

Ariela Benigni and Silvia Orisio contributed equally to this work.

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Benigni, A., Orisio, S., Noris, M. et al. Variations of the angiotensin II type 1 receptor gene are associated with extreme human longevity. AGE 35, 993–1005 (2013). https://doi.org/10.1007/s11357-012-9408-8

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  • DOI: https://doi.org/10.1007/s11357-012-9408-8

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