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AGE

, Volume 35, Issue 3, pp 993–1005 | Cite as

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

  • Ariela Benigni
  • Silvia OrisioEmail author
  • Marina Noris
  • Paraskevas Iatropoulos
  • Davide Castaldi
  • Kei Kamide
  • Hiromi Rakugi
  • Yasumichi Arai
  • Marta Todeschini
  • Giulia Ogliari
  • Enyu Imai
  • Yasuyuki Gondo
  • Nobuyoshi Hirose
  • Daniela Mari
  • Giuseppe Remuzzi
Article

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.

Keywords

Angiotensin II type I receptor Genetic polymorphism Centenarians Human longevity 

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

Notes

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.

Supplementary material

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ESM 1 (DOC 38 kb)
11357_2012_9408_MOESM2_ESM.doc (38 kb)
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11357_2012_9408_MOESM3_ESM.doc (40 kb)
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Copyright information

© American Aging Association 2012

Authors and Affiliations

  • Ariela Benigni
    • 1
  • Silvia Orisio
    • 1
    Email author
  • Marina Noris
    • 2
  • Paraskevas Iatropoulos
    • 3
  • Davide Castaldi
    • 4
  • Kei Kamide
    • 5
  • Hiromi Rakugi
    • 5
  • Yasumichi Arai
    • 6
  • Marta Todeschini
    • 2
  • Giulia Ogliari
    • 7
  • Enyu Imai
    • 8
  • Yasuyuki Gondo
    • 9
  • Nobuyoshi Hirose
    • 6
  • Daniela Mari
    • 7
  • Giuseppe Remuzzi
    • 10
    • 11
  1. 1.Department of Molecular MedicineMario Negri Institute for Pharmacological ResearchBergamoItaly
  2. 2.Transplant Research Center, “Chiara Cucchi De Alessandri & Gilberto Crespi”Mario Negri Institute for Pharmacological ResearchRanicaItaly
  3. 3.Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”Mario Negri Institute for Pharmacological ResearchRanicaItaly
  4. 4.Ph.D. School of Informatics, DISCoUniversity of Milan—BicoccaMilanItaly
  5. 5.Department of Geriatric Medicine and NephrologyOsaka University Graduate School of MedicineOsakaJapan
  6. 6.Division of Geriatric Medicine, Department of Internal MedicineKeio University School of MedicineTokyoJapan
  7. 7.Department of Medical Sciences, Geriatric Unit, IRCCS Ca’ Granda Foundation Maggiore Policlinico HospitalUniversity of MilanMilanItaly
  8. 8.Department of NephrologyNagoya University Graduate School of MedicineNagoyaJapan
  9. 9.Department of Clinical Thanatology and Geriatric Behavioral ScienceOsaka University Graduate School of MedicineOsakaJapan
  10. 10.Mario Negri Institute for Pharmacological ResearchBergamoItaly
  11. 11.Unit of Nephrology and DialysisAzienda Ospedaliera Ospedali Riuniti di BergamoBergamoItaly

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