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

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.

Benigni, Ariela
Orisio, Silvia
Noris, Marina
Iatropoulos, Paraskevas
Castaldi, Davide
Kamide, Kei
Rakugi, Hiromi
Arai, Yasumichi
Todeschini, Marta
Ogliari, Giulia
Imai, Enyu
Gondo, Yasuyuki
Hirose, Nobuyoshi
Mari, Daniela
Remuzzi, Giuseppe
Item Type: 
Journal Article
Publication Title: 
Age (Dordrecht, Netherlands)
Journal Abbreviation: 
Age (Dordr)
Publication Date: 
Publication Year: 
Library Catalog: 
NCBI Published Medical (?)
PMID: 22569962 PMCID: PMC3636412

Turabian/Chicago Citation

Ariela Benigni, Silvia Orisio, Marina Noris, Paraskevas Iatropoulos, Davide Castaldi, Kei Kamide, Hiromi Rakugi, Yasumichi Arai, Marta Todeschini, Giulia Ogliari, Enyu Imai, Yasuyuki Gondo, Nobuyoshi Hirose, Daniela Mari and Giuseppe Remuzzi. 2013-06. "Variations of the angiotensin II type 1 receptor gene are associated with extreme human longevity." Age (Dordrecht, Netherlands) 35: 3: 993-1005. 10.1007/s11357-012-9408-8.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1007/s11357-012-9408-8 | issn = 1574-4647 | volume = 35 | pages = 993-1005 | last = Benigni | first = Ariela | coauthors = Orisio, Silvia, Noris, Marina, Iatropoulos, Paraskevas, Castaldi, Davide, Kamide, Kei, Rakugi, Hiromi, Arai, Yasumichi, Todeschini, Marta, Ogliari, Giulia, Imai, Enyu, Gondo, Yasuyuki, Hirose, Nobuyoshi, Mari, Daniela, Remuzzi, Giuseppe | title = Variations of the angiotensin II type 1 receptor gene are associated with extreme human longevity | journal = Age (Dordrecht, Netherlands) | date = 2013-06 | pmid = | pmc = }} </ref>