title: Variations of the angiotensin II type 1 receptor gene are associated with extreme human longevity.
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.
authors.affiliation: 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.
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
authors.forename: Silvia
authors.initials: S
authors.lastname: Orisio
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Paraskevas
authors.initials: P
authors.lastname: Iatropoulos
authors.forename: Davide
authors.initials: D
authors.lastname: Castaldi
authors.forename: Kei
authors.initials: K
authors.lastname: Kamide
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Arai
authors.forename: Marta
authors.initials: M
authors.lastname: Todeschini
authors.forename: Giulia
authors.initials: G
authors.lastname: Ogliari
authors.forename: Enyu
authors.initials: E
authors.lastname: Imai
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Gondo
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Hirose
authors.forename: Daniela
authors.initials: D
authors.lastname: Mari
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D004247:DNA / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007558:Italy; D015810:Linkage Disequilibrium; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D044140:Receptor, Angiotensin, Type 1; D004247:DNA