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

Received: 24 November 2011 /Accepted: 4 April 2012 /Published online: 9 May 2012 # American Aging Association 2012

– (3):524 530, 2009). Based on the above study in mice, here we sought to search for AGTR1 variations associ- ated to reduced AT receptor protein levels and to pro- 1 longed lifespan in humans. AGTR1 was sequenced in 173 Italian centenarians and 376 younger controls. A novel non-synonymous mutation was detected in a cen- tenarian. Two polymorphisms in AGTR1 promoter, rs422858 and rs275653, in complete linkage disequilib- rium, were significantly associated with the ability to

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 ho- molog of the human angiotensin II type 1 receptor (AT R) gene (AGTR1) translates into marked prolonga- 1 tion of animal lifespan (Benigni et al., J Clin Invest 119

Ariela Benigni and Silvia Orisio contributed equally to this work.

Electronic supplementary material The online version of this article (doi:10.1007/s11357-012-9408-8) contains supplementary material, which is available to authorized users.

A. Benigni S. Orisio Department of Molecular Medicine, Mario Negri Institute for Pharmacological Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano

,

Bergamo, Italy e-mail: silvia.orisio@marionegri.it

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

Human angiotensin II type

receptor Forkhead box O

A Reactive oxygen species Angiotensin II National Center of Biotechnology Information Peripheral blood mononuclear cells Polymorphonuclear cells Odds ratio Fluorescence activated cell sorting Hardy-Weinberg

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 associ- ation with exceptional old age. In combined analyses, rs275653 was associated to extreme longevity either at 0 recessive model (P 0.007, odds ratio (OR) 3.57) or at 0 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 AT R-positive peripheral blood polymorphonuclear 1 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.

Introduction

The phenotype of human longevity has many diverse determinants. Non-genetic factors such as health habits, socioeconomic conditions, diet and physical activity account for an important part; however, emerging evi- dence suggests that genetic factors contribute in a major way to variation in human lifespan particularly in pop- ulations known for exceptional survival (Sirtori et al. 2001; Bilal et al. 2008). Genetic determinants of lon- gevity were initially reported in small, short-lived organ- isms including yeast, worm and flies, but a considerable number of these genes turned out to extend lifespan in mammals as well. Among plausible candidates for human longevity, polymorphisms in apolipoprotein E gene have been found to influence lifespan in multiple populations, probably through their association with lower risk of cardiovascular disease and dementia (Corder et al. 1996). More recently, findings in two independent populations documented that polymor- phisms in the human forkhead box O3A (FOXO3A) gene, which encodes a key regulator of the insulin/ insulin growth factor 1 signalling pathway, were asso- ciated with the ability to attain exceptional old age (Flachsbart et al. 2009; Willcox et al. 2008). However, as can be expected for a polygenic trait like lon- gevity, variations of FOXO3A and of other genes in the insulin/insulin growth factor 1 signalling pathway found no or only modest effect on human lifespan (Flachsbart et al. 2009; Willcox et al. 2008; Pawlikowska et al. 2009). Thus, investiga- tions on further candidates with substantial benefi- cial effects on human lifespan are needed to fully disclose the determinants of human ageing.

Keywords Angiotensin II type I receptor. Genetic polymorphism . Centenarians . Human longevity

R Angiotensin II type

receptor

R Angiotensin II type

A receptor

A R Angiotensin II type

B receptor

B R−/− Mouse deficient for angiotensin II type

A

A receptor

Geriatric Unit, IRCCS Ca’ Granda Foundation Maggiore Policlinico Hospital, University of Milan, 20122 Milan, Italy

E. Imai

Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan

Y. Gondo

Department of Clinical Thanatology and Behavioral Science, Osaka University Graduate School of Medicine,

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Osaka, Japan

G. Remuzzi

Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano

,

Bergamo, Italy

G. Remuzzi

A recent study demonstrated that mice deficient for angiotensin II type 1A receptor (AT R) (AT R−/− ) 1A 1A

Lombardy region, northern Italy, was recruited through – years 2004 2009. The gender ratio was 83 % females to 17 % males. Subjects aged more than 99 years and 6 months were considered centenarians as they were in their 100th year of life. Centenarians were recruited through PRIN 2006 study. The younger control subjects (between 49 and 78 years of age, mean 65.9±9.1 years, 43 % females and 57 % males) were Italians unrelated to centenarians and recruited in the same geographical area through COFIN 2000 study.