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 associated with reduced AT receptor protein levels and 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 with 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 fewer AT R-positive peripheral blood polymorphonuclear cells. Moreover, rs275653 was associated with 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 evidence suggests that genetic factors contribute in a major way to variation in human lifespan particularly in populations known for exceptional survival (Sirtori et al. 2001; Bilal et al. 2008). Genetic determinants of longevity were initially reported in small, short-lived organisms 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 polymorphisms in the human forkhead box O3A (FOXO3A) gene, which encodes a key regulator of the insulin/insulin growth factor 1 signaling pathway, were associated 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 longevity, variations of FOXO3A and of other genes in the insulin/insulin growth factor 1 signaling pathway found no or only modest effects on human lifespan (Flachsbart et al. 2009; Willcox et al. 2008; Pawlikowska et al. 2009). Thus, investigations on further candidates with substantial beneficial effects on human lifespan are needed to fully disclose the determinants of human aging.

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, - 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

Materials and Methods