Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity

replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was signifi- cantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68–0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan associa- tion among women only (rs1935949, OR = 1.35, 95%CI = 1.15–1.57, adjusted P = 0.0093). These results demon- strate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan. Key words: AKT1; FOXO3A; gene; IGF1; longevity; SNP.

Ludmila Pawlikowska,1,2,* Donglei Hu,3,* Scott Huntsman,3 Andrew Sung,4 Catherine Chu,4 Justin Chen,4 Alexander H. Joyner,5 Nicholas J. Schork,5 Wen-Chi Hsueh,2,3 Alexander P. Reiner,6 Bruce M. Psaty,6,7 Gil Atzmon,8 Nir Barzilai,8 Steven R. Cummings,9 Warren S. Browner,9 Pui-Yan Kwok2,4 and Elad Ziv2,3 for the Study of Osteoporotic

of Anesthesia and Perioperative Care, University San Francisco, CA, USA for Human Genetics, University of California, San CA, USA of Medicine, University of California, San USA Research Institute, University of California, San CA, USA Genomic Medicine, The Scripps Translational Science and Department of Molecular and Experimental The Scripps Research Institute, La Jolla, CA, USA Health Research Unit, Departments of and Health Services, University of Washington, WA, USA for Health Studies, Group Health, Seattle, WA, USA for Aging Research and Department of Medicine, College of Medicine, Bronx, NY, USA Pacific Medical Center Research Institute, San CA, USA

Introduction

Genes in the insulin/IGF1 signaling pathway affect lifespan in yeast, nematodes, fruit flies and mice (Kuningas et al., 2008). Mutation of genes in this signaling pathway confers greater resistance to oxidative stress and phenotypic characteristics

The insulin/IGF1 pathway was first implicated in aging in Caenorhabditis elegans (Kenyon et al., 1993; Larsen et al., 1995; Morris et al., 1996). Mutation of daf-2, the nematode ortholog of the IGF1 and insulin receptors, results in extended lifespan and increased stress resistance (Kenyon et al., 1993; Kimura et al., 1997); these effects are mediated by the nuclear transcription factor, DAF-16, which is a homolog of the mam- malian forkhead (FKHRL or FOXO) transcription factors (Ogg et al., 1997). Mutations in age-1, the homolog of mammalian PI3Kinase, which is involved in signal transduction from the insulin and IGF1 receptors (Dorman et al., 1995), also increase lifespan in C. elegans. Similarly, in Drosophila, mutations of the insulin receptor homolog, its substrate, chico (Clancy et al., 2001), and of the daf-16/foxo homolog (Hwangbo et al., 2004)

Summary

The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Cau- casian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan ‡ 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average-lifespan controls (life- span £ 79y, mean = 75.7 ± 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then

In vertebrates, growth and glucose metabolism are regulated by two parallel pathways, with separate receptors for insulin and IGF1. In mice, mutations that result in growth hormone deficiency or mutations in growth hormone receptors cause reduced size, lower insulin levels, increased stress resistance and longer lifespan (Bartke, 2005). Heterozygous deletion of the IGF1R gene in mice causes a modest reduction in size, improves stress resistance and extends lifespan in females. Disruption of the INSR gene globally or in most tissues leads to insulin resis- tance and shortened lifespan (Joshi et al., 1996; Okamoto & Accili, 2003); however, mice homozygous for INSR deletion specific to fat cells have extended lifespan in both sexes (Bluher et al., 2002), indicating the presence of tissue-specific effects.

Elad Ziv, MD,

Divisadero Street, Suite

, UCSF Box

San Francisco, CA

, USA. Tel.: +

(

)

-

; fax: +

e-mail: elad.ziv@ucsf.edu *These authors contributed equally to this study.

authors contributed equally to this study.

Accepted for publication 6 May 2009

Table 1 Characteristics of the three study cohorts

SOF CHS AJC Characteristic Cases Controls Cases Controls Cases Controls N 293 603 279 797 383 363 Age (years) 95.3 ± 2.2 75.7 ± 2.6 94.5 ± 2.1 76.1 ± 3.1 99.8 (95–108) 85.5 (43–94) Sex (% male) 0 0 47.0 52.6 25.2 42.7 % Alive 55.6 0 33.7 0 24 96 % Atherosclerosis death 17.7 30.2 16.8 26.1 NA NA % Cancer death 4.1 40.8 12.9 37.5 NA NA % Other death 22.5 29.0 36.6 39.1 NA NA

Age refers to the age at death for deceased subjects, and age at last follow-up for subjects still alive. SOF, Study of Osteoporotic Fractures; CHS, Cardiovascular Health Study; AJC, Ashkenazi Jewish Centenarians; NA,