adjusted 3MS score of 86 or less, they were excluded from the SA arm of the study and referred to the dementia arm of the study. The next requirement was independence in activities of daily living (ADLs) defined as needing no more than occasional help with ADLs. The third requirement was absence of major medical conditions, including cancer, myocardial infarction, stroke, Parkinson's disease, chronic obstructive pulmonary disease, and end-stage renal disease. Finally, individuals needed to live in the community and be socially engaged as defined by being a member of a social group or organization.

Linkage and association of successful aging to the 6q25 region in large Amish kindreds

Received: 9 December 2011 / Accepted: 11 June 2012 / Published online: 7 July 2012 # American Aging Association 2012

Abstract

Successful aging (SA) is a multidimensional phenotype involving living to an older age with high physical function, preserved cognition, and continued social engagement. Several domains underlying SA are heritable, and identifying health-promoting polymorphisms and their interactions with the environment could provide important information regarding the health of older adults. In the present study, we examined 263 cognitively intact Amish individuals age 80 and older (74 SA and 189 normally aged) all of whom are part of a single 13-generation pedigree. A genome-wide association study of 630,309 autosomal single nucleotide polymorphisms (SNPs) was performed and analyzed for linkage using multipoint analyses and for association using the modified quasi-likelihood score test. There was evidence for linkage on 6q25-27 near the fragile site FRA6E region with a dominant model maximum multipoint heterogeneity LOD score 3.2. The 1-LOD-down support interval for this linkage contained one SNP for which there was regionally significant evidence of association (rs205990, p < 2.36105). This marker survived interval-wide Bonferroni correction for multiple testing and was located between the genes QKI and PDE10A. Other areas of chromosome 6q25-q27 (including the FRA6E region) contained several SNPs associated with SA (minimum p 2.89 × 10-6). These findings suggest potentially novel genes in the 6q25-q27 region linked and associated with SA in the Amish; however, these findings should be verified in an independent replication cohort.

Previous genetic studies of SA have focused on three primary categories of genes selected primarily for their relevance to aging-associated pathophysiological processes or processes that are known to change during the aging process (Glatt et al. 2007). These categories include: (1) genes involved in the maintenance of cholesterol, lipid, and/or lipoproteins (Arking et al. 2005; Cellini et al. 2005; Taioli et al. 2001); (2) genes that influence inflammation and immune response, particularly cytokines, many of which also influence cell cycling, growing, motility, and signaling (Capurso et al. 2004; Naumova et al. 2004); and (3) genes involved in drug metabolism (Taioli et al. 2001). To date, few of the candidate genes associated with SA have been successfully replicated, with the exception of a few studies that have associated with longevity but not SA (Atzmon et al. 2009a; Banasik et al. 2011; Chung et al. 2010; Deelen et al. 2011; Kleindorp et al. 2011; Li et al. 2009; Nebel et al. 2011; Snejdrlova et al. 2011), suggesting that this approach may not be the best for a complex trait such as SA.

Introduction

With the rapid expansion of the population over age 60, understanding the components of successful aging (SA) is becoming a critical component of the medical and public health response to this demographic shift. The number of adults over age 60 is predicted to reach two billion worldwide by the year 2050, more than doubling from 2000 (US Census Bureau Population Division and Housing and Household Economic Statistics Division 2001). This growing elderly population could dramatically impact our healthcare system depending on how successfully this population ages with regard to multiple factors such as physical, mental, and social well-being. Surprisingly, a large proportion of older adults have continued to function at a high level and have aged successfully (Depp and Jeste 2006). Understanding why some individuals avoid significant decline in physical function and susceptibility to age-related diseases might help guide clinical care and provide the basis for novel programs to prevent or slow such declines.