HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging

S. Michal Jazwinski,1 Sangkyu Kim,1,* Jianliang Dai,1,2,* Li Li,3 Xiuhua Bi,1 James C. Jiang,1 Jonathan Arnold,2 Mark A. Batzer,4 Jerilyn A. Walker,4 David A. Welsh,5 Christina M. Lefante,6 Julia Volaufova,6

inferred ethnic affiliation to account for population struc- ture. Haplotype analysis was performed in three candi- date genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further aug- mented its magnitude. These results were replicated in a second population. A profile of healthy aging was devel- oped using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, caus- ing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congru- ence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mecha- nisms underlying exceptional survival and healthy aging that involve lipotoxicity. Key words: haplotypes; healthy aging profile; lipotoxic-

Leann Myers,7 L. Joseph Su,6,† Dorothy B. Hausman,8 Michael V. Miceli,1 Eric Ravussin,9 Leonard W. Poon,10 Katie E. Cherry11 and Michael A. Welsch12 for the Georgia Centenarian Study and the Louisiana Healthy Aging Study

1Tulane Center for Aging and Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA 2Genetics Department, University of Georgia, Athens, GA 30602,

Department, University of Georgia, Athens, GA Center, Louisiana State University Health New Orleans, LA

, USA of Biological Sciences, Louisiana State University, Rouge, LA

, USA of Medicine, Louisiana State University Health Center, New Orleans, LA

, USA of Public Health, Louisiana State University Health Center, New Orleans, LA

, USA of Biostatistics, School of Public Health and Tulane University Health Sciences Center, New

, USA of Foods and Nutrition, University of Georgia, GA

, USA Biomedical Research Center, Baton Rouge, LA USA of Gerontology, University of Georgia, Athens, GA USA of Psychology, Louisiana State University, Baton LA

, USA of Kinesiology, Louisiana State University, Baton LA

, USA

Introduction

Exceptional longevity has genetic and environmental compo- nents, but in humans they have often been difficult to identify (Christensen et al., 2006). Most of the research on the genet- ics of human aging has focused on the genetic risk factors associated with age-related diseases and disorders, with APOE being one prime candidate (Christensen et al., 2006). This is not surprising given the impact of variation in this gene on cardiovascular and neuropathological aspects of aging (Stritt- matter et al., 1993; Scha¨chter et al., 1994; Song et al., 2004; Christensen et al., 2006). Studies in model systems have also recently guided the search for genetic determinants of human longevity, pointing to several pathways and processes contrib- uting to enhanced lifespan (Jazwinski, 1996; Finch & Ruvkun, 2001; Kenyon, 2005). However, this approach has largely been limited to components of the insulin⁄IGF-1 pathway (Hong et al., 2008; Suh et al., 2008; Willcox et al., 2008). We decided to expand on this approach by examining the Ras and ceramide signaling pathways. The involvement of Ras signaling in lifespan determination has been adduced in studies in yeast (Chen et al., 1990; Sun et al., 1994) and in mice (Migliaccio et al., 1999), while the role of ceramide signaling emerges from research in yeast (D’mello et al., 1994; Jazwinski & Con- zelmann, 2002; Guillas et al., 2003) and in Caenorhabditis

Summary

The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were

S. Michal Jazwinski, P

, Department of Medicine, Tulane University Health Sciences Center,

Tulane Ave., SL-

, New Orleans, LA

, USA. Tel.:

; fax:

; e-mail: sjazwins@tulane.edu *Contributed equally. †Present address: Modifiable Risk Factors Branch, National Cancer Institute, Rockville, MD

, USA.

for publication 22 May 2010

elegans (Tedesco et al., 2008; Mehta et al., 2009; Menuz et al., 2009).

(A) All others European African (B) All others European African