Biogerontology 5: 169–176, 2004.   2004 Kluwer Academic Publishers. Printed in the Netherlands. BN

Association between low self-rated health and heterozygosity for 110A>C polymorphism in the promoter region of HSP70-1 in aged Danish twins

Ripudaman Steen Peter Niels Bjørn Andersen Frederiksen4 , Kaare Christensen4 & Suresh I. S. Rattan2,(cid:1) 1Department of Human Genetics University of Aarhus, DK-8000, Aarhus-C, Denmark; 2Department Molecular Biology, University of Aarhus, DK-8000, Aarhus-C, Denmark; 3Research Unit for Medicine, Aarhus University Hospital and Faculty of Health Sciences, Skejby Sygehus, DK-8200, Denmark; 4Institute of Public Health, University of Southern Denmark, DK-5000, Odense-C, Denmark *Author for correspondence (e-mail: rattan@imsb.au.dk; fax: 45-8612-3178)

Received 2 September 2003; accepted in revised form 15 December 2003

Key words: aging, gerontogenes, heat shock proteins, longevity, stress response

Abstract

We have studied the possible association between the 110A > C polymorphism in the promoter region of one of the heat shock protein genes HSP70-1 with human longevity in a cohort of aged Danish twins. This cohort includes individuals aged between 70 and 91 years (mean ¼ 75.6 years), who are categorized according to the presence or absence of various diseases and according to the various, age-related parameters for which a genetic component has already been defined. Four hundred DNA samples from the cohort were genotyped using real-time PCR. Aging phenotypes (diseases, physical and cognitive func- tioning) were compared with regard to genotype. Of all the aging phenotypes studied, self-rated health and relative self-rated health, which represent an individual’s overall sense of physical well-being and which have been shown to be both predictors of survival at older ages and better indicators of future survival than objectively measured health status, were associated with the polymorphism. An association was found ) between low self-rated health and heterozygosity for 110A > C polymorphism in the promoter region of

Introduction

demonstrate an association between polymor- phisms in Hsp genes (HSP) and parameters of organismal aging.

In most eukaryotic cells, a slight increase in stress in the form of heat, heavy metals, nutrient depri- vation, oxygen radicals or viral infection induces a heat shock (HS) response, marked by the repres- sion of normal protein synthesis, induction of HS genes and the preferential synthesis of several HS proteins (Hsp) or stress proteins (for a review see, Verbeke et al. 2001). HS response protects cells from subsequent damage and aids them to coun- teract the effects of the stress. The capacity to re- spond rapidly to stress at the gene level determines the adaptive and, therefore, the survival capacity and longevity of the organism (Minois 2000; Rattan 2001). One way to indicate relationship between organismal aging and stress response is to

Of the various stress proteins, Hsp70 is the most prominent and best characterised in the stress protein families. Hsp70 is a highly inducible and most actively synthesised protein in the cell upon HS (Tavaria et al. 1996; Verbeke et al. 2001). Hsp70 protein family members have a highly con- served sequence from E. coli to man (Kiang and Tsokos 1998). Cognate members of the Hsp70 family are found within all the major intercellular compartments while the inducible isoforms appear to be predominantly cytoplasmic or nuclear in distribution (Tavaria et al. 1996). Hsp70 acts either as a chaperone, or cooperates with the proteolytic pathways in the cells. In humans there are 11

different isoforms of Hsp70 encoded by different genes located at dispersed loci. Three of the HSP70 are mapped within major histocompatibility com- plex (MHC) class III region on the short arm of chromosome 6 (Goate et al. 1987). These are in- tron-less HSP70-1, HSP70-2 and HSP70-Hom (Milner and Campbell 1990), which have homolo- gous gene sequence but differ in their regulation. There are 14 polymorphic sites within these three MHC-linked HSP70: six in HSP70-1 and four each in HSP70-2 and HSP70-Hom. Polymorphisms in these three genes have been extensively studied for their association with various autoimmune diseases such as systemic lupus erythematosus (Jarjour et al. 1996), rheumatoid arthritis (Reid et al. 1991), multiple sclerosis (Casino et al. 1994; Freedman et al. 1995; Niio et al. 2000), and insulin-dependent diabetes mellitus (Pociot et al. 1993). So far, no association between polymorphisms of the MHC- linked HSP and diseases has been found that would not be explained by linkage disequilibrium with other HLA markers. However, protective ef- fects of Hsp70 against oxidative stress suggest that it might be very valuable to study HSP polymor- phism in conditions associated with oxidant/anti- oxidant imbalance, for example aging.

DNA samples