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Mechanisms of Ageing and Development 127 (2006) 862–868

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heat shock protein 70 level as a biomarker of exceptional longevity

a a a b Dellara F. Terry , Diego F. Wyszynski , Vikki G. Nolan , Gil Atzmon , a a a a Emily A. Schoenhofen , JaeMi Y. Pennington , Stacy L. Andersen , Marsha A. Wilcox a b a c,* Lindsay A. Farrer , Nir Barzilai , Clinton T. Baldwin , Alexzander Asea

aGeriatrics Section, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA bDepartment of Medicine, Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY, USA cDivision of Investigative Pathology, Scott & White Memorial Hospital and Clinic and The Texas A&M University System Health Science Center College of Medicine, Temple, TX, USA

Received 12 May 2006; received in revised form 16 August 2006; accepted 23 August 2006

Abstract

Heat shock proteins are highly conserved proteins that, when produced intracellularly, protect stress exposed cells. In contrast, extracellular heat shock protein 70 (Hsp70) has been shown to have both protective and deleterious effects. In this study, we assessed heat shock protein 70 for its potential role in human longevity. Because of the importance of HSP to disease processes, cellular protection, and inflammation, we hypothesized that: (1) Hsp70 levels in centenarians and centenarian offspring are different from controls and (2) alleles in genes associated with Hsp70 explain these differences. In this cross-sectional study, we assessed serum Hsp70 levels from participants enrolled in either the New England Centenarian Study (NECS) or the Longevity Genes Project (LGP): 87 centenarians (from LGP), 93 centenarian offspring (from NECS), and 126 controls (43 from NECS, 83 from LGP). We also examined genotypic and allelic frequencies of polymorphisms in HSP70-A1A and HSP70-A1B in 347 centenarians (266 from the NECS, 81 from the LGP), 260 NECS centenarian offspring, and 238 controls (NECS: 53 spousal controls and 106 septuagenarian offspring controls; LGP: 79 spousal controls). The adjusted mean serum Hsp70 levels (ng/mL) for the NECS centenarian offspring, LGP centenarians, LGP spousal controls, and NECS controls were 1.05, 1.13, 3.07, 6.93, respectively, suggesting that a low serum Hsp70 level is associated with longevity; however, no genetic associations were found with two SNPs within two hsp70 genes. #

Keywords: Ageing; Centenarian; Chaperokine; Heat shock proteins;

1. Introduction

cell viability by binding to polypeptide chains and preventing protein denaturation and incorrect assembly intracellularly (Georgopoulos and Welch, 1993; Hartl, 1996). Intracellular Hsp70 is also thought to exert an anti-apoptotic function by binding to the tumor suppressor protein p53 and the cellular transcription factor, c-myc, thereby inhibiting the activation of the caspase cascade (Pinhasi-Kimhi et al., 1986; Koskinen et al., 1991).

Heat shock proteins (HSPs) are highly conserved proteins that function by chaperoning, transporting, and folding proteins when cells are exposed to a variety of stresses. Normally, HSP is expressed at low levels within all known cells; however, in response to various stressful conditions, a self-protective reaction occurs resulting in the synthesis of intracellular HSPs (Lindquist and Craig, 1988; Villar et al., 1993). One particular HSP, the inducible 70-kd heat shock protein (Hsp70), preserves

Although the numerous functions of intracellular Hsp70 have been elucidated, only recently has the role of extracellular Hsp70 (also referred to as serum Hsp70) begun to be addressed. Accumulating evidence indicates that extracellular Hsp70 activates innate immune cells leading to an inflammatory cascade. Prior research has shown that extracellular Hsp70 possesses potent cytokine activity, with the ability to bind with

* Corresponding author. Tel.: +

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E-mail addresses: aasea@swmail.sw.org, asea@medicine.tamhsc.edu (A. Asea).

0047-6374/$ – see front matter # 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mad.2006.08.007

high affinity to the plasma membrane, elicit a rapid intracellular Ca2+ flux, activate the transcription factor NF-kB nuclear translocation, augment the expression and release of pro- inflammatory cytokines (Basu et al., 1998; Asea et al., 2000a,b; Binder et al., 2000), induce nitric oxide release (Panjwani et al., 2002), upregulate co-stimulatory molecule expression (Asea et al., 2002), and induce dendritic cell maturation (Kuppner et al., 2001; Asea et al., 2002; Noessner et al., 2002). These functions can be protective if activated in the context of a cellular insult; however, they can also be detrimental if they lead to excessive inflammation.