;

:

-

Rattan SI. Hormesis in aging. Ageing Res Rev

;

:

-

Soti C, Csermely P. Molecular chaperones and the aging Biogerontology

;

:

-

Hooper PL, Hooper PL. Inflammation, heat shock proteins, type

diabetes. Cell Stress Chaperones

;

:

-

Njemini R, Demanet C, Mets T. Inflammatory status as an tant determinant of heat shock protein

serum during aging. Biogerontology

;

:

-

Njemini R, Bautmans I, Lambert M, Demanet C, Mets T. shock proteins and chemokine/cytokine secretion profile in and inflammation. Mech Ageing Dev

;

:

-

Rattan SI, Clark BF. Understanding and modulating IUBMB Life

;

:

-

Singh R, Kolvraa S, Rattan SI. Genetics of human longevity emphasis on the relevance of HSP

as candidate genes. Biosci

;

:

-

Altomare K, Greco V, Bellizzi D, Berardelli M, Dato S, F, et al. The allele (A)(-

) in the promoter region of the gene is unfavorable to longevity in women. Biogerontology

:

-

Ross OA, Curran MD, Crum KA, Rea IM, Barnett YA, D. Increased frequency of the

T allele of the heat shock

-Hom gene in an aged Irish population. Exp Gerontol

;

-

Singh R, Kolvraa S, Bross P, Gregersen N, Nexo BA, H, et al. Association between low self-rated health and zygosity for -

A > C polymorphism in the promoter region HSP

-

in aged Danish twins. Biogerontology

;

:

-

Singh R, Kolvraa S, Bross P, Christensen K, Gregersen N, Tan et al. Heat-shock protein

genes and human longevity: a from Denmark. Ann NY Acad Sci

;

:

-

Tavaria M, Gabriele T, Kola I, Anderson RL. A hitchhiker's to the human Hsp

family. Cell Stress Chaperones

;

:

-

Goate AM, Cooper DN, Hall C, Leung TKC, Solomon E, Lim Localization of a human heat-shock Hsp-

gene sequence chromosome-

and detection of

other loci by somatic-cell and restriction-fragment-length-polymorphism analysis. Hum

;

:

-

Milner CM, Campbell RD. Structure and expression of the MHC-linked HSP

genes. Immunogenetics

;

:

-

Milner CM, Campbell RD. Polymorphic analysis of the MHC-linked HSP

genes. Immunogenetics

;

:

-

Christensen K, Johnson TE, Vaupel JW. The quest for determinants of human longevity: challenges and insights. Nat Genet

;

:

-

De Benedictis G, Tan Q, Jeune B, Christensen K, Ukraintseva Bonafe M, et al. Recent advances in human association studies. Mech Ageing Dev

;

:

-

Tan Q, Christiansen L, Bathum L, Li S, Kruse TA, Christensen Genetic association analysis of human longevity in cohort studies elderly subjects: an example of the PON

Gene in the Danish Birth Cohort. Genetics

;

:

-

Christiansen L, Bathum L, Frederiksen H, Christensen K. xonase

polymorphisms and survival. Eur J Hum Genet

;

-

Tan Q, Christiansen L, Bathum L, Zhao JH, Yashin AI, Vaupel

The polymorphism HSPA1L (2437T>C) is present in the coding region of the gene and leads to an amino acid change at position 493 from a non-polar hydrophobic methionine (Met) to a polar neutral threonine (Thr). This may have biofunctional relevance, since amino acid 493 corresponds to amino acid position 489 in E. coli DnaK, which in the crystal structure of the DnaK peptide binding domain is localised on the beta sheet beneath the peptide binding groove [29]. An amino acid change at this position could be associated with the peptide-binding specificity of Hsp70. A change to a polar neutral Thr (allele C) may affect the chaperone activity and hence the functional efficiency of HSPA1L by lowering the strength of the hydrophobic interactions between chaperones and the target protein [12]. Also in a recent study we were able to show that after heat stimulation mononuclear cells from the carriers of genotype HSPA1L-TT had better HSR than HSPA1L-CC [30]. And this difference was more prevalent among females. This fits quite well into our current observations of the effects of haplotypes, carrying these alleles, on human survival.

In a recent study it was shown that the females from the 1905 cohort had lower self reported disability levels, and were fitted with respect to different parameters of Activities of Daily Living (ADL) as compared to the females from another centenarian cohort [31]. However this difference was not observed among males. It remains to be seen if those females who have better ADL carry the geno- types/haplotypes which have predisposition towards longer duration

These results from the association of genotypes/haplotypes of HSP70 genes on human survival reiterate the view that the genes involved in stress response are suitable candidates for studying the genetics of longevity.

ACKNOWLEDGEMENTS

This study received financial support from the Faculty of Health Sciences, Aarhus University, Danish Centre for Molecular Gerontology, Velux Foundation, National Institute on Aging (grant P01-AG08761) and the Danish Research Councils, FNU and FSS.

Activities of Daily Genotype Relative Risk Haplotype Relative Risk Heath shock proteins

Tan Q, Christiansen L, Bathum L, Zhao JH, Yashin AI, Vaupel JW, et al. Estimating haplotype relative risks on human survival in population-based association studies. Hum Hered 2005; 59: 88-97.

Nebel A, Croucher PJ, Stiegeler R, Nikolaus S, Krawczak M, Schreiber S. No association between microsomal triglyceride transfer protein (MTP) haplotype and longevity in humans. Proc Natl Acad Sci USA

;

:

-

Bathum L, Christiansen L, Jeune B, Vaupel J, Mcgue M, Christensen K. Apolipoprotein e genotypes: relationship to cog- nitive functioning, cognitive decline, and survival in nonagenarians. J Am Geriatr Soc

;

:

-

Nybo H, Gaist D, Jeune B, Bathum L, Mcgue M, Vaupel JW, et al. The Danish

cohort: a genetic-epidemiological nationwide survey. J Aging Health

;

:

-

Favatier F, Jacquier-Sarlin MR, Swierczewski E, Polla BS. Polymorphism in the regulatory sequence of the human hsp

-

gene does not affect heat shock factor binding or heat shock protein synthesis. Cell Mol Life Sci

;

:

-

Wu YR, Wang CK, Chen CM, Hsu Y, Lin SJ, Lin YY, et al. Analysis of heat-shock protein