Immunogenetics, gender, and longevity. Ann. N.Y. Acad. Sci.

,

–

Christensen,K.,Johnson,T.E.,Vaupel,J.W.,

Thequestforgeneticdeterminants of human longevity: challenges and insights. Nat. Rev. Genet.

,

–

Flachsbart,F.,Caliebe,A.,Kleindorp,R.,Blanche,H.,vo

ller-Eberstein,H.,Nikolaus, S., Schreiber, S., Nebel, A.,

Association of FOXO

A variation with human longevity confirmed in German centenarians. Proc. Natl. Acad. Sci. U.S.A.

,

–

Franceschi, C., Motta, L., Valensin, S., Rapisarda, R., Franzone, A., Berardelli, M., Motta, M., Monti, D., Bonafe, M., Ferrucci, L., Deiana, L., Pes, G.M., Carru, C., Desole, M.S., Barbi, C., Sartoni, G., Gemelli, C., Lescai, F., Olivieri, F., Marchegiani, F., Cardelli, M., Cavallone, L., Gueresi, P., Cossarizza, A., Troiano, L., Pini, G., Sansoni,P.,Passeri,G.,Lisa,R.,Spazzafumo,L.,Amadio,L.,Giunta,S.,Stecconi,R., Morresi, R., Viticchi, C., Mattace, R., De Benedictis, G., Baggio, G.,

Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE). Aging (Milano)

,

–

Franke, A., Wollstein, A., Teuber, M., Wittig, M., Lu, T., Hoffmann, K., Nurnberg, P., Krawczak,M.,Schreiber,S.,Hampe,J.,

GENOMIZER:anintegratedanalysis system for genome-wide association data. Hum. Mutat.

,

–

Frasca, D., Nguyen, D., Riley, R.L., Blomberg, B.B.,

Decreased E

and/or E

transcription factor activity in the bone marrow as well as in the spleen of aged mice. J. Immunol.

,

–

Frasca,D.,Vande

ut,E.,Riley,R.L.,Blomberg,B.B.,

Reduce

gclassswitchin aged mice correlates with decreased E

and activation-induced cytidine deaminase. J. Immunol.

,

–

Hampe, J., Franke, A., Rosenstiel, P., Till, A., Teuber, M., Huse, K., Albrecht, M., Mayr, G., De La Vega, F.M., Briggs, J., Gunther, S., Prescott, N.J., Onnie, C.M., Hasler, R., Sipos, B., Folsch, U.R., Lengauer, T., Platzer, M., Mathew, C.G., Krawczak, M., Schreiber, S.,

A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG

L

Nat. Genet.

,

–

Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H., Vijg, J.,

Aging and genome maintenance: lessons from the mouse? Science

,

–

Hasty,P.,

Theimpacto

NAdamage,geneticmutationandcellularresponses on cancer prevention, longevity and aging: observations in humans and mice. Mech. Ageing Dev.

,

–

Hitt, R., Young-Xu, Y., Silver, M., Perls, T.,

Centenarians: the older you get, the healthier you have been. Lancet

,

Hjelmborg, J.V.B., Iachine, I., Skytthe, A., Vaupel, J.W., M

ue, M., Koskenvuo, M., Kaprio, J., Pedersen, N.L., Christensen, K.,

Genetic influence on human lifespan and longevity. Hum. Genet.

,

–

Supplementary data associated with this article can be found, in online version, at doi:10.1016/j.mad.2009.08.004.

References

Our study demonstrates a female-specific association of an EXO1 promoter SNP with longevity. Such sex-specificity is not surprising since gender is a major determinant of longevity, favouring women. It also accounts for important differences in the frequency of various age-related diseases. There is a distinct prevalence of women among long-lived individuals, reaching up to 85% in some populations of centenarians and super-centenarians (Perls and Terry, 2003). It has been suggested that the mortality rates in men and women follow different trajectories during aging and that a complex interaction of environmental and genetic factors is likely to affect the gender-specific probability of reaching old age (Candore et al., 2006; Franceschi et al., 2000).

Our results highlight the general importance of centenarians for genetic longevity research (Tan et al., 2008). Since the genetic contribution to life expectancy is strongest at very advanced ages (Hjelmborg et al., 2006), centenarians may be particularly enriched for beneficial variants in longevity-enabling genes (Flachsbart et al., 2009; Perls et al., 2002). This hypothesis is strengthened by our findings that variation in EXO1 leads to higher gene expression and confers a survival advantage at very old age. Hence, EXO1 could be considered a candidate for a novel longevity-enabling gene.

Competing interests

The authors have declared no competing interests.

Hjelmborg, J.V.B., Iachine, I., Skytthe, A., Vaupel, J.W., McGue, M., Koskenvuo, M., Kaprio, J., Pedersen, N.L., Christensen, K., 2006. Genetic influence on human lifespan and longevity. Hum. Genet. 119, 312–321.

This study was supported by (1) the DFG Excellence Clusters ‘Inflammation at Interfaces’ and ‘Future Ocean’, (2) the German

NOD

(CARD

) gene in human intestinal epithelial cells. Gastroenterology

,

–

Schaetzlein, S., Kodandaramireddy, N.R., Ju, Z., Lechel, A., Stepczynska, A., Lilli, D.R., Clark, A.B., Rudolph, C., Kuhnel, F., Wei, K., Schlegelberger, B., Schirmacher, P., Kunkel, T.A., Greenberg, R.A., Edelmann, W., Rudolph, K.L.,

Exonuclease-

deletion impairs DNA damage signaling and prolongs lifespan of telomere- dysfunctional mice. Cell

,

–

Schwartz, R., Engel, I., Fallahi-Sichani, M., Petrie, H.T., Murre, C.,

Gene expression patterns define novel roles for E

in cell cycle progression, cyto- kine-mediatedsignaling,an

lineagedevelopment.Proc.Natl.Acad.Sci.U.S.A.

,

–

Sharma, S., Sommers, J.A., Driscoll, H.C., Uzdilla, L., Wilson, T.M., Brosh Jr., R.M.,

The exonucleolytic and endonucleolytic cleavage activities of human exonuclease

are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein. J. Biol. Chem.

,

–

Slattery, C., Ryan, M.P., M

orrow, T.,

E

A proteins: regulators of cell phenotype in normal physiology and disease. Int. J. Biochem. Cell Biol.

,

–

Tan, Q., Zhao, J.H., Zhang, D., Kruse, T.A., Christensen, K.,

Power for genetic association study of human longevity using the case–control design. Am. J. Epidemiol.

,

–