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journal homepage: www.elsevier.com/locate/expgero

Contribution of genetic polymorphisms on functional status at very old age: A gene-based analysis of 38 genes (311 SNPs) in the oxidative stress pathway

S. Dato a,b, , M. Soerensen b,c, V. Lagani d, A. Montesanto a, G. Passarino a, K. Christensen Q. Tan b,c, L. Christiansen b,c

a Department of Biology, Ecology and Heart Sciences, University of Calabria, Ponte Pietro Bucci cubo4C, 87036 Rende, CS, Italy b The Danish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winslows Vej 9B, 5000 Odense C, c Department of Clinical Genetics, OdenseUniversity Hospital, Sdr. Boulevard 29, 5000 OdenseC, Denmark d Bio Informatics Laboratory, Institute of Computer Science, Foundation for Research and Technology (Hellas), Heraklion, Greece e Department of Clinical Biochemistry and Pharmacology, OdenseUniversity Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark

Preservation of functional ability is a well-recognized marker of longevity. At a molecular level, a major de- terminant of the physiological decline occurring with aging is the imbalance between production and accu- mulation of oxidative damage to macromolecules, together with a decreased efficiency of stress response to avoid or repair such damage. In this paper we investigated the association of 38 genes (311 SNPs) belonging to the pro–antioxidant pathways with physical and cognitive performances, by analyzing single SNP and gene-based associations with Hand Grip strength (HG), Activities of Daily Living (ADL), Walking Speed (WS), Mini Mental State Examination (MMSE) and Composite Cognitive Score (CCS) in a Cohort of 1089 Danish nonagenarians. Moreover, for each gene analyzed in the pro–antioxidant pathway, we tested the in- fluence on longitudinal survival. In the whole sample, nominal associations were found for TXNRD1 variability with ADL and WS, NDUFS1 and UCP3 with HG and WS, GCLC and UCP2 with WS (p b 0.05). Stronger associations although not holding the multiple comparison correction, were observed between MMSE and NDUFV1, MT1A and GSTP1 variabil- ity (p b 0.009). Moreover, we found that association between genetic variability in the pro–antioxidant pathway and functional status at old age is influenced by sex. In particular, most significant associations were observed in nonagenarian females, between HG scores and GLRX and UCP3 variability, between ADL levels and TXNRD1, MMSE and MT1A genetic variability. In males, a borderline statistically significant asso- ciation with ADL level was found for UQCRFS1 gene. Nominally significant associations in relation to survival were found in the female sample only with SOD2, NDUFS1, UCP3 and TXNRD1 variability, the latter two confirming previous observations reported in the same co- hort. Overall, our work supports the evidence that genes belonging to the pro–anti-oxidant pathway are able to

of functional ability is a well-recognized marker of longevity. At a molecular level, a major de- of the physiological decline occurring with aging is the imbalance between production and accu- of oxidative damage to macromolecules, together with a decreased efficiency of stress response to or repair such damage. In this paper we investigated the association of 38 genes (311 SNPs) belonging the pro–antioxidant pathways with physical and cognitive performances, by analyzing single SNP and associations with Hand Grip strength (HG), Activities of Daily Living (ADL), Walking Speed Mini Mental State Examination (MMSE) and Composite Cognitive Score (CCS) in a Cohort of 1089 nonagenarians. Moreover, for each gene analyzed in the pro–antioxidant pathway, we tested the in- on longitudinal survival.

Danish nonagenarians. Moreover, for each gene analyzed in the pathway, we tested the in- fluence on longitudinal survival. In the whole sample, nominal associations were found for TXNRD1 variability with ADL and WS, NDUFS1 and UCP3 with HG and WS, GCLC and UCP2 with WS (p b 0.05). Stronger associations although not holding the multiple comparison correction, were observed between MMSE and NDUFV1, MT1A and GSTP1 variabil- ity (p b 0.009). Moreover, we found that association between genetic variability in the pro–antioxidant pathway and functional status at old age is influenced by sex. In particular, most significant associations were observed in nonagenarian females, between HG scores and GLRX and UCP3 variability, between ADL levels and TXNRD1, MMSE and MT1A genetic variability. In males, a borderline statistically significant asso- ciation with ADL level was found for UQCRFS1 gene.

Nominally significant associations in relation to survival were found in the female sample only with SOD2, NDUFS1, UCP3 and TXNRD1 variability, the latter two confirming previous observations reported in the same co- hort. Overall, our work supports the evidence that genes belonging to the pro–anti-oxidant pathway are able to modulate physical and cognitive performance after the ninth decade of life, finally influencing extreme survival. © 2014 Elsevier Inc. All rights reserved.

1. Introduction

ability to repair such damage (Balaban et al., 2005; Harman, 2009). The balance between pro-oxidants and enzymatic anti-oxidant systems may be of particular importance in the elderly, whose nutritional defi- ciencies and sedentary lifestyle concur with a depletion of dietary anti- oxidants and increased susceptibility to oxidative stress.

Aging is a very complex phenomenon, which negatively impacts the functioning ofdifferentbiological systems, leadingtoasystemic impair- ment and ultimately to death. The physiological decline occurring with aging can be determined by an imbalance between the production and accumulation of oxidative damages to macromolecules, and cellular