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

Preservation of functional ability is a well-recognized marker of longevity. At a molecular level, a major determinant of the physiological decline occurring with aging is the imbalance between production and accumulation 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 influence 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<0.05). Stronger associations although not holding the multiple comparison correction, were observed between MMSE and NDUFV1, MT1A and GSTP1 variability (p<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 association 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 cohort. 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.