As for cognitive functioning, studies found an involvement of genes specifically involved in neurological metabolism and dopaminergic neuromodulation, such as APOE, COMT, BDNF, and DTNBP1 genes, with cognitive ability in older adults less than 85 years (De Blasi et al., 2009; Lindenberger et al., 2008). In particular, studies demonstrated an involvement of genetic variability in specific cognitive areas. Moreover, they suggest that aging magnifies the functional consequences of common genetic polymorphisms on specific abilities such as executive functioning and working memory, contributing to the marked heterogeneity in late-life cognitive functioning.

We moved forward exploring the association with functional status of genes belonging to a specific metabolic pathway demonstrated to be biologically involved in physical and cognitive impairment. Overall, only 2 of the top 14 genes found associated with functional status in this work have been previously reported in association studies on physical status at old age in Italian and Danish Cohorts (the latter the same used in the present paper), and they belong to UCPs family (et al., 2011; Dato et al., 2012b). Both UCP2 and UCP3 confirmed have a major effect on physical tests such as HG and WS in the whole sample as well as in the two genders separately, with the rs11235972 survival at old age too. The association of UCP3 gene variant with physical exercise is particularly relevant, considering its expression in skeletal muscle where it regulates fatty acid metabolism, status, and ROS production. This suggests a correlation between uncoupling process and the regulation of muscle metabolism/oxidative stress in the elderly (Dato et al., 2012b and references therein).

All the other associations are new and open the investigation of their variability in future studies. Furthermore, associations holding the multiple comparison correction were found in the female sub-sample, suggesting a sex-specific effect of the pro-antioxidant pathway on the analyzed functional parameters.

4. Discussions

Physical activity has many well-established health benefits, going from the maintenance of muscle mass to the delay of cognitive impairment, to the promotion of psychological wellness. However, it is known that strenuous exercise can be disadvantageous for longevity because it can increase muscle oxygen flux, stimulating intracellular events leading to enhanced oxidative stress (Dato et al., 2013 and references therein). A moderate exercise can instead induce antioxidant adaptation, thereby balancing oxidative stress and muscle deterioration, as demonstrated by an increase of two years in the average lifespan and a delay in disabilities of physically active people in comparison with less active (Ji, 2002).

Progressive oxidative damage is also a conserved central mechanism of age-related cognitive decline because of the higher consumption of oxygen (more than 20% than other tissues) in the brain, with the consequent exposure to ROS from mitochondrial respiration. As for muscle mass, regular physical activity seems to protect against brain damage by preventing brain.

The gene having a major effect on ADL phenotype is TXNRD1, both in the whole sample (pInflammatory status is a typical feature of old age (Vitale et al., 2013). Moreover, a new association was found in relation to MMSE levels with the metallothionein gene MT1A. This discovery opens new avenues of investigation into this gene family's relation to cognitive functioning in humans. Final conclusions on the genetic variants' role in stress mechanisms can only be drawn after confirmation by functional analyses. However, we believe that all associations found in this study should receive attention for future replication studies.

In general, the variability of genes affecting stress response in different individuals and populations deserves future study. Although the oxidative stress pathway has been extensively characterized from a biochemical and molecular point of view, thanks to experimental models and knockout approaches, population association studies investigating the role of genetic variability in genes coding for proteins belonging to the oxidative stress cascade, such as key point regulators NFkB or MAP kinases, are still scarce. A deeper understanding of the genetic background that can provide a more or less efficient stress response and influence age-associated traits can help understand the link between stress response and human aging, ultimately adding a piece to the complex scenario of determinants of human longevity.

NDUFS1's variability was found to be related to HG and WS in the whole sample, suggesting non-negligible effects on physical functioning. The strong association (p = 0.009) of the same gene with survival in the female subsample suggests that NDUFS1 gene, which codes for the largest subunit of mitochondrial complex 1, and whose mutations were correlated with inefficiency of oxidative phosphorylation in Leigh Syndrome (Martin et al., 2005), can also play a role in preserving physical functioning at old age and influence survival.

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.exger.2014.01.014.