Decline of functional capacity and stress resistance to internal and external factors are strictly related (Simm et al., 2008) and together can be used as measures of the aging rate (Vasto et al., 2010).

The importance of the oxidative stress pathway in aging and lon- gevity, in particular, was firstly proposed by Harman in 1956 with the “oxidative stress theory of aging” (Harman, 1956) and supported by genetic screenings in model organisms, demonstrating that longevi- ty can be promoted through the manipulation of metabolism (i.e. calo- ric restriction) and resistance to oxidative stress (Vijg and Suh, 2005).

⁎ Corresponding author at: Department of Biology, Ecology and Earth Science, UniversityofCalabria,87036Rende,Italy.Tel.:+390984492933;fax:+390984492911.

(M. Soerensen), vlagani@ics.forth.gr (V. Lagani), amontesanto@unical.it (A. Montesanto), giuseppe.passarino@unical.it(G.Passarino),kchristensen@health.sdu.dk(K.Christensen), qtan@health.sdu.dk (Q. Tan), lchristiansen@health.sdu.dk (L. Christiansen).

0531-5565/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.exger.2014.01.014

Table 1

Despite considerable divergence during evolution, the same mecha- nisms appear to act in mammals too and it is considered that decreased metabolism and increased resistance to oxidative stress represent key mechanisms of prolonged lifespan in mutant mice (Bartke et al., 2001). In humans, the worsened efficiency of stress response represents a health risk, leading to the onset and accrual of major age-related dis- eases, including Alzheimer's, cancer, cardiovascular diseases (CVD) and diabetes (Lloret et al., 2008). Moreover, an association between oxida- tive imbalance and frailty syndrome was demonstrated, with an in- crease of oxidative stress in frail, institutionalized elderly people, leadingtoanaccelerationofagingprocessesincomparisonwithfreeliv- ing elderly (Serviddio et al., 2009).

General characteristics and post-survey mortality inthe Danish 1905-Cohort.

Men Women Total (n = 313) (n = 776) (n = 1089) Survival ⁎ Deaths [n(%)] 382 (97.9) 963 (97.3) 1345 (97.5) Person-Years 1244 3990 5234 Mortality rate per 100 30.7 24.1 25.6 Age (year) Mean (SD) 93.2 (0.3) 93.1 (0.3) 93.2 (0.3) Range 92.7–93.8 92.7–93.8 92.7–93.8 HG strength [kg] Mean (SD) 23.2 (6.5) 13.6 (4.4) 16.3 (6.7) Range 3–46 2–29 2–46 ⁎⁎ ADL [n (%)] Not disabled 180 (46.2) 318 (32.1) 498 (36.1) Disabled 210 (53.8) 672 (67.9) 882 (63.9) Walking speed [m/s] Mean (SD) 0.22 (0.09) 0.18 (0.08) 0.19 (0.09) Range 0.05–0.50 0.05–0.50 0.05–0.50 BMI Mean (SD) 24.1 (3.2) 22.9 (4.0) 23.2 (3.8) Range 15.2–37.6 14.0–74.9 14.0–74.9 MMSE Mean (SD) 22.3 (5.9) 21.7 (5.4) 21.8 (5.6) Range 2–30 0–30 0–30 CCS Mean (SD) 0.47 (3.4) 0.25 (3.4) 0.32 (3.4) Range −7.47–11.84 −7.47–11.81 −7.47–11.84

Although many association studies explored the effect of genetic variability at candidate genes belonging to the oxidative stress pathway in relation to age-related clinical conditions (Crawford et al., 2012), as well as with human longevity (see Dato et al., 2013 for a complete list), few papers investigated their role on the quality of human aging, and in particular on the functional decline characterizing human senes- cence. To date, efforts were mainly devoted to investigating the associ- ation of genes related to oxidative stress with cognitive ability and cognitive aging in healthy older people (Deary et al., 2004; Harris and Deary, 2011; Harris et al., 2007; Kachiwala et al., 2005; Starr and Quinn, 2008), mainly because brain is particularly vulnerable to oxida- tive damage as a result of its high aerobic metabolism and high concen- tration of polyunsaturated fatty acids, which are susceptible to lipid peroxidation (Halliwell, 2006). These studies found an involvement of apolipoprotein E (APOE), catechol-O-methyl transferase (COMT), brain- derived neurotrophic factor (BDNF) and dystrobrevin binding protein 1(DTNBP1) genes in cognitive ability in older people; however, they did not consider very old subjects, analyzing sample population aged around 85 years as maximum (De Blasi et al., 2009; Lindenberger et al., 2008).

ADL, Activity Daily Living; HG, Hand Grip; BMI, Body Mass Index; MMSE, Mini Mental State Examination; CCS, Composite Cognitive Score. ⁎ Survival data are calculated from a 12 year follow-up period. ⁎⁎ Participantsweredefinedas“notdisabled”ifindependentinallitemsand“disabled”if dependent inat least one item.

Briefly, this population based survey started in 1998, when 2.262 of the participants were 92.22–93.82 years of age (mean age 93.2), and survivors were subsequently re-assessed in 2000, 2003 and 2005 (Christensen et al., 2008; Nybo et al., 2001, 2003). Home-based ques- tionnaires were submitted for the collection of socio-demographic information, assessment of physical, cognitive, depressive status, sen- sory impairments, medications, self-reported health status and DNA was sampled for each subjects participating to the survey. Vital status was followed until death or January 1st 2013, whichever came first, resulting in a mean follow-up time for survivors of 13.4 years (range: 13.2–13.6). Information on survival status was retrieved from the Danish Central Population Register (Pedersen et al., 2006).

Preservation of functional ability (together with cognitive perfor- mance) is a well-recognized marker of longevity (Schupf et al., 2004). Consistently, predictors of functional status as HG and disability are key components of frailty definition at old age (Dato et al., 2012a;