2. Allele distribution of the ACTN3R577X polymorphism in our study cohorts. Symbol: *P=0.019 for centenarians vs.

phenotypes, e.g. preservation of muscle mass/strength, included in people aged 60 years and over [19], seems to be more frequent in some cohorts of European centenarians compared with their younger ethnically-matched referents [20,21,22]. Here, we hypothesized that the ACTN3 R577X variation is a strong candidate to influence survival over human evolution. Indeed, among the numerous genes that contribute to the ‘fitness’ or ‘performance’ phenotype, the ACTN3 is the first structural skeletal muscle gene for which such an association has been demonstrated [23]. The propagation of ACTN3 deficiency in humans with marked variations in X-allele frequencies among different ethnic groups [7,24] has raised the possibility that the X allele has been positively selected in some populations. Owing to its effect on skeletal muscle metabolism (see below), the X allele probably provided some sort of fitness advantage to modern humans adapting to the novel Eurasian environment [25].

other hand, there appears to be an evolutionary predetermined ‘trade-off’achieved over human evolution through the mainte- nance of genetic variation by balancing natural selection in performance traits for power vs. more endurance oriented exercise tasks [28,29]. That is, an individual is inherently predisposed towards being more of a ‘sprinter’or a ‘stayer’ [23]. With regards to this, those genotypes associated with the latter type of phenotype (e.g. the XX genotype) might have provided a certain survival benefit over human evolution as opposed to other animals for which the ability to produce ‘explosive’ muscle actions (rapid accelerations and decelerations) is vital for survival, i.e. predator and prey quadrupeds [30].

Published data on ACTN3 genotypes and muscle phenotypes with regards to ageing are controversial. Compared with the age- matched wild type mouse, the ageing KO mouse shows greater loss of fast muscle force generation and male muscle mass, good maintenance of grip strength, and increased oxidative metabolism and greater force recovery after fatigue [31]. San Juan et al. [32] observed no association between ACTN3 genotypes and functional capacity and muscle phenotypes (included 1RM leg press) in women aged 61–80 years; whereas others found that (i) in adults with a mean age ,65 years, the XX genotype was associated with higher knee extensor concentric peak power compared with RR/ RX genotypes, especially in women [33], and (ii) in women (aged ,60 years on average) the XX genotype was associated with lower peak torque in knee extensor muscles [34]. Recently, we observed no major influence of ACTN3 genotypes on muscle phenotypes (leg and grip strength, walking and stair climbing ability) in nonagenarians [35]. Differences in the age, baseline physical capacity and ethnic origin make comparison between studies difficult. Assessing the putative effects of ACTN3 genotypes on the muscle phenotypes of centenarians is nevertheless a very difficult task: the expected poor physical condition and lack of indepen- dence in most of them (which at least was the case in our cohort) precludes the use of valid tools for phenotype assessment in this population.

Compared with wild-type mice, the muscles of the a-actinin-3 deficient mouse exhibit 33% higher endurance (during treadmill running) and a shift towards more oxidative pathways of metabolism, i.e. increased activity of mitochondrial oxidative metabolism [11,25]. The XX genotype shows especially high frequency (26%) in professional road cyclists, who exhibit extremely high values of aerobic capacity and muscle efficiency. The high muscle efficiency of these athletes is attributable to a higher contribution of slow (type I) muscle type fibers compared with the less efficient type II (‘anaerobic’) subtype, in which a- actinin-3 is almost exclusively expressed [26]. In addition, a shift towards more oxidative muscle phenotypes associated with the XX genotype could have a beneficial influence on health related phenotypes. Classic studies in rats by Koch and Britton’s group showed that improved oxidative pathways in mitochondria may be a common factor linking physical fitness and decreased disease risk [12,13]. In humans, the metabolic effects of ACTN3 genotype may act as a modifier of disease severity: the X allele has recently been shown to benefit exercise capacity phenotypes (i.e. aerobic capacity) in women with muscle (McArdle) disease [27]. On the

In summary, although we did not find significant differences with the younger, control population, overall the ACTN3 genotype profile of centenarians resembles that of world-class elite endurance athletes and seems to differ from that of elite power athletes. Our preliminary data would suggest a certain ‘survival’ advantage brought about by a-actinin-3 deficiency and the ‘endurance’/oxidative muscle phenotype that is commonly associated with this condition; yet, more data on larger cohorts and on other ethnicities are necessary. Despite its uniqueness, the ‘oldest old’ is the most rapidly growing age group in western countries [36]. It is also the least physically active, and that generating the highest healthcare expenditures, largely due to loss of physical function [37]. Thus, identifying those genetic variants that are associated with exceptional longevity and rate of decline of physical function at the end of the human lifespan is of potential medical relevance. Our results might provide insights into the putative role on human survival of some genetic polymorphisms which are known to influence muscle function, of which the ACTN3 R577X is currently the best example.