Ageing Research Reviews 12 (2013) 90–102

Contents lists available at SciVerse ScienceDirect

Ageing Research Reviews

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

Review

Genes, physical fitness and ageing

Nuria Garatachea ∗ , Alejandro Lucia
Faculty of Health and Sport Science, University of Zaragoza, Huesca, Spain (Dr. Garatachea); Universidad Europea de Madrid, Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Persons aged 80 years and older are the fastest growing segment of the population. As more
Received 21 June 2012 individuals live longer, we should try to understand the mechanisms involved in healthy ageing and
Received in revised form 6 September 2012 preserving functional independence in later life. In elderly people, functional independence is directly
Accepted 6 September 2012
dependent on physical fitness, and ageing is inevitably associated with the declining functions of sys-
Available online xxx
tems and organs (heart, lungs, blood vessels, skeletal muscles) that determine physical fitness. Thus,
age-related diminished physical fitness contributes to the development of sarcopenia, frailty or disabil-
Keywords:
ity, all of which severely deteriorate independent living and thus quality of life. Ageing is a complex
Ageing
Genes
process involving many variables that interact with one another, including – besides lifestyle factors or
Physical fitness chronic diseases – genetics. Thus, several studies have examined the contribution of genetic endowment
Genetic variation to a decline in physical fitness and subsequent loss of independence in later life. In this review, we com-
pile information, including data from heritability, candidate-gene association, linkage and genome-wide
association studies, on genetic factors that could influence physical fitness in the elderly.
© 2012 Elsevier B.V. All rights reserved.

1. Introduction genome-wide association studies, that have been so far identified to

influence physical fitness and physical fitness related phenotypes
The number of persons aged ≥60 years worldwide is expected in the elderly.
to nearly triple—from 760 million in 2010 to 2 billion (∼22% of
the total population) in 2050 (United-Nations, 2011). The oldest- 1.1. Main physical fitness related phenotypes: definitions and
old group (≥80 years, including centenarians) is the most rapidly ageing effects
expanding group among westerners (Robine and Paccaud, 2005;
Waite, 2004). However, longevity comes at a price, including Among the physiological changes associated with ageing, those
an eventual loss of functional independence (Christensen et al., affecting the cardiorespiratory and vascular system and skeletal
2008). In the elderly, functional independence is directly depend- muscles most affect physical fitness (Fig. 1).
ent on physical fitness, as explained below. Physical fitness has
been recently defined as ‘the ability to carry out daily tasks with 1.1.1. Cardiorespiratory fitness
vigour and alertness, without undue fatigue and with ample energy Maximal oxygen uptake (abbreviated V̇ O2 max, and sometimes
to enjoy [leisure] pursuits and to meet unforeseen emergencies’ referred to as ‘maximal aerobic capacity’ or simply ‘aerobic capac-
(Garber et al., 2011). Importantly, physical fitness is operationalized ity’ or ‘aerobic endurance’) is a main indicator of cardiorespiratory
as several measurable health-related phenotypes including mainly fitness. V̇ O2 max is the product of multiplying maximal cardiac out-
cardiorespiratory fitness and muscle performance/function (Garber put by maximal arteriovenous oxygen difference (a-vO2 diff), and
et al., 2011). With regards to this, old people commonly experience is usually expressed in milliliters of O2 consumed per kilogram of
an age-associated decline in the systems and organs that deter- body weight per minute (ml kg−1 min−1 ). This variable indicates
mine the aforementioned physical fitness phenotypes (see below, the maximum capacity of the cardiorespiratory and vascular sys-
Section 1.1). tem to transport O2 from the air to the working muscles, and of
It is important to understand how ageing and its interactions the latter to consume O2 during dynamic exercise involving large
with lifestyle and genetic factors affect physical fitness. This paper muscles, e.g. running, very brisk-walking, bicycling. In a 6-year lon-
reviews the available information on the genetic factors, includ- gitudinal study whose participants were of initial median age 70
ing data from heritability, candidate-gene association, linkage and years, V̇ O2 max losses of 6.9 and 3.9 ml kg−1 min−1 /decade were
estimated in men and women respectively (Hollenberg et al., 2006).
In a similar study (participants aged 55–85 years), 10-year losses
∗ Corresponding author. were 4.3 and 1.9 ml kg−1 min−1 in men and women (Stathokostas
E-mail address: [email protected] (N. Garatachea). et al., 2004). The 7.9-year longitudinal Baltimore study reported

1568-1637/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.arr.2012.09.003
 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102 91

Fig. 1. Summary of the main factors that contribute to age-related declines in physical fitness and physical fitness related phenotypes, resulting in loss of independence.
Abbreviations: a-vO2 diff, arteriovenous oxygen difference; Q, cardiac output; V̇ O2 max, maximal oxygen uptake (or maximal aerobic capacity). See text for recent definitions
of sarcopenia, frailty and disability.

V̇ O2 max losses of 5%/decade in young adults, and 20%/decade in (Fielding et al., 2011): appendicular mass/height2 ≤7.23 kg m−2
middle-old (60–69 years) and old-old (≥70 years) individuals (Fleg (men) and ≤5.67 kg m−2 (women) for muscle mass; and gait
et al., 2005). Thus, although there are differences between stud- speed <1 m s−1 for muscle function. Factors explaining sarcope-
ies, it seems that a V̇ O2 max decline ≥4–5 ml kg−1 min−1 /decade nia include: gradual muscle denervation (Deschenes, 2004; Saini
continues into later life (Shephard, 2009). et al., 2009); diminished satellite cell numbers/functions (Verdijk
Reduced maximal cardiac output [=maximal stroke vol- et al., 2007); impaired muscle protein turnover, reduced pro-
ume × maximum heart rate (HRmax)] is the main contributor to tein synthesis (Kumar et al., 2009); malnutrition (Doherty, 2003);
this age-related decline in V̇ O2 max. HRmax usually decreases by lower anabolic hormone levels (Volpi et al., 2004); increased pro-
3–5%/decade, independently of fitness level or sex (Eskurza et al., inflammatory cytokines (Kamel, 2003); greater oxidative stress
2002; Hawkins et al., 2001), and the relative contribution of this (Howard et al., 2007); and lower physical activity levels (Cesari
HRmax drop to reduced maximal cardiac output with ageing ranges and Pahor, 2008). The prevalence of sarcopenia is difficult to deter-
from 40 to 100% (Hagberg et al., 1985; Ogawa et al., 1992; Stratton mine, mostly because of practical difficulties in assessing muscle
et al., 1994). Older adults also show lower stroke volumes dur- mass (von Haehling et al., 2010) and between-study differences
ing maximal exercise (Hagberg et al., 1985; Ogawa et al., 1992; in participants’ ethnic origin, age or sex (Abellan van Kan, 2009).
Stratton et al., 1994). A maximal a-vO2 diff decrease with ageing On average, 5–13% and 11–50% of people aged 60–70 years and
(∼−3%/decade) (Hossack and Bruce, 1982; Ogawa et al., 1992) par- ≥80 years respectively suffer sarcopenia (Baumgartner et al., 1998;
tially contributes to age-reductions in V̇ O2 max (Rivera et al., 1989; Frisoli et al., 2011; Janssen, 2006; Janssen et al., 2002; Lauretani
Wiebe et al., 1999) and reflects less O2 utilization by skeletal mus- et al., 2003; Rolland et al., 2003). Higher prevalences (68%) have
cles owing to: decreased muscle mass and increased fat (Proctor been reported in male nursing home residents ≥70 years (Landi
and Joyner, 1997; Toth et al., 1994), increased peripheral resistance et al., 2012).
(Lakatta and Levy, 2003), reduced muscle capillary density (Coggan
et al., 1992), endothelial dysfunction (Schrage et al., 2007), changes 1.1.3. Frailty and disability
in skeletal muscle microcirculation (Degens, 1998), and reduced A consequence of the aforementioned effects of ageing on car-
muscle oxidative capacity (Conley et al., 2000). diorespiratory fitness and muscle performance/function, alone or in
combination with comorbidities, is the frailty syndrome (Heuberger,
1.1.2. Muscle performance/function 2011). Although there is no clear consensus, frailty can be defined
Muscle mass (i.e. the amount of body mass that is made of as ‘unintentional weight and muscle loss, exhaustion, and declines
skeletal muscle tissue) usually peaks at 25–30 years and there- in grip strength, gait speed, and activity’ (Fried et al., 2001). A main
after begins to decline (Janssen et al., 2000; Lexell et al., 1988). outcome of frailty is disability (Sternberg et al., 2011), i.e. ‘difficulty
This decline speeds up at the end of the fifth decade, when approx- or dependency in carrying out activities necessary for independent
imately 10% of total muscle mass is usually lost, such that by 80 living, including roles, tasks needed for self-care and household
years, 40% of muscle mass on average has disappeared (Lexell et al., chores, and other activities important for a person’s quality of life’
1988; Saini et al., 2009). Both a low muscle mass (criterion 1) (Fried et al., 2004).
and low muscle function [i.e. strength (criterion 2) or performance Thus, in this review we will report the results of those studies in
(criterion 3)] are necessary for a diagnosis of sarcopenia (Cruz- elderly people which analyzed one or more of the abovementioned
Jentoft et al., 2010), with the following recently established cut-offs phenotypes that determine physical fitness, i.e. mainly V̇ O2 max,
92 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102

cardiac output, stroke volume, HR, a-vO2 diff, peripheral resistance, be tested are selected according to their features, e.g. known or
indicators of muscle performance/function including muscle mass postulated biology or function (Attia et al., 2009). The results of
(e.g. muscle cross sectional area, muscle volume, body composi- genetic association studies can be very useful. Besides providing
tion) and strength (e.g. results of dynamic/isometric strength tests, new insights into pathways involved in disease or disease-related
or walking speed in the oldest cohorts) sarcopenia, frailty, or dis- phenotypes and identify new therapeutic targets (e.g. myostatin-
ability. inhibitors to increase muscle mass—see below), the most likely
short-term clinical application of this genetic information is to
1.2. Genetic studies are important for the non-geneticist: basic enhance risk stratification, by providing individuals with informa-
concepts and main research approaches tion about their disease risk or prognosis, e.g. risk of developing
sarcopenia, or sarcopenia-induced disability (Attia et al., 2009). The
Human genetic studies analyze the influence of our genotype entire bp sequence of the 25,000 genes that constitute the human
(our genetic makeup) on our phenotype (observable character- genome is ∼99% identical in different people (Lander et al., 2001),
istics). Hair or eye color, how strong a person’s muscles are or yet the human genome contains 3.3 billion bp; as such, there are still
V̇ O2 max are examples of phenotypes (sometimes also called phe- more than 12 million potential variations between the genomes of
notype traits or simply traits). Most phenotypes traits, such as those two different persons of the same age, sex, or exercise habits that
studied in this review, are not Mendelian, i.e. they are complex may partly explain inter-individual differences in phenotype traits
traits, and their heritance is based on the combined influence of such as those indicative of physical fitness, e.g. V̇ O2 max, muscle
multiple genes, environment, and gene-environment interactions. performance/function (International HapMap Consortium, 2005;
As such, to study the genetic influence on a given phenotype is Frazer et al., 2007; Sachidanandam et al., 2001).
a difficult task. Rare variations in gene structure (<1% of popula- Most published studies have used a candidate gene approach
tion) are known as mutations; whereas more frequent ones (≥1%) based on the rationale that a single gene (or a few genes) plays
are called polymorphisms. The different forms that a particular an important role in a given disease or disease-related phenotype.
polymorphism may take are called alleles, e.g. the angiotensin- However, the more ‘agnostic’ approach of genome-wide association
converting enzyme (ACE) gene has two common alleles, Insertion (GWA) studies has also proved fruitful. GWA studies examine the
(I) and Deletion (D), with three possible allele combinations or ‘association of genetic variation with outcomes or phenotypes of
genotypes, II, ID or DD. The location of a particular allele within interest by analyzing 100,000 to millions SNPs across the entire
a chromosome is called a locus. Alleles that occur more frequently genome without any previous hypotheses about potential mecha-
in the population are called wild-type or major alleles, whereas the nisms’ (Attia et al., 2009). These two types of study are not mutually
less common alleles are known as minor or variant alleles. The dif- exclusive: thus GWA studies serve to identify candidate genes for
ferent types of polymorphisms include: (i) the presence/absence of gene association studies. Both approaches can be used on relatives
an entire stretch of DNA (insertion/deletion polymorphisms, such as in genetic linkage studies, in which the presence or absence of cer-
the aforementioned ACE I/D polymorphism), (ii) DNA duplication, tain variant alleles in family members with or without a disease
called copy number variation; (iii) repeating patterns of DNA that or phenotype is analyzed (Attia et al., 2009). Notwithstanding, the
vary in the number of repeats (200–300 base pair (bp) stretches results of linkage studies are interpreted in an entirely different
repeated a few to hundreds of times); and (iii) a single-bp change, manner to population-based (gene-association or GWA) studies
called a single-nucleotide polymorphism (SNP), which are the most (Dawn Teare and Barrett, 2005; Risch, 1997).
common type of polymorphism, with 12 million SNPs already iden-
tified (International HapMap Consortium, 2005; Frazer et al., 2007;
2. Method
Sachidanandam et al., 2001). Some SNPs affect parts of a gene
(exons) that code for the gene-product (protein), leading or not
2.1. Literature search
to a change in the amino-acid sequence of the resultant protein,
whereas other SNPs occur in non-coding chromosome areas but
A three-step literature search was conducted: (1) identify-
may still influence gene function, e.g. by controlling the amount of
ing physical fitness phenotypes, (2) searching for heritability,
protein produced (Attia et al., 2009). Owing to the high number of
candidate-gene association, linkage and genome-wide association
SNPs, the most common nomenclature system assigns a number
studies (3) expansion by cross-referencing. The following databases
with the prefix “rs” (for ‘reference SNP’), e.g. rs805086. Since they
were searched: MEDLINE and the National Library of Medicine. For
are responsible for most genetic variations in humans and are rel-
step 1, keywords used were: ‘muscle mass’, ‘strength’, ‘muscular
atively easy and cheap to detect, SNPs have been the main focus of
fitness’, ‘cardiorespiratory fitness’, ‘aerobic endurance’, ‘physical
research into gene–disease associations. The basic idea is relatively
fitness’, ‘sarcopenia’, ‘frailty’, ‘disability’, ‘exercise’, ‘physical activ-
simple. For instance, if the variant allele of a SNP is more frequent
ity’, ‘physical or functional performance’. For step 2, the search was
in old men with accelerated sarcopenia compared to similarly aged
expanded to include the terms: ‘genetics’, ‘genotype’, ‘polymor-
men with better muscle mass/function, then we can say that this
phism’. To enable inclusion of all relevant studies, reference lists of
SNP is associated with sarcopenia in the elderly. Thus, in the same
relevant articles were cross- referenced and hand searched while
way that variation in an environmental or lifestyle factor is linked to
applying the above criteria systematically.
an outcome in traditional epidemiologic studies, genetic variation
can be associated with an outcome (or phenotype). Some alleles
form haplotypes i.e. they tend to occur together on the same chro- 2.2. Inclusion criteria
mosome and are therefore inherited together. Thus, some genetic
studies also include haplotype analyses. The following inclusion criteria were required: (a) studies pub-
Heritability describes the extent to which differences in a pheno- lished in a peer-reviewed journal (b) studies written in the English
type are explained by genetic differences in a certain population at a language (c) the mean or minimum age of the study cohort (or
certain time (Plomin et al., 2001). Knowing the heritability of a phe- at least of one sub-cohort) was ≥60 years, (d) at least one of the
notype is important to define the biological mechanism underlying main identified physical fitness phenotypes (e.g., muscle mass,
the phenotype (Visscher et al., 2008). Candidate gene association muscle strength, V̇ O2 max, sarcopenia, frailty or disability) was
studies assess the association of one or more specific genetic vari- objectively measured (i.e. not self-reported or estimated). For those
ants with outcomes or phenotypes of interest; genetic variants to candidate-gene association studies including cohorts of old (mean
 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102 93

or minimum age ≥60 years) and also younger individuals (maxi- Table 1
Gene candidates under investigation for their association with physical fitness-
mum age <60 years) and analyzing the different cohorts separately,
related phenotypes in old people.
we also reported the results obtained in the younger people. Indeed,
comparing the genetic influence on physical fitness phenotypes in Abbreviation Gene
young vs. old people is of interest to understand how genetic factors ACE angiotensin-converting enzyme
interact with ageing and these phenotypes. Candidate–gene asso- ACTN3 ␣-actinin-3
ciation studies also had to meet at least 3 of the 5 validity criteria ACVR activin-type receptor B
ADR adrenergic receptor
proposed by Attia et al. (2009).
AGT angiotensinogen
A total of 73 studies were identified in the literature using the AMPD1 AMP deaminase (skeletal-muscle isoform)
aforementioned search terms and criteria. (Of these, only 2 studies ApoE apolipoprotein E
analyzed separately the influence of the same genetic factors on AR androgen receptor
BTRC beta-transducin repeat containing
physical fitness phenotypes in cohorts of young and old people).
CASP8 caspase 8
Although we have cited all of them to provide the reader with all the CNTF ciliary neurotrophic factor
available information, a quality criterion that is particularly impor- CNTFR ciliary neurotrophic factor receptor
tant to ensure the external validity of a gene–candidate association COL1A1 collagen type I alpha 1
study is the replication of the findings in at least one different, CREBBP CREB-binding protein
FST follistatin
independent cohort (Attia et al., 2009). Only 4 gene–candidate
GR glucocorticoid receptor
association studies (summarized in supplementary tables) met this IGF insulin-like growth factor
important criterion of external validity. IL6 interleukin-6
KAT2B lysine acetyltransferase 2B
MSTN myostatin
3. Heritability studies MTR 5-methyltetrahydrofolate-homocysteine methyltransferase
NOS3 nitric oxide synthase 3
Sarcopenia-related phenotypes are highly heritable, with TERT telomerase reverse transcriptase
TRHR thyrotropin-releasing hormone receptor
genetic contributions reported of up to ∼65–66% for muscle mass
UCP uncoupling protein
(Abney et al., 2001) and strength (Reed et al., 1991), 52–80% for lean VDR vitamin D receptor
body mass (LBM) (Deng et al., 2001; Hsu et al., 2005), 70–90% for V1aR vasopressin 1a receptor
muscle size (Huygens et al., 2004b) and 45–65% for fat free mass
(FFM) (Abney et al., 2001). Studies conducted on elderly twins have
established that heritability can explain 22–52% of variance in mus- and skeletal muscle growth (Gordon et al., 2001; Westerkamp and
cle strength (Arden and Spector, 1997; Carmelli and Reed, 2000; Gordon, 2005). Studies conducted mainly on sexagenarians have
Frederiksen et al., 2002; Reed et al., 1991). In sedentary individ- reported a positive association between the D-allele and muscle
uals, the heritability of V̇ O2 max can be as high as 50% (Bouchard mass (Charbonneau et al., 2008), LBM (Vigano et al., 2009), and
et al., 1998). A genetic influence was found in frailty variability appendicular FFM (Lima et al., 2011), while others have observed no
among 3719 individuals aged ≥75 years (Dato et al., 2012), yet with association with whole-body or thigh non-skeletal LBM (McCauley
considerable between-sex differences: in men, frailty status was et al., 2010), or thigh-muscle cross-sectional area (CSA) (Garatachea
more genetic-dependent whereas in women environmental fac- et al., 2012). Controversy also exists concerning the link between
tors were more important. A more modest extent of physical fitness I/D genotypes and physical fitness phenotypes.
heritability (determined through a validated physical ability score) The ACE I/D polymorphism was associated with: handgrip-
was described in Danish twins (≥70 years); the heritability of over- strength in advanced cancer patients (Vigano et al., 2009),
all muscle strength amounting to ∼10% in men and ∼30% in women handgrip-strength and 10 m maximum walking speed in Japanese
(Christensen et al., 2003). men and women (Yoshihara et al., 2009), and several hemody-
namic variables (e.g. HR) recorded during submaximal exercise
in postmenopausal women (Hagberg et al., 2002). No associa-
4. Candidate–gene association studies tion was detected between ACE genotypes and muscle strength or
ability to cope with activities of daily living (ADLs, according to
The reader is referred to Fig. 2 for a diagram showing the main Barthel index) in octogenarians (Garatachea et al., 2012), handgrip-
functions of the genes described below, to Table 1 for a list of strength, leg-muscle strength, and functional mobility (walk-stair
candidate genes and their abbreviations, and to supplementary tests) in nonagenarians (Bustamante-Ara et al., 2010), and muscle
tables for the detailed results of gene–candidate association studies strength in chronic heart failure patients (Williams et al., 2011).
in the field. As discussed later (Section 6), to note is that differ- The association between ACE I/D polymorphism and physical
ences among studies in population characteristics (sample size, fitness phenotype responses to specific exercise training programs
age, gender, health state, ethnic/geographic origin) and phenotype has also been addressed. Obese DD homozygotes showed greater
assessment largely explain the heterogeneity of the results pub- gains in knee-extensor strength than II-allele homozygotes, after
lished in the literature and preclude drawing solid conclusions at an 18-month walking and light resistance training (RT) program
present. (Giaccaglia et al., 2008) and, in women who performed quadriceps
RT for 24 weeks, FFM increased after training only in the I-allele car-
4.1. ACE I/D polymorphism riers (Lima et al., 2011). However, other authors observed no link
between the ACE I/D polymorphism and muscle volume adaptation
The D and I alleles of the ACE I/D polymorphism have been linked to RT (Charbonneau et al., 2008), muscle strength (30 s sit–stand
to a higher and lower ACE enzyme activity respectively (Danser test) and endurance (3 min-walk test) responses to a brisk-walking
et al., 1995; Tiret et al., 1992; Williams et al., 2005). The role of ACE program (Okamoto et al., 2010), or the training response of muscle
in the renin–angiotensin–aldosterone system (RAAS) is to convert strength/endurance and V̇ O2 max in chronic heart failure patients
angiotensin I (AngI) into AngII (Rigat et al., 1990), which, besides (though an association was found for peak power output during
working as a potent vasoconstrictor (thereby increasing cardiac cycle-ergometry) (Williams et al., 2011). When examining data
after-load), also stimulates smooth (Berk et al., 1989; Geisterfer in elderly Danes (n = 203), Frederiksen et al. found no association
et al., 1988), cardiac (Ishigai et al., 1997; Sadoshima et al., 1993), between the ACE I/D polymorphism and baseline levels or time
94 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102

NOS3 AGT .
G894T Met235Thr
Q and hemodynamics

.
VO2max disability
β 2-ADR

a-vO2 diff
MTR CASP8 CREBBP
frailty KAT2B BTRC
mtDNA (mt146, mt204, mt228)
ADR
muscle fat infiltration
α2b

VDR TRHR AR muscle mass

ACE ACTN3 IGF sarcopenia VDR FokI

I/D R577X genes

ApoE CNTF COL1A1 muscle strength

ε4 CNTFR UCP3
Myostatin-pathway genes (ACVR1B,
ACVR2B, FST, MSTN)

Fig. 2. Summary of the main possible functions (still remaining confirmation and thus marked with dash lines) of candidate genes.

changes (whether induced by training or not) in muscle strength, XX women had lower thigh-muscle CSA compared to the other
walking speed or body composition (Frederiksen et al., 2003a). In genotypes (Zempo et al., 2010). Other studies on aged Caucasians
a 2-year longitudinal study performed in elderly twins, ACE geno- found no association between the ACTN3 R577X polymorphism and
types could not be correlated with baseline levels or changes in muscularity indices in men (McCauley et al., 2010), mid-thigh CSA
self-reported physical fitness (Frederiksen et al., 2003b). in old men and women at baseline or after 5 years (Delmonico
et al., 2008), or thigh-muscle CSA in octogenarians (Garatachea
et al., 2012). The XX genotype was associated with higher knee-
4.2. Angiotensinogen (AGT) gene
extensor concentric peak power compared to RR/RX genotypes,
especially in women (Delmonico et al., 2007). However, in another
Another important RAAS gene is AGT, which encodes
cohort of women, the XX genotype was related to lower peak torque
angiotensinogen, a circulating protein produced by the liver that
in knee-extensor muscles (Walsh et al., 2008). Genotype XX men
is cleaved by renin to yield Ang I. A common AGT polymorphism,
showed a significantly greater adjusted 5-year increase in 400 m-
T-for-C substitution at nucleotide 704 causing a methionine-to-
walk time compared to their RR/RX peers whereas in women, the
threonine substitution at codon 235 (Met235Thr, rs699), was
XX genotype was linked to a ∼35% greater risk of lower extremity
associated with cardiovascular responses to dynamic exercise (HR,
limitation compared to RR (Delmonico et al., 2008). Several authors
systolic blood pressure, and a-vO2 diff) in postmenopausal women
have detected no relationship between ACTN3 genotypes and phys-
(McCole et al., 2002).
ical fitness phenotypes, i.e. quadriceps strength in Brazilian women
(Lima et al., 2011), one-repetition maximum (1RM) leg press, sit-
4.3. ˛-Actinin-3 (ACTN3) gene stand test and 1-mile walk test in women aged 61–80 years (San
Juan et al., 2006), muscle strength and ability to cope with ADLs
␣-Actinin-3 is a sarcomere protein almost exclusively expressed (Barthel index) in octogenarians (Garatachea et al., 2012), leg and
in fast, glycolytic type II skeletal-muscle fibers where it is used to handgrip strength, walking and stair climbing in nonagenarians
produce powerful contractions (MacArthur and North, 2004, 2007). (Bustamante-Ara et al., 2010), or muscle function (absolute/relative
A polymorphism (R577X, rs1815739) identified in its gene (ACTN3) isokinetic strength during knee-extension and quadriceps muscle
causes replacement of an arginine (R) residue by a premature stop- twitch-response) in Caucasian men (McCauley et al., 2010).
codon (X) at amino-acid 577 (North et al., 1999). Approximately The putative effects of ACTN3 genotypes (whether beneficial or
18% of the world-population is homozygous for this stop-codon not) may also differ between baseline and post-training. At base-
(i.e. has the XX genotype) and is thus completely deficient in the line, XX women had higher absolute and relative peak power values
protein (MacArthur and North, 2007; Yang et al., 2003). However, compared to RR/RX genotypes with no differences existing in men,
compared to age-matched wild-type mice, ACTN3-knock-out (␣- whereas after 10 weeks of knee-extensor RT, RR women showed
actinin-3 deficient) mice showed a greater loss of fast muscle force significantly greater training improvements in relative peak power
generation and male muscle mass, yet good maintenance of grip than their XX counterparts (Delmonico et al., 2007). Lima et al.
strength, increased oxidative metabolism and greater force recov- found no ACTN3 genotype effect on quadriceps strength after 24
ery after fatigue (Seto et al., 2011). Although the R- and X-alleles weeks of RT in women (Lima et al., 2011).
seem to favor performance in ‘power’ (jumping, throwing, sprint-
ing) and endurance athletic events respectively (Yang et al., 2003),
the association between ACTN3 genotypes and physical fitness in 4.4. ˇ-Adrenergic receptors’ genes
old people remains unclear, including the putative roles of the R-
and X-alleles. ␤-Adrenergic receptors (␤-ADR) are members of a family of
Brazilian women who were X-allele carriers showed a higher G protein-coupled receptors stimulated by naturally occurring
relative FFM than RR women (Lima et al., 2011), whereas Japanese catecholamines. In humans, three ␤-ADRs have been identified:
 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102 95

␤1 -ADR, ␤2 -ADR and ␤3 -ADR. Two common genetic variations at in North-American men (Kenny et al., 2005). In older Caucasian
the ␤2 -ADR (Gln27Glu, rs1042714) and ␤3 -ADR (Trp64Arg, rs4994) men, body composition and muscularity measures (% body fat, FFM,
gene loci were linked to physical fitness-related phenotypes during thigh lean mass) were not different across CAG-repeat length geno-
treadmill exercise in old women; V̇ O2 max being lower in the ␤2 - types (Folland et al., 2012).
ADR Glu/Glu group than the other genotypes, and higher in ␤3 -ADR
Trp/Arg women than in their ␤3 -ADR Trp/Trp peers, and the ␤2 -ADR 4.8. Ciliary neutrophic factor (CNTF) gene
Gln/Gln group having a greater a-vO2 diff than their Glu/Glu coun-
terparts (McCole et al., 2004). In another study, ␤2 -ADR Gln27Glu The ciliary neurotrophic factor (CNTF) exerts trophic effects
and the inhibitory adrenergic receptor (ADR␣2b)gene Glu9 poly- on neuronal (Sleeman et al., 2000) and muscle tissues (Guillet
morphism influenced mid-thigh muscle fat infiltration in old men et al., 1999). Roth et al. found an association between the A-
(a phenotype associated with low muscle strength, poor leg func- allele of the G-to-A polymorphism (rs1800169) in the CNTF gene
tion and limited mobility in elderly persons); intra-muscle fat and muscular strength; old (>60 years) GA individuals exhibit-
accumulation being reduced after RT in participants carrying the ing an 11% greater peak torque than their GG peers (Roth et al.,
mutant alleles Glu27 and Glu9 compared to non-carriers (Yao et al., 2001). In another study conducted in women (70–79 years), AA
2007). individuals homozygous for the rs1800169 polymorphism showed
lower handgrip-strength, but no link to frailty syndrome was
4.5. Skeletal-muscle AMP deaminase (AMPD1) gene detected (Arking et al., 2006). After a 3-month low-intensity RT pro-
gram, CC genotype older Japanese people improved their 32-meter
Young adults, especially TT homozygotes, featuring the C34T walking-performance more than CT/TT genotypes (Murakami et al.,
mutation (rs17602729) [also termed Gln(Q)12Ter(X)] in the gene 2009). On the other hand, C1703 T (rs3808871) and T1069A
(AMPD1) encoding skeletal-muscle AMP deaminase, an important (rs2070802) polymorphisms of the CNTF receptor (CNTFR) gene
regulator of energy metabolism during exercise (Gross, 1997), can have been associated with muscle strength, with the presence of
exhibit easy fatigability, cramps, as well as an increased severity of a T allele of the C1703 T variation resulting in overall higher levels
coexisting neuromuscular disorders (Sabina, 2000). However, the of muscle force production than the presence of a C allele in both
T-allele was not related to endurance (V̇ O2 max, 1-mile walk test) old (60–78 years) and middle-aged men (45–49 years) but not in
or muscle performance (sit-stand test) in a study with old women old (60–80 years) or middle-aged women (38–44 years), and with
(Perez et al., 2006). carriage of the T allele of the T1069A variation leading to overall
higher muscle force in old and middle-aged women, but not in men
4.6. Apolipoprotein E (ApoE) gene of either age (De Mars et al., 2007).

The ApoE gene polymorphism is related to significant lipopro- 4.9. Collagen type I genes
tein profile modifications, as well as to the incidence of several
diseases, including cardiovascular and Alzheimer’s disease or vas- Type I collagen, the main bone protein, consists of two alpha1
cular dementia, and could also be involved in the ageing selection and one alpha2 chains encoded by COL1A1 and COL1A2 genes
process. Although it has been also proposed as a ‘frailty gene’, respectively. The Sp1 binding site polymorphism in COL1A1 has
no association has been reported with frailty (Rockwood et al., been associated with hand-grip and biceps strength in men aged
2008), or longevity and disability (Bader et al., 1998). Controversy ≥70 years (Van Pottelbergh et al., 2001). The mechanisms for this
also exists regarding the association of ApoE genotypes and phys- association remain unclear. However, both bone and muscle dete-
ical fitness in old people. Thus, the ␧4 allele has been linked to riorate with age, and since bone geometry is partly determined by
more (Albert et al., 1995) but also to less disability during ADLs muscle mass/strength, there might be a common genetic etiology to
(Kulminski et al., 2008), while other studies report no associa- sarcopenia and osteoporosis, whereby some genetic variants con-
tion (Bader et al., 1998; Gustafson et al., 2012). Three studies have tribute to both muscle and bone phenotypes (Karasik et al., 2009).
suggested that the presence of the ␧4 allele is a risk factor for
more rapid functional decline with ageing (Buchman et al., 2009; 4.10. Follistatin (FST) and activin-type I and II receptor B
Melzer et al., 2005; Snejdrlova et al., 2011), whereas others have (ACVR1B and ACVR2B) genes
detected no association with lower extremity function (Carmelli
et al., 2000), self-reported functional capacity in men (Blazer et al., FST and ACVR1B and ACVR2B genes participate in myostatin reg-
2001), handgrip-strength (Deary et al., 2006), or aerobic capacity ulation and signaling (see below, Section 4.14). In a study in old
expressed as 6 min-walking performance (Deary et al., 2006) or men (60–78 years) designed to replicate the findings of a larger
V̇ O2 max (Etnier et al., 2007). study through combined linkage and family-based association, the
rs2854464 SNP in ACVR1B was related to knee muscle strength
4.7. Androgen receptor (AR) gene (Windelinckx et al., 2011). In another report, women carriers of
ACVR2B Haplotype Group 1 showed less quadriceps muscle strength
Androgen (total and free testosterone) concentrations decline than women homozygous for Haplotype Group 2, whereas no asso-
progressively with age, and low androgen levels have been linked ciation was observed in men (Walsh et al., 2007). Male carriers
to skeletal-muscle mass loss and physical fitness in old people of FST Haplotype Group 3 exhibited less total leg FFM than non-
(Bhasin and Storer, 2009) and could thus contribute to the develop- carriers, but no link was found in women.
ment of sarcopenia and frailty (Travison et al., 2010). The AR gene
contains a polymorphic trinucleotide CAG microsatellite repeat 4.11. Glucocortoicoid receptor (GR) gene
sequence that modifies either the amount of AR protein inside
the cell (GGNn, polyglycine) or its transcriptional activity (CAGn, Cortisol levels increase with age and hypercortisolism causes
polyglutamine). North-American men bearing a greater number muscle weakness. Although the ER22/23EK polymorphism of the
of CAG repeats exhibited higher total FFM than those with fewer GR gene has been associated with relative glucocorticoid resis-
CAG repeats (Walsh et al., 2005), but other studies detected no tance, a healthier metabolic condition, and better survival in old
correlation between CAG-repeat length and body composition in people (Manenschijn et al., 2009), other studies have noted no
community-dwelling men (Lapauw et al., 2007) or physical fitness association with mean appendicular skeletal-muscle mass and
96 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102

handgrip-strength (Peeters et al., 2008), or with 2-year changes in Huygens et al., 2004a; Seibert et al., 2001). Reduced overall muscle
Barthel scale (Mora et al., 2012). strength (several muscle groups) has been reported in old African-
American women (Seibert et al., 2001) and Italian Caucasians of
4.12. Insulin-like growth factors genes both sexes carrying the R-allele (Corsi et al., 2002). The muscle
mass and function (gait and balance) and ability to cope with ADLs
Insulin-like growth factors (IGFs) are peptides that regulate cell (Barthel score) of a 96-year-old woman with the very rare RR
growth, differentiation and regeneration (O’Dell and Day, 1998). genotype was in the lowest 25th sex- and age-specific percentile
Age-related skeletal muscle fiber loss may be partly related to (Gonzalez-Freire et al., 2010). In the same study, the 1RM leg press
diminished local IGF production (Sayer et al., 2002). The IGF1 gene and muscle mass of KR nonagenarian women was low-to-normal
cytosine adenine (CA)-repeat polymorphism was found to affect (∼25th–50th percentile) compared to peers with the wild-type
knee-extensor peak power at baseline in old adults, but not in (KK) genotype. Some findings also suggest a possible role for the
response to RT (Sood et al., 2012), whereas Hand et al. correlated MSTN K153R polymorphism in the muscle volume response to RT
this polymorphism with RT-induced changes in muscle strength (Ivey et al., 2000), yet definitive data for old people are lacking.
and volume (Hand et al., 2007). Black old women (70–79 years) with Genetic studies on the MSTN gene have provided the rationale for
the CC genotype of the IGF1 C1245 T (rs35767) polymorphism had therapeutic trials on myostatin-inhibitors, such as MYO-029; the
lower total muscle mass than their TT counterparts, while white latter has an adequate safety margin and is able to improve the
CC women showed reduced muscle function compared with white muscle strength/function or muscle contractile properties in some
TT women (Kostek et al., 2010). Yet these results were not repli- patients with muscular dystrophy (Krivickas et al., 2009; Wagner
cated in the same study with a cohort of young women (mean age et al., 2008). Given this type of treatment could also stimulate mus-
∼25 years). This polymorphism was also associated with functional cle growth in healthy humans (Wagner et al., 2008), it would be
state in Spanish elderly subjects (Mora et al., 2011). Two stud- interesting to determine its effect in ageing people.
ies have analyzed the influence of gene IGF2 on muscle mass and
strength in old people (Sayer et al., 2002; Schrager et al., 2004):
in one, IGF2 820G > A (ApaI, rs680) genotypes emerged as indepen- 4.15. Mitochondrial DNA (mtDNA)
dent predictors of handgrip-strength in men, but not in women
(Sayer et al., 2002), and in a study by Schrager et al. performed at Mitochondrial DNA (mtDNA) codes for 13 of the 83 polypeptides
∼2-year intervals in two Caucasian cohorts, IGF2 genotypes were involved in the respiratory chain. mtDNA is more prone to oxida-
found to affect muscle mass and function at age 65 years, the AA tive damage than nuclear DNA owing to a lack of histone-mediated
genotype exerting a negative effect on arm strength in men, and on protection, and the build-up of somatic mtDNA mutations over a
total body FFM and arm and leg strength in women (Schrager et al., lifespan is one of the main features of age-related loss of mitochon-
2004). However, the results were not corroborated in one cohort. drial function (Wallace et al., 2003). Since mtDNA variations could
Moreover, a recent multi-cohort study (Alfred et al., 2012) found influence individual susceptibility to mtDNA damage, they could
no evidence for associations between two polymorphisms of IGF also affect human longevity (Eynon et al., 2011), as well as cause a
genes (IGF1 rs35767and IGF2 rs7127900) and grip strength, timed functional decline and vulnerability to disease in later life. Moore
get up and go/walks and timed chair rises after adjusting for age et al. (2010) identified three mtDNA SNPs associated with frailty:
and sex. mt146, mt204, and mt228. These data were later corroborated in
a larger cohort, in which the mt204 C allele was associated with
4.13. Interleukin-6 (IL6) gene a greater likelihood of frailty and lower handgrip-strength in later
life.
Interleukin-6 (IL6) is a multifunctional cytokine primarily
involved in immune functions. However, recent data also ascribe
a pivotal role to IL6 in muscle repair and hypertrophy following
4.16. Mitochondrial uncoupling protein (UCPs) genes
exercise-induced damage (Serrano et al., 2008). A functional G/C
polymorphism at position -174 (rs1800795) has been described in
Five UCPs have been identified in humans to play an important
the IL6 gene (Fishman et al., 1998), the G allele enhancing the trans-
role in the regulation of reactive oxygen species (ROS) formation
criptional response (Bennermo et al., 2004; Fishman et al., 1998).
in mitochondria (Cannon et al., 2006). UCP3 is mainly expressed
Although elevated levels of IL6 have been linked to disability, frailty,
in skeletal muscle where it regulates fatty acid metabolism, redox
and mortality in older adults, Walston et al. (2005) found no asso-
state, and ROS formation (Echtay, 2007). Polymorphism rs1800849
ciation between IL6 genotypes and serum IL6, handgrip, knee and
in the UCP3 gene was related to handgrip-strength in elderly Ital-
hip strength, or frailty in older women, and no relationship was
ians, with carriers of the T-allele showing greater strength than the
detected between IL6 genotypes and muscle strength in Brazilian
other genotypes (Crocco et al., 2011).
women despite an observed genotype effect on serum IL6 (Pereira
et al., 2011).

4.14. Myostatin gene 4.17. Endothelial nitric oxide synthase (NOS3) gene

The myostatin (MSTN or growth differentiation factor 8, GDF8) The NOS3 gene encoding endothelial nitric oxide synthase
gene (Huygens et al., 2004a) encodes myostatin, a skeletal muscle- (eNOS) has been proposed as a candidate to explain individual
specific secreted peptide that essentially modulates myoblast variability in several health-related phenotypes, owing to the key
proliferation and thus muscle mass/strength (McPherron et al., role of nitric oxide (NO) in regulating vascular tone (Cooke et al.,
1997). Old MSTN- knock-out (myostatin-deficient) mice show 1991; Quyyumi et al., 1995). The T-allele of the Glu298Asp (G894
minimal muscle atrophy compared to wild-type controls (Siriett T) polymorphism (rs1799983) leads to reduced eNOS activity and
et al., 2006). Of the MSTN variations identified in humans, the basal NO production (Wang et al., 2000; Yoshimura et al., 1998). In
Lys(K)153Arg(R) polymorphism (rs1805086) is thought to influ- postmenopausal women, the T-allele was associated with a higher
ence skeletal-muscle phenotypes in old people, the rare variant stroke volume and lower HR during submaximal dynamic exercise
R-allele possibly exerting a negative influence (Ferrell et al., 1999; (Hand et al., 2006).
 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102 97

4.18. Telomerase reverse transcriptase (TERT) gene for walking speed on chromosome 13q22.1, muscle strength on
chromosome 15q14, 2, muscle power on chromosome 8q24.23,
Several age- and disease-related traits have been associated and muscle CSA on chromosomes 9q34.32 and 20q13.31 (Tiainen
with shorter telomeres, the structures that protect the ends of et al., 2008). In two cohorts of the Framingham Heart Study
chromosomes. A common polymorphism (rs401681) near the TERT (men and women of mean age ≥60 years), Karasik et al. (2009)
gene, which is involved in telomere maintenance that is linked to identified chromosome regions potentially linked to leg lean
cancer risk, could not be associated with physical fitness pheno- mass and femoral bone geometry, including 12p12.3–12p13.2 and
types (handgrip-strength, timed up-rises, timed chair-rises) in 9 14q21.3–22.1.
UK cohorts (5 of which met the age criteria for this review) (Alfred In a recent GWA study examining 379,319 SNPs in a cohort
et al., 2011). of US unrelated whites (492 men, 481 women, mean age 50
years) (Liu et al., 2009), the authors associated with LBM two
4.19. Vitamin D receptor (VDR) gene SNPs within the thyrotropin-releasing hormone receptor (TRHR)
gene, rs16892496 and rs7832552. Individuals carrying ‘unfavor-
Although there is some controversy regarding its expression able’ rs16892496 and rs7832552 genotypes showed lower LBM
in skeletal-muscle fibers (Wang and DeLuca, 2011), the vita- respectively, compared to the other genotypes. These results were
min D receptor (VDR) is thought to play an important role in confirmed in other cohorts, including unrelated old US whites
skeletal-muscle function, through activation of signal transduc- (659 men, 829 women, mean age 63 and 61 years respectively).
tion pathways that regulate contractility and myogenesis (Wang Thus, their findings indicate TRHR is an important gene for LBM
and DeLuca, 2011). The b-allele of the VDR BsmI polymorphism variation.
(rs1544410) was found to exert a beneficial effect on muscle There is a need for more GWA studies in older people, mainly to
strength (Geusens et al., 1997; Hopkinson et al., 2008), muscle propose new candidate genes for more detailed association studies.
boundary length (Murakami et al., 2009), balance (Barr et al., 2010)
and fall risk (Barr et al., 2010; Onder et al., 2008) in some stud-
ies. In contrast, Bahat et al. reported a desirable effect of the BsmI 6. Discussion
B-allele, BB homozygous men (>65 years) showing higher knee-
extensor muscle strength compared to the Bb/bb group (Bahat The controversy existing in the field is likely the consequence
et al., 2010). People with the CC genotype of the VDR FokI poly- of differences among the different study cohorts such as partic-
morphism (rs2228570) had reduced quadriceps strength relative ipant age, sex or ethnic/geographic origin and mainly, sample
to T-allele carriers (Hopkinson et al., 2008), but this polymorphism size. The sample size for detecting associations between disease
was not associated with fall risk in nonagenarians (Onder et al., or health related phenotypes (as those reviewed here) and SNP
2008). The potential link between VDR genotypes and muscle mass markers is known to be highly affected by factors such as allele
in the elderly has also been disputed, with two studies reporting frequency, degree of linkage disequilibrium (i.e. a measure of
no association (Bahat et al., 2010; Moreno Lima et al., 2007), and association between alleles at different loci), inheritance models
one reporting the risk of sarcopenia (defined as appendicular FFM (e.g. additive vs. dominant), or the effect size of the genetic vari-
<7.26 kg m−2 ) to be 2.17-fold higher in men homozygous for the ants (e.g. odds ratio). Nevertheless, it could be estimated that,
FokI polymorphism (FF) compared to their peers with one or more for instance, testing a single SNP would require ∼250 cases to
f-alleles (Roth et al., 2004). obtain a statistical power of 80% (Hong and Park, 2012). With
regards to this, only 38 studies reviewed here included more than
4.20. Vasopressin V1a receptor (V1aR) gene 250 cases.
Differences in the tests used to assess physical fitness pheno-
Although the vasopressin V1a receptor (V1aR) has metabolic types are further possible confounding factors. For instance, 1RM
and cardiovascular effects related to physical fitness phenotypes, strength tests or the 1-mile walk test can be used in healthy sex-
notably lipid metabolism modulation, Masuki et al. (2010) detected agenarians or septuagenarians, whereas more debilitated or older
no association between the rs1042615 polymorphism in the V1aR cohorts are better assessed using ambulation tests. Furthermore, a
gene and the V̇ O2 max response to a 5-month walking training main confounder and limitation in the field lies on the very limited
program in old people. number of studies (n = 4) that have corroborated their main findings
on the same phenotypes using an independent replication cohort of
4.21. Other genes old people. Thus, although a comprehensive meta-analysis would
provide an accurate perspective of the question addressed here,
To address the hypothesis that variations in genes related to this is not yet recommended due to heterogeneity among stud-
inflammation and muscle maintenance are associated with frailty, ies. To standardize research in the field, future studies should
Ho et al. (2011) performed the most comprehensive candidate- adhere to the recent guidelines for ‘STrengthening the REporting
gene study in the field, including 1,354 SNPs across 134 genes, of Genetic Association’ studies (STREGA) (Little et al., 2009), built
in women aged 70 − 79 years. These authors were able to asso- on the ‘Strengthening the Reporting of Observational Studies in
ciate with frailty, several SNPs located in genes involved mainly Epidemiology’ (STROBE). Besides the need for reported associa-
in apoptosis- and transcription regulation-related pathways [5- tions to be externally validated with replication cohorts, functional
methyltetrahydrofolate-homocysteine methyltransferase (MTR), studies examining gene expression are also recommended for
caspase 8 (CASP8), CREB-binding protein (CREBBP), lysine acetyl- understanding the molecular mechanisms underlying potential
transferase 2B (KAT2B), and beta-transducin repeat containing links between a given polymorphism and physical fitness pheno-
(BTRC)]. types in advanced ages. However, this will require tissue biopsies
(i.e. skeletal-muscle) in old people, which is not always feasible.
5. Linkage and GWA studies Finally, we believe that, in order to understand how genetic fac-
tors interfere with ageing and physical fitness, ideally the same
In the first genome-wide linkage investigation into several phys- cohort should be followed over decades to assess if the interaction
ical fitness-related phenotypes in older people (Finnish female between the same genetic variants and physical fitness phenotypes
twins aged 66–75 years), Tiainen et al. found suggestive linkage changes as a result of the ageing process.
98 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102

7. Conclusions polymorphisms, falls, balance and muscle power: results from two independent
studies (APOSS and OPUS). Osteoporos Int. 21, 457–466.
Baumgartner, R.N., Koehler, K.M., Gallagher, D., Romero, L., Heymsfield, S.B., Ross,
Studies assessing the contribution of genetic makeup to R.R., Garry, P.J., Lindeman, R.D., 1998. Epidemiology of sarcopenia among the
age-related diminished physical fitness and subsequent loss of elderly in New Mexico. Am. J. Epidemiol. 147, 755–763.
independence are of broad interest owing to our ever-increasing Bennermo, M., Held, C., Stemme, S., Ericsson, C.G., Silveira, A., Green, F., Tornvall,
P., 2004. Genetic predisposition of the interleukin-6 response to inflammation:
longevity and accompanying health problems. For instance, the implications for a variety of major diseases? Clin. Chem. 50, 2136–2140.
estimated direct healthcare cost attributable to sarcopenia in the Berk, B.C., Vekshtein, V., Gordon, H.M., Tsuda, T., 1989. Angiotensin II-stimulated
United States in 2000 was US$ 18.5 billion, representing some protein synthesis in cultured vascular smooth muscle cells. Hypertension 13,
305–314.
1.5% of the entire healthcare budget for that year (Janssen et al.,
Bhasin, S., Storer, T.W., 2009. Anabolic applications of androgens for functional
2004). Heritability studies have identified an important genetic limitations associated with aging and chronic illness. Front. Horm. Res. 37,
component of physical fitness-related phenotypes among old peo- 163–182.
Blazer, D.G., Fillenbaum, G., Burchett, B., 2001. The APOE-E4 allele and the risk of
ple. Published data on specific gene variants are however relatively
functional decline in a community sample of African American and white older
recent and controversial. As such, no solid evidence currently adults. J. Gerontol. A Biol. Sci. Med. Sci. 56, M785–M789.
exists supporting an ‘unfavorable’ genotype associated, for exam- Bouchard, C., Daw, E.W., Rice, T., Perusse, L., Gagnon, J., Province, M.A., Leon, A.S.,
ple, with accelerated sarcopenia or frailty. Among many candidates Rao, D.C., Skinner, J.S., Wilmore, J.H., 1998. Familial resemblance for V̇ O2 max
in the sedentary state: the HERITAGE family study. Med. Sci. Sports Exerc. 30,
(most of which probably remain to be identified), variations in the 252–258.
MSTN gene and genes involved in the myostatin signaling path- Buchman, A.S., Boyle, P.A., Wilson, R.S., Beck, T.L., Kelly, J.F., Bennett, D.A., 2009.
way (e.g. ACVR1B) warrant further, in-depth research due their Apolipoprotein E e4 allele is associated with more rapid motor decline in older
persons. Alzheimer Dis. Assoc. Disord. 23, 63–69.
important role in muscle mass modulation. Future studies should Bustamante-Ara, N., Santiago, C., Verde, Z., Yvert, T., Gomez-Gallego, F., Rodriguez-
consider that physical fitness is the result of complex interactions Romo, G., Gonzalez-Gil, P., Serra-Rexach, J.A., Ruiz, J.R., Lucia, A., 2010. ACE and
among several organ (heart, lung, muscle) functions. Accordingly, ACTN3 genes and muscle phenotypes in nonagenarians. Int. J. Sports Med. 31,
221–224.
physical fitness is a polygenic phenotype, not reducible to specific Cannon, B., Shabalina, I.G., Kramarova, T.V., Petrovic, N., Nedergaard, J., 2006. Uncou-
polymorphisms. Thus, the question that needs to be resolved in pling proteins: a role in protection against reactive oxygen species—or not?
the foreseeable future is: how do multiple genes interact with Biochim. Biophys. Acta 1757, 449–458.
Carmelli, D., DeCarli, C., Swan, G.E., Kelly-Hayes, M., Wolf, P.A., Reed, T., Guralnik,
each other and environmental factors to determine healthy age-
J.M., 2000. The joint effect of apolipoprotein E epsilon4 and MRI findings on
ing allowing for an independent, active lifestyle up until the end of lower-extremity function and decline in cognitive function. J. Gerontol. A Biol.
life? Sci. Med. Sci. 55, M103–M109.
Carmelli, D., Reed, T., 2000. Stability and change in genetic and environmental influ-
ences on hand-grip strength in older male twins. J. Appl. Physiol. 89, 1879–1883.
Acknowledgements Cesari, M., Pahor, M., 2008. Target population for clinical trials on sarcopenia. J. Nutr.
Health Aging 12, 470–478.
Charbonneau, D.E., Hanson, E.D., Ludlow, A.T., Delmonico, M.J., Hurley, B.F., Roth,
We thank Ana Burton for her lingustic assistance. Research in S.M., 2008. ACE genotype and the muscle hypertrophic and strength responses
the field by the authors is supported by the Fondo de Investigaciones to strength training. Med. Sci. Sports Exerc. 40, 677–683.
Sanitarias (grant # FIS PI09-00194). Christensen, K., Frederiksen, H., Vaupel, J.W., McGue, M., 2003. Age trajectories of
genetic variance in physical functioning: a longitudinal study of Danish twins
aged 70 years and older. Behav. Genet. 33, 125–136.
Appendix A. Supplementary data Christensen, K., McGue, M., Petersen, I., Jeune, B., Vaupel, J.W., 2008. Exceptional
longevity does not result in excessive levels of disability. Proc. Natl. Acad. Sci. U.
S. A. 105, 13274–13279.
Supplementary data associated with this article can be found, in Coggan, A.R., Spina, R.J., King, D.S., Rogers, M.A., Brown, M., Nemeth, P.M., Holloszy,
the online version, at http://dx.doi.org/10.1016/j.arr.2012.09.003. J.O., 1992. Histochemical and enzymatic comparison of the gastrocnemius mus-
cle of young and elderly men and women. J. Gerontol. 47, B71–B76.
Conley, K.E., Jubrias, S.A., Esselman, P.C., 2000. Oxidative capacity and ageing in
References human muscle. J. Physiol. 526 (Pt 1), 203–210.
Cooke, J.P., Rossitch Jr., E., Andon, N.A., Loscalzo, J., Dzau, V.J., 1991. Flow activates
Abellan van Kan, G., 2009. Epidemiology and consequences of sarcopenia. J. Nutr. an endothelial potassium channel to release an endogenous nitrovasodilator. J.
Health Aging 13, 708–712. Clin. Invest. 88, 1663–1671.
Abney, M., McPeek, M.S., Ober, C., 2001. Broad and narrow heritabilities of quanti- Corsi, A.M., Ferrucci, L., Gozzini, A., Tanini, A., Brandi, M.L., 2002. Myostatin poly-
tative traits in a founder population. Am. J. Hum. Genet. 68, 1302–1307. morphisms and age-related sarcopenia in the Italian population. J. Am. Geriatr.
Albert, S.M., Gurland, B., Maestre, G., Jacobs, D.M., Stern, Y., Mayeux, R., 1995. APOE Soc. 50, 1463.
genotype influences functional status among elderly without dementia. Am. J. Crocco, P., Montesanto, A., Passarino, G., Rose, G., 2011. A common polymorphism in
Med. Genet. 60, 583–587. the UCP3 promoter influences hand grip strength in elderly people. Biogeron-
Alfred, T., Ben-Shlomo, Y., Cooper, R., Hardy, R., Cooper, C., Deary, I.J., Elliott, J., Gun- tology 12, 265–271.
nell, D., Harris, S.E., Kivimaki, M., Kumari, M., Martin, R.M., Power, C., Sayer, A.A., Cruz-Jentoft, A.J., Baeyens, J.P., Bauer, J.M., Boirie, Y., Cederholm, T., Landi, F., Mar-
Starr, J.M., Kuh, D., Day, I.N., 2011. Absence of association of a single-nucleotide tin, F.C., Michel, J.P., Rolland, Y., Schneider, S.M., Topinkova, E., Vandewoude, M.,
polymorphism in the TERT-CLPTM1L locus with age-related phenotypes in a Zamboni, M., 2010. Sarcopenia: European consensus on definition and diagno-
large multicohort study: the HALCyon programme. Aging Cell 10, 520–532. sis: Report of the European Working Group on Sarcopenia in Older People. Age
Alfred, T., Ben-Shlomo, Y., Cooper, R., Hardy, R., Cooper, C., Deary, I.J., Gaunt, T.R., Ageing 39, 412–423.
Gunnell, D., Harris, S.E., Kumari, M., Martin, R.M., Sayer, A.A., Starr, J.M., Kuh, D., Danser, A.H., Schalekamp, M.A., Bax, W.A., van den Brink, A.M., Saxena, P.R., Riegger,
Day, I.N., 2012. A multi-cohort study of polymorphisms in the GH/IGF axis and G.A., Schunkert, H., 1995. Angiotensin-converting enzyme in the human heart.
physical capability: the HALCyon programme. PLoS One 7, e29883. Effect of the deletion/insertion polymorphism. Circulation 92, 1387–1388.
Arden, N.K., Spector, T.D., 1997. Genetic influences on muscle strength, lean body Dato, S., Montesanto, A., Lagani, V., Jeune, B., Christensen, K., Passarino, G., 2012.
mass, and bone mineral density: a twin study. J. Bone Miner. Res. 12, 2076–2081. Frailty phenotypes in the elderly based on cluster analysis: a longitudinal study
Arking, D.E., Fallin, D.M., Fried, L.P., Li, T., Beamer, B.A., Xue, Q.L., Chakravarti, A., of two Danish cohorts. Evidence for a genetic influence on frailty. Age 34,
Walston, J., 2006. Variation in the ciliary neurotrophic factor gene and muscle 571–582.
strength in older Caucasian women. J. Am. Geriatr. Soc. 54, 823–826. Dawn Teare, M., Barrett, J.H., 2005. Genetic linkage studies. Lancet 366, 1036–1044.
Attia, J., Ioannidis, J.P., Thakkinstian, A., McEvoy, M., Scott, R.J., Minelli, C., Thomp- De Mars, G., Windelinckx, A., Beunen, G., Delecluse, C., Lefevre, J., Thomis, M.A., 2007.
son, J., Infante-Rivard, C., Guyatt, G., 2009. How to use an article about genetic Polymorphisms in the CNTF and CNTF receptor genes are associated with muscle
association: B: Are the results of the study valid? JAMA 301, 191–197. strength in men and women. J. Appl. Physiol. 102, 1824–1831.
Bader, G., Zuliani, G., Kostner, G.M., Fellin, R., 1998. Apolipoprotein E polymorphism Deary, I.J., Whalley, L.J., Batty, G.D., Starr, J.M., 2006. Physical fitness and lifetime
is not associated with longevity or disability in a sample of Italian octo- and cognitive change. Neurology 67, 1195–1200.
nonagenarians. Gerontology 44, 293–299. Degens, H., 1998. Age-related changes in the microcirculation of skeletal muscle.
Bahat, G., Saka, B., Erten, N., Ozbek, U., Coskunpinar, E., Yildiz, S., Sahinkaya, T., Karan, Adv. Exp. Med. Biol. 454, 343–348.
M.A., 2010. BsmI polymorphism in the vitamin D receptor gene is associated with Delmonico, M.J., Kostek, M.C., Doldo, N.A., Hand, B.D., Walsh, S., Conway, J.M.,
leg extensor muscle strength in elderly men. Aging Clin. Exp. Res. 22, 198–205. Carignan, C.R., Roth, S.M., Hurley, B.F., 2007. Alpha-actinin-3 (ACTN3) R577X
Barr, R., Macdonald, H., Stewart, A., McGuigan, F., Rogers, A., Eastell, R., Felsenberg, D., polymorphism influences knee extensor peak power response to strength train-
Gluer, C., Roux, C., Reid, D.M., 2010. Association between vitamin D receptor gene ing in older men and women. J. Gerontol. A Biol. Sci. Med. Sci. 62, 206–212.
 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102 99

Delmonico, M.J., Zmuda, J.M., Taylor, B.C., Cauley, J.A., Harris, T.B., Manini, T.M., Frederiksen, H., Gaist, D., Petersen, H.C., Hjelmborg, J., McGue, M., Vaupel, J.W., Chris-
Schwartz, A., Li, R., Roth, S.M., Hurley, B.F., Bauer, D.C., Ferrell, R.E., Newman, tensen, K., 2002. Hand grip strength: a phenotype suitable for identifying genetic
A.B., 2008. Association of the ACTN3 genotype and physical functioning with variants affecting mid- and late-life physical functioning. Genet. Epidemiol. 23,
age in older adults. J. Gerontol. A Biol. Sci. Med. Sci. 63, 1227–1234. 110–122.
Deng, H.W., Lai, D.B., Conway, T., Li, J., Xu, F.H., Davies, K.M., Recker, R.R., 2001. Char- Fried, L.P., Ferrucci, L., Darer, J., Williamson, J.D., Anderson, G., 2004. Untangling
acterization of genetic and lifestyle factors for determining variation in body the concepts of disability, frailty, and comorbidity: implications for improved
mass index, fat mass, percentage of fat mass, and lean mass. J. Clin. Densitom. 4, targeting and care. J. Gerontol. A Biol. Sci. Med. Sci. 59, 255–263.
353–361. Fried, L.P., Tangen, C.M., Walston, J., Newman, A.B., Hirsch, C., Gottdiener, J., Seeman,
Deschenes, M.R., 2004. Effects of aging on muscle fibre type and size. Sports Med. T., Tracy, R., Kop, W.J., Burke, G., McBurnie, M.A., 2001. Frailty in older adults:
34, 809–824. evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 56, M146–M156.
Doherty, T.J., 2003. Invited review: Aging and sarcopenia. J. Appl. Physiol. 95, Frisoli Jr., A., Chaves, P.H., Ingham, S.J., Fried, L.P., 2011. Severe osteopenia and osteo-
1717–1727. porosis, sarcopenia, and frailty status in community-dwelling older women:
Echtay, K.S., 2007. Mitochondrial uncoupling proteins–what is their physiological Results from the Women’s Health and Aging Study (WHAS) II. Bone 48,
role? Free Radic. Biol. Med. 43, 1351–1371. 952–957.
Eskurza, I., Donato, A.J., Moreau, K.L., Seals, D.R., Tanaka, H., 2002. Changes in max- Garatachea, N., Fiuza-Luces, C., Torres-Luque, G., Yvert, T., Santiago, C., Gomez-
imal aerobic capacity with age in endurance-trained women: 7-yr follow-up. J. Gallego, F., Ruiz, J.R., Lucia, A., 2012. Single and combined influence of ACE and
Appl. Physiol. 92, 2303–2308. ACTN3 genotypes on muscle phenotypes in octogenarians. Eur. J. Appl. Physiol.
Etnier, J.L., Caselli, R.J., Reiman, E.M., Alexander, G.E., Sibley, B.A., Tessier, D., 112, 2409–2420.
McLemore, E.C., 2007. Cognitive performance in older women relative to ApoE- Garber, C.E., Blissmer, B., Deschenes, M.R., Franklin, B.A., Lamonte, M.J., Lee,
epsilon4 genotype and aerobic fitness. Med. Sci. Sports Exerc. 39, 199–207. I.M., Nieman, D.C., Swain, D.P., 2011. American College of Sports Medicine
Eynon, N., Moran, M., Birk, R., Lucia, A., 2011. The champions’ mitochondria: is position stand. Quantity and quality of exercise for developing and maintain-
it genetically determined? A review on mitochondrial DNA and elite athletic ing cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently
performance. Physiol. Genom. 43, 789–798. healthy adults: guidance for prescribing exercise. Med. Sci. Sports Exerc. 43,
Ferrell, R.E., Conte, V., Lawrence, E.C., Roth, S.M., Hagberg, J.M., Hurley, B.F., 1999. 1334–1359.
Frequent sequence variation in the human myostatin (GDF8) gene as a marker Geisterfer, A.A., Peach, M.J., Owens, G.K., 1988. Angiotensin II induces hypertro-
for analysis of muscle-related phenotypes. Genomics 62, 203–207. phy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ. Res. 62,
Fielding, R.A., Vellas, B., Evans, W.J., Bhasin, S., Morley, J.E., Newman, A.B., Abellan 749–756.
van Kan, G., Andrieu, S., Bauer, J., Breuille, D., Cederholm, T., Chandler, J., De Geusens, P., Vandevyver, C., Vanhoof, J., Cassiman, J.J., Boonen, S., Raus, J., 1997.
Meynard, C., Donini, L., Harris, T., Kannt, A., Keime Guibert, F., Onder, G., Papani- Quadriceps and grip strength are related to vitamin D receptor genotype in
colaou, D., Rolland, Y., Rooks, D., Sieber, C., Souhami, E., Verlaan, S., Zamboni, M., elderly nonobese women. J. Bone Miner. Res. 12, 2082–2088.
2011. Sarcopenia: an undiagnosed condition in older adults. Current consensus Giaccaglia, V., Nicklas, B., Kritchevsky, S., Mychalecky, J., Messier, S., Bleecker, E.,
definition: prevalence etiology, and consequences. International working group Pahor, M., 2008. Interaction between angiotensin converting enzyme inser-
on sarcopenia. J. Am. Med. Dir. Assoc. 12, 249–256. tion/deletion genotype and exercise training on knee extensor strength in older
Fishman, D., Faulds, G., Jeffery, R., Mohamed-Ali, V., Yudkin, J.S., Humphries, S., Woo, individuals. Int. J. Sports Med. 29, 40–44.
P., 1998. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on Gonzalez-Freire, M., Rodriguez-Romo, G., Santiago, C., Bustamante-Ara, N., Yvert,
IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset T., Gomez-Gallego, F., Serra Rexach, J.A., Ruiz, J.R., Lucia, A., 2010. The K153R
juvenile chronic arthritis. J. Clin. Invest. 102, 1369–1376. variant in the myostatin gene and sarcopenia at the end of the human lifespan.
Fleg, J.L., Morrell, C.H., Bos, A.G., Brant, L.J., Talbot, L.A., Wright, J.G., Lakatta, E.G., 2005. Age (Dordr.) 32, 405–409.
Accelerated longitudinal decline of aerobic capacity in healthy older adults. Gordon, S.E., Davis, B.S., Carlson, C.J., Booth, F.W., 2001. ANG II is required for opti-
Circulation 112, 674–682. mal overload-induced skeletal muscle hypertrophy. Am. J. Physiol. Endocrinol.
Folland, J.P., Mc Cauley, T.M., Phypers, C., Hanson, B., Mastana, S.S., 2012. The rela- Metab. 280, E150–E159.
tionship of testosterone and AR CAG repeat genotype with knee extensor muscle Gross, M., 1997. Clinical heterogeneity and molecular mechanisms in inborn muscle
function of young and older men. Exp. Gerontol. 47, 437–443. AMP deaminase deficiency. J. Inherit. Metab. Dis. 20, 186–192.
Frazer, K.A., Ballinger, D.G., Cox, D.R., Hinds, D.A., Stuve, L.L., Gibbs, R.A., Belmont, Guillet, C., Auguste, P., Mayo, W., Kreher, P., Gascan, H., 1999. Ciliary neurotrophic
J.W., Boudreau, A., Hardenbol, P., Leal, S.M., Pasternak, S., Wheeler, D.A., Willis, factor is a regulator of muscular strength in aging. J. Neurosci. 19, 1257–1262.
T.D., Yu, F., Yang, H., Zeng, C., Gao, Y., Hu, H., Hu, W., Li, C., Lin, W., Liu, S., Pan, Gustafson, D.R., Mazzuco, S., Ongaro, F., Antuono, P., Forloni, G., Albani, D., Gajo,
H., Tang, X., Wang, J., Wang, W., Yu, J., Zhang, B., Zhang, Q., Zhao, H., Zhou, J., G.B., Durante, E., Caberlotto, L., Zanardo, A., Siculi, M., Gallucci, M., 2012. Body
Gabriel, S.B., Barry, R., Blumenstiel, B., Camargo, A., Defelice, M., Faggart, M., mass index, cognition, disability, APOE genotype, and mortality: the “Treviso
Goyette, M., Gupta, S., Moore, J., Nguyen, H., Onofrio, R.C., Parkin, M., Roy, J., Longeva” Study. Am. J. Geriatr. Psychiatry 20, 594–602.
Stahl, E., Winchester, E., Ziaugra, L., Altshuler, D., Shen, Y., Yao, Z., Huang, W., Hagberg, J.M., Allen, W.K., Seals, D.R., Hurley, B.F., Ehsani, A.A., Holloszy, J.O., 1985. A
Chu, X., He, Y., Jin, L., Liu, Y., Sun, W., Wang, H., Wang, Y., Xiong, X., Xu, L., Waye, hemodynamic comparison of young and older endurance athletes during exer-
M.M., Tsui, S.K., Xue, H., Wong, J.T., Galver, L.M., Fan, J.B., Gunderson, K., Murray, cise. J. Appl. Physiol. 58, 2041–2046.
S.S., Oliphant, A.R., Chee, M.S., Montpetit, A., Chagnon, F., Ferretti, V., Leboeuf, Hagberg, J.M., McCole, S.D., Brown, M.D., Ferrell, R.E., Wilund, K.R., Huberty,
M., Olivier, J.F., Phillips, M.S., Roumy, S., Sallee, C., Verner, A., Hudson, T.J., Kwok, A., Douglass, L.W., Moore, G.E., 2002. ACE insertion/deletion polymorphism
P.Y., Cai, D., Koboldt, D.C., Miller, R.D., Pawlikowska, L., Taillon-Miller, P., Xiao, and submaximal exercise hemodynamics in postmenopausal women. J. Appl.
M., Tsui, L.C., Mak, W., Song, Y.Q., Tam, P.K., Nakamura, Y., Kawaguchi, T., Kita- Physiol. 92, 1083–1088.
moto, T., Morizono, T., Nagashima, A., Ohnishi, Y., Sekine, A., Tanaka, T., Tsunoda, Hand, B.D., Kostek, M.C., Ferrell, R.E., Delmonico, M.J., Douglass, L.W., Roth, S.M.,
T., Deloukas, P., Bird, C.P., Delgado, M., Dermitzakis, E.T., Gwilliam, R., Hunt, S., Hagberg, J.M., Hurley, B.F., 2007. Influence of promoter region variants of insulin-
Morrison, J., Powell, D., Stranger, B.E., Whittaker, P., Bentley, D.R., Daly, M.J., de like growth factor pathway genes on the strength-training response of muscle
Bakker, P.I., Barrett, J., Chretien, Y.R., Maller, J., McCarroll, S., Patterson, N., Pe’er, phenotypes in older adults. J. Appl. Physiol. 103, 1678–1687.
I., Price, A., Purcell, S., Richter, D.J., Sabeti, P., Saxena, R., Schaffner, S.F., Sham, Hand, B.D., McCole, S.D., Brown, M.D., Park, J.J., Ferrell, R.E., Huberty, A., Douglass,
P.C., Varilly, P., Stein, L.D., Krishnan, L., Smith, A.V., Tello-Ruiz, M.K., Thorisson, L.W., Hagberg, J.M., 2006. NOS3 gene polymorphisms and exercise hemodynam-
G.A., Chakravarti, A., Chen, P.E., Cutler, D.J., Kashuk, C.S., Lin, S., Abecasis, G.R., ics in postmenopausal women. Int. J. Sports Med. 27, 951–958.
Guan, W., Li, Y., Munro, H.M., Qin, Z.S., Thomas, D.J., McVean, G., Auton, A., Bot- Hawkins, S.A., Marcell, T.J., Victoria Jaque, S., Wiswell, R.A., 2001. A longitudinal
tolo, L., Cardin, N., Eyheramendy, S., Freeman, C., Marchini, J., Myers, S., Spencer, assessment of change in VO2max and maximal heart rate in master athletes.
C., Stephens, M., Donnelly, P., Cardon, L.R., Clarke, G., Evans, D.M., Morris, A.P., Med. Sci. Sports Exerc. 33, 1744–1750.
Weir, B.S., Mullikin, J.C., Sherry, S.T., Feolo, M., Skol, A., Zhang, H., Matsuda, I., Heuberger, R.A., 2011. The frailty syndrome: a comprehensive review. J. Nutr. Geron-
Fukushima, Y., Macer, D.R., Suda, E., Rotimi, C.N., Adebamowo, C.A., Ajayi, I., Ani- tol. Geriatr. 30, 315–368.
agwu, T., Marshall, P.A., Nkwodimmah, C., Royal, C.D., Leppert, M.F., Dixon, M., Ho, Y.Y., Matteini, A.M., Beamer, B., Fried, L., Xue, Q.L., Arking, D.E., Chakravarti, A.,
Peiffer, A., Qiu, R., Kent, A., Kato, K., Niikawa, N., Adewole, I.F., Knoppers, B.M., Fallin, M.D., Walston, J., 2011. Exploring biologically relevant pathways in frailty.
Foster, M.W., Clayton, E.W., Watkin, J., Muzny, D., Nazareth, L., Sodergren, E., J. Gerontol. A Biol. Sci. Med. Sci. 66, 975–979.
Weinstock, G.M., Yakub, I., Birren, B.W., Wilson, R.K., Fulton, L.L., Rogers, J., Bur- Hollenberg, M., Yang, J., Haight, T.J., Tager, I.B., 2006. Longitudinal changes in aerobic
ton, J., Carter, N.P., Clee, C.M., Griffiths, M., Jones, M.C., McLay, K., Plumb, R.W., capacity: implications for concepts of aging. J. Gerontol. A Biol. Sci. Med. Sci. 61,
Ross, M.T., Sims, S.K., Willey, D.L., Chen, Z., Han, H., Kang, L., Godbout, M., Wal- 851–858.
lenburg, J.C., L’Archeveque, P., Bellemare, G., Saeki, K., An, D., Fu, H., Li, Q., Wang, Hong, E.P., Park, J.W., 2012. Sample size and statistical power calculations. Genom.
Z., Wang, R., Holden, A.L., Brooks, L.D., McEwen, J.E., Guyer, M.S., Wang, V.O., Inform. 10, 117–122.
Peterson, J.L., Shi, M., Spiegel, J., Sung, L.M., Zacharia, L.F., Collins, F.S., Kennedy, Hopkinson, N.S., Li, K.W., Kehoe, A., Humphries, S.E., Roughton, M., Moxham, J.,
K., Jamieson, R., Stewart, J., 2007. A second generation human haplotype map of Montgomery, H., Polkey, M.I., 2008. Vitamin D receptor genotypes influence
over 3.1 million SNPs. Nature 449, 851–861. quadriceps strength in chronic obstructive pulmonary disease. Am. J. Clin. Nutr.
Frederiksen, H., Bathum, L., Worm, C., Christensen, K., Puggaard, L., 2003a. ACE geno- 87, 385–390.
type and physical training effects: a randomized study among elderly Danes. Hossack, K.F., Bruce, R.A., 1982. Maximal cardiac function in sedentary normal men
Aging Clin. Exp. Res. 15, 284–291. and women: comparison of age-related changes. J. Appl. Physiol. 53, 799–804.
Frederiksen, H., Gaist, D., Bathum, L., Andersen, K., McGue, M., Vaupel, J.W., Chris- Howard, C., Ferrucci, L., Sun, K., Fried, L.P., Walston, J., Varadhan, R., Guralnik,
tensen, K., 2003b. Angiotensin I-converting enzyme (ACE) gene polymorphism J.M., Semba, R.D., 2007. Oxidative protein damage is associated with poor grip
in relation to physical performance, cognition and survival—a follow-up study strength among older women living in the community. J. Appl. Physiol. 103,
of elderly Danish twins. Ann. Epidemiol. 13, 57–65. 17–20.
100 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102

Hsu, F.C., Lenchik, L., Nicklas, B.J., Lohman, K., Register, T.C., Mychaleckyj, J., Langefeld, P., Koonin, E.V., Korf, I., Kulp, D., Lancet, D., Lowe, T.M., McLysaght, A., Mikkelsen,
C.D., Freedman, B.I., Bowden, D.W., Carr, J.J., 2005. Heritability of body compo- T., Moran, J.V., Mulder, N., Pollara, V.J., Ponting, C.P., Schuler, G., Schultz, J., Slater,
sition measured by DXA in the diabetes heart study. Obes. Res. 13, 312–319. G., Smit, A.F., Stupka, E., Szustakowski, J., Thierry-Mieg, D., Thierry-Mieg, J., Wag-
Huygens, W., Thomis, M.A., Peeters, M.W., Aerssens, J., Janssen, R., Vlietinck, R.F., ner, L., Wallis, J., Wheeler, R., Williams, A., Wolf, Y.I., Wolfe, K.H., Yang, S.P., Yeh,
Beunen, G., 2004a. Linkage of myostatin pathway genes with knee strength in R.F., Collins, F., Guyer, M.S., Peterson, J., Felsenfeld, A., Wetterstrand, K.A., Patri-
humans. Physiol. Genom. 17, 264–270. nos, A., Morgan, M.J., de Jong, P., Catanese, J.J., Osoegawa, K., Shizuya, H., Choi, S.,
Huygens, W., Thomis, M.A., Peeters, M.W., Vlietinck, R.F., Beunen, G.P., 2004b. Deter- Chen, Y.J., 2001. Initial sequencing and analysis of the human genome. Nature
minants and upper-limit heritabilities of skeletal muscle mass and strength. Can. 409, 860–921.
J. Appl. Physiol. 29, 186–200. Landi, F., Liperoti, R., Fusco, D., Mastropaolo, S., Quattrociocchi, D., Proia, A., Tosato,
International HapMap Consortium, 2005. A haplotype map of the human genome. M., Bernabei, R., Onder, G., 2012. Sarcopenia and mortality among older nursing
Nature 437, 1299–1320. home residents. J. Am. Med. Directors Assoc. 13, 121–126.
Ishigai, Y., Mori, T., Ikeda, T., Fukuzawa, A., Shibano, T., 1997. Role of bradykinin-NO Lapauw, B., Goemaere, S., Crabbe, P., Kaufman, J.M., Ruige, J.B., 2007. Is the effect
pathway in prevention of cardiac hypertrophy by ACE inhibitor in rat cardiomy- of testosterone on body composition modulated by the androgen receptor gene
ocytes. Am. J. Physiol. 273, H2659–H2663. CAG repeat polymorphism in elderly men? Eur. J. Endocrinol. 156, 395–401.
Ivey, F.M., Roth, S.M., Ferrell, R.E., Tracy, B.L., Lemmer, J.T., Hurlbut, D.E., Martel, G.F., Lauretani, F., Russo, C.R., Bandinelli, S., Bartali, B., Cavazzini, C., Di Iorio, A., Corsi, A.M.,
Siegel, E.L., Fozard, J.L., Jeffrey Metter, E., Fleg, J.L., Hurley, B.F., 2000. Effects of Rantanen, T., Guralnik, J.M., Ferrucci, L., 2003. Age-associated changes in skeletal
age, gender, and myostatin genotype on the hypertrophic response to heavy muscles and their effect on mobility: an operational diagnosis of sarcopenia. J.
resistance strength training. J. Gerontol. A Biol. Sci. Med. Sci. 55, M641–M648. Appl. Physiol. 95, 1851–1860.
Janssen, I., 2006. Influence of sarcopenia on the development of physical disability: Lexell, J., Taylor, C.C., Sjostrom, M., 1988. What is the cause of the ageing atrophy?
the Cardiovascular Health Study. J. Am. Geriatr. Soc. 54, 56–62. Total number, size and proportion of different fiber types studied in whole vastus
Janssen, I., Heymsfield, S.B., Ross, R., 2002. Low relative skeletal muscle mass (sar- lateralis muscle from 15- to 83-year-old men. J. Neurol. Sci. 84, 275–294.
copenia) in older persons is associated with functional impairment and physical Lima, R.M., Leite, T.K., Pereira, R.W., Rabelo, H.T., Roth, S.M., Oliveira, R.J., 2011. ACE
disability. J. Am. Geriatr. Soc. 50, 889–896. and ACTN3 genotypes in older women: muscular phenotypes. Int. J. Sports Med.
Janssen, I., Heymsfield, S.B., Wang, Z.M., Ross, R., 2000. Skeletal muscle mass and 32, 66–72.
distribution in 468 men and women aged 18-88 yr. J. Appl. Physiol. 89, 81–88. Little, J., Higgins, J.P., Ioannidis, J.P., Moher, D., Gagnon, F., von Elm, E., Khoury, M.J.,
Janssen, I., Shepard, D.S., Katzmarzyk, P.T., Roubenoff, R., 2004. The healthcare costs Cohen, B., Davey-Smith, G., Grimshaw, J., Scheet, P., Gwinn, M., Williamson, R.E.,
of sarcopenia in the United States. J. Am. Geriatr. Soc. 52, 80–85. Zou, G.Y., Hutchings, K., Johnson, C.Y., Tait, V., Wiens, M., Golding, J., van Duijn, C.,
Kamel, H.K., 2003. Sarcopenia and aging. Nutr. Rev. 61, 157–167. McLaughlin, J., Paterson, A., Wells, G., Fortier, I., Freedman, M., Zecevic, M., King,
Karasik, D., Zhou, Y., Cupples, L.A., Hannan, M.T., Kiel, D.P., Demissie, S., 2009. Bivari- R., Infante-Rivard, C., Stewart, A., Birkett, N., 2009. Strengthening the reporting
ate genome-wide linkage analysis of femoral bone traits and leg lean mass: of genetic association studies (STREGA): an extension of the STROBE Statement.
Framingham study. J. Bone Miner. Res. 24, 710–718. Hum. Genet. 125, 131–151.
Kenny, A.M., McGee, D., Joseph, C., Covault, J., Abreu, C., Raisz, L.G., 2005. Lack of asso- Liu, X.G., Tan, L.J., Lei, S.F., Liu, Y.J., Shen, H., Wang, L., Yan, H., Guo, Y.F., Xiong, D.H.,
ciation between androgen receptor polymorphisms and bone mineral density Chen, X.D., Pan, F., Yang, T.L., Zhang, Y.P., Guo, Y., Tang, N.L., Zhu, X.Z., Deng, H.Y.,
or physical function in older men. Endocr. Res. 31, 285–293. Levy, S., Recker, R.R., Papasian, C.J., Deng, H.W., 2009. Genome-wide association
Kostek, M.C., Devaney, J.M., Gordish-Dressman, H., Harris, T.B., Thompson, P.D., and replication studies identified TRHR as an important gene for lean body mass.
Clarkson, P.M., Angelopoulos, T.J., Gordon, P.M., Moyna, N.M., Pescatello, L.S., Am. J. Hum. Genet. 84, 418–423.
Visich, P.S., Zoeller, R.F., Seip, R.L., Garcia, M., Li, R., Zmuda, J.M., Delmonico, M.J., MacArthur, D.G., North, K.N., 2004. A gene for speed? The evolution and function of
Kanaya, A., Hoffman, E.P., 2010. A polymorphism near IGF1 is associated with alpha-actinin-3. Bioessays 26, 786–795.
body composition and muscle function in women from the Health, Aging, and MacArthur, D.G., North, K.N., 2007. ACTN3: A genetic influence on muscle function
Body Composition Study. Eur. J. Appl. Physiol. 110, 315–324. and athletic performance. Exerc. Sport Sci. Rev. 35, 30–34.
Krivickas, L.S., Walsh, R., Amato, A.A., 2009. Single muscle fiber contractile properties Manenschijn, L., van den Akker, E.L., Lamberts, S.W., van Rossum, E.F., 2009. Clinical
in adults with muscular dystrophy treated with MYO-029. Muscle Nerve 39, 3–9. features associated with glucocorticoid receptor polymorphisms. An overview.
Kulminski, A., Ukraintseva, S.V., Arbeev, K.G., Manton, K.G., Oshima, J., Martin, G.M., Ann. N. Y. Acad. Sci. 1179, 179–198.
Yashin, A.I., 2008. Association between APOE epsilon 2/epsilon 3/epsilon 4 poly- Masuki, S., Mori, M., Tabara, Y., Miki, T., Sakurai, A., Morikawa, M., Miyagawa, K.,
morphism and disability severity in a national long-term care survey sample. Higuchi, K., Nose, H., 2010. Vasopressin V1a receptor polymorphism and inter-
Age Ageing 37, 288–293. val walking training effects in middle-aged and older people. Hypertension 55,
Kumar, V., Selby, A., Rankin, D., Patel, R., Atherton, P., Hildebrandt, W., Williams, J., 747–754.
Smith, K., Seynnes, O., Hiscock, N., Rennie, M.J., 2009. Age-related differences in McCauley, T., Mastana, S.S., Folland, J.P., 2010. ACE I/D and ACTN3 R/X polymor-
the dose-response relationship of muscle protein synthesis to resistance exer- phisms and muscle function and muscularity of older Caucasian men. Eur. J.
cise in young and old men. J. Physiol. 587, 211–217. Appl. Physiol. 109, 269–277.
Lakatta, E.G., Levy, D., 2003. Arterial and cardiac aging: major shareholders in cardio- McCole, S.D., Brown, M.D., Moore, G.E., Ferrell, R.E., Wilund, K.R., Huberty, A.,
vascular disease enterprises: Part I: aging arteries: a set up for vascular disease. Douglass, L.W., Hagberg, J.M., 2002. Angiotensinogen M235 T polymorphism
Circulation 107, 139–146. associates with exercise hemodynamics in postmenopausal women. Physiol.
Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., Baldwin, J., Devon, K., Genom. 10, 63–69.
Dewar, K., Doyle, M., FitzHugh, W., Funke, R., Gage, D., Harris, K., Heaford, A., McCole, S.D., Shuldiner, A.R., Brown, M.D., Moore, G.E., Ferrell, R.E., Wilund, K.R.,
Howland, J., Kann, L., Lehoczky, J., LeVine, R., McEwan, P., McKernan, K., Meldrim, Huberty, A., Douglass, L.W., Hagberg, J.M., 2004. Beta2- and beta3-adrenergic
J., Mesirov, J.P., Miranda, C., Morris, W., Naylor, J., Raymond, C., Rosetti, M., Santos, receptor polymorphisms and exercise hemodynamics in postmenopausal
R., Sheridan, A., Sougnez, C., Stange-Thomann, N., Stojanovic, N., Subramanian, women. J. Appl. Physiol. 96, 526–530.
A., Wyman, D., Rogers, J., Sulston, J., Ainscough, R., Beck, S., Bentley, D., Burton, McPherron, A.C., Lawler, A.M., Lee, S.J., 1997. Regulation of skeletal muscle mass in
J., Clee, C., Carter, N., Coulson, A., Deadman, R., Deloukas, P., Dunham, A., Dun- mice by a new TGF-beta superfamily member. Nature 387, 83–90.
ham, I., Durbin, R., French, L., Grafham, D., Gregory, S., Hubbard, T., Humphray, Melzer, D., Dik, M.G., van Kamp, G.J., Jonker, C., Deeg, D.J., 2005. The apolipoprotein
S., Hunt, A., Jones, M., Lloyd, C., McMurray, A., Matthews, L., Mercer, S., Milne, E e4 polymorphism is strongly associated with poor mobility performance test
S., Mullikin, J.C., Mungall, A., Plumb, R., Ross, M., Shownkeen, R., Sims, S., Water- results but not self-reported limitation in older people. J. Gerontol. A Biol. Sci.
ston, R.H., Wilson, R.K., Hillier, L.W., McPherson, J.D., Marra, M.A., Mardis, E.R., Med. Sci. 60, 1319–1323.
Fulton, L.A., Chinwalla, A.T., Pepin, K.H., Gish, W.R., Chissoe, S.L., Wendl, M.C., Moore, A.Z., Biggs, M.L., Matteini, A., O’Connor, A., McGuire, S., Beamer, B.A., Fallin,
Delehaunty, K.D., Miner, T.L., Delehaunty, A., Kramer, J.B., Cook, L.L., Fulton, M.D., Fried, L.P., Walston, J., Chakravarti, A., Arking, D.E., 2010. Polymorphisms
R.S., Johnson, D.L., Minx, P.J., Clifton, S.W., Hawkins, T., Branscomb, E., Predki, in the mitochondrial DNA control region and frailty in older adults. PLoS One 5,
P., Richardson, P., Wenning, S., Slezak, T., Doggett, N., Cheng, J.F., Olsen, A., Lucas, e11069.
S., Elkin, C., Uberbacher, E., Frazier, M., Gibbs, R.A., Muzny, D.M., Scherer, S.E., Mora, M., Perales, M.J., Serra-Prat, M., Palomera, E., Buquet, X., Oriola, J., Puig-
Bouck, J.B., Sodergren, E.J., Worley, K.C., Rives, C.M., Gorrell, J.H., Metzker, M.L., Domingo, M., 2011. Aging phenotype and its relationship with IGF-I gene
Naylor, S.L., Kucherlapati, R.S., Nelson, D.L., Weinstock, G.M., Sakaki, Y., Fujiyama, promoter polymorphisms in elderly people living in Catalonia. Growth Horm.
A., Hattori, M., Yada, T., Toyoda, A., Itoh, T., Kawagoe, C., Watanabe, H., Totoki, IGF Res. 21, 174–180.
Y., Taylor, T., Weissenbach, J., Heilig, R., Saurin, W., Artiguenave, F., Brottier, P., Mora, M., Sanchez, L., Serra-Prat, M., Palomera, E., Blanco, J., Aranda, G., Falcon, I.,
Bruls, T., Pelletier, E., Robert, C., Wincker, P., Smith, D.R., Doucette-Stamm, L., Cadenas, I., Boquet, X., Oriola, J., Puig-Domingo, M., 2012. Hormonal determi-
Rubenfield, M., Weinstock, K., Lee, H.M., Dubois, J., Rosenthal, A., Platzer, M., nants and effect of ER22/23EK glucocorticoid receptor gene polymorphism on
Nyakatura, G., Taudien, S., Rump, A., Yang, H., Yu, J., Wang, J., Huang, G., Gu, J., health status deterioration in the participants of the Mataro Ageing Study. Age
Hood, L., Rowen, L., Madan, A., Qin, S., Davis, R.W., Federspiel, N.A., Abola, A.P., 34, 553–561.
Proctor, M.J., Myers, R.M., Schmutz, J., Dickson, M., Grimwood, J., Cox, D.R., Olson, Moreno Lima, R., Silva de Abreu, B., Gentil, P., Cesar de Lima Lins, T., Grat-
M.V., Kaul, R., Shimizu, N., Kawasaki, K., Minoshima, S., Evans, G.A., Athanasiou, tapaglia, D., Pereira, R.W., Jaco de Oliveira, R., 2007. Lack of association
M., Schultz, R., Roe, B.A., Chen, F., Pan, H., Ramser, J., Lehrach, H., Reinhardt, R., between vitamin D receptor genotypes and haplotypes with fat-free mass
McCombie, W.R., de la Bastide, M., Dedhia, N., Blocker, H., Hornischer, K., Nord- in postmenopausal Brazilian women. J. Gerontol. A Biol. Sci. Med. Sci. 62,
siek, G., Agarwala, R., Aravind, L., Bailey, J.A., Bateman, A., Batzoglou, S., Birney, 966–972.
E., Bork, P., Brown, D.G., Burge, C.B., Cerutti, L., Chen, H.C., Church, D., Clamp, M., Murakami, S., Otsuki, T., Maeda, M., Miura, Y., Morii, S., Kiyokane, K., Hayakawa,
Copley, R.R., Doerks, T., Eddy, S.R., Eichler, E.E., Furey, T.S., Galagan, J., Gilbert, S., Maeda, A., Imakawa, T., Harada, S., Handa, T., Nishimura, Y., Kumagai, N.,
J.G., Harmon, C., Hayashizaki, Y., Haussler, D., Hermjakob, H., Hokamp, K., Jang, Hayashi, H., Chen, Y., Suemori, S., Fukushima, Y., Nishida, S., Fukushima, K., 2009.
W., Johnson, L.S., Jones, T.A., Kasif, S., Kaspryzk, A., Kennedy, S., Kent, W.J., Kitts, Effects of vitamin D receptor gene polymorphisms on low-resistance training
 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102 101

using exercise machines: the ‘Power Rehabilitation’ program. Int. J. Mol. Med. Schrager, M.A., Roth, S.M., Ferrell, R.E., Metter, E.J., Russek-Cohen, E., Lynch, N.A.,
23, 81–88. Lindle, R.S., Hurley, B.F., 2004. Insulin-like growth factor-2 genotype, fat-free
North, K.N., Yang, N., Wattanasirichaigoon, D., Mills, M., Easteal, S., Beggs, A.H., mass, and muscle performance across the adult life span. J. Appl. Physiol. 97,
1999. A common nonsense mutation results in alpha-actinin-3 deficiency in 2176–2183.
the general population. Nat. Genet. 21, 353–354. Seibert, M.J., Xue, Q.L., Fried, L.P., Walston, J.D., 2001. Polymorphic variation in
O’Dell, S.D., Day, I.N., 1998. Insulin-like growth factor II (IGF-II). Int. J. Biochem. Cell the human myostatin (GDF-8) gene and association with strength measures
Biol. 30, 767–771. in the Women’s Health and Aging Study II cohort. J. Am. Geriatr. Soc. 49,
Ogawa, T., Spina, R.J., Martin 3rd, W.H., Kohrt, W.M., Schechtman, K.B., Holloszy, J.O., 1093–1096.
Ehsani, A.A., 1992. Effects of aging, sex, and physical training on cardiovascular Serrano, A.L., Baeza-Raja, B., Perdiguero, E., Jardi, M., Munoz-Canoves, P., 2008.
responses to exercise. Circulation 86, 494–503. Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle
Okamoto, N., Nakatani, T., Okamoto, Y., Iwamoto, J., Saeki, K., Kurumatani, N., 2010. hypertrophy. Cell Metab. 7, 33–44.
Increasing the number of steps walked each day improves physical fitness in Seto, J.T., Chan, S., Turner, N., Macarthur, D.G., Raftery, J.M., Berman, Y.D., Quinlan,
Japanese community-dwelling adults. Int. J. Sports Med. 31, 277–282. K.G., Cooney, G.J., Head, S., Yang, N., North, K.N., 2011. The effect of alpha-actinin-
Onder, G., Capoluongo, E., Danese, P., Settanni, S., Russo, A., Concolino, P., Bernabei, 3 deficiency on muscle aging. Exp. Gerontol. 46, 292–302.
R., Landi, F., 2008. Vitamin D receptor polymorphisms and falls among older Shephard, R.J., 2009. Maximal oxygen intake and independence in old age. Br. J.
adults living in the community: results from the ilSIRENTE study. J. Bone Miner. Sports Med. 43, 342–346.
Res. 23, 1031–1036. Siriett, V., Platt, L., Salerno, M.S., Ling, N., Kambadur, R., Sharma, M., 2006. Prolonged
Peeters, G.M., van Schoor, N.M., van Rossum, E.F., Visser, M., Lips, P., 2008. The rela- absence of myostatin reduces sarcopenia. J. Cell Physiol. 209, 866–873.
tionship between cortisol muscle mass and muscle strength in older persons Sleeman, M.W., Anderson, K.D., Lambert, P.D., Yancopoulos, G.D., Wiegand, S.J., 2000.
and the role of genetic variations in the glucocorticoid receptor. Clin. Endocrinol. The ciliary neurotrophic factor and its receptor, CNTFR alpha. Pharm. Acta Helv.
(Oxf.) 69, 673–682. 74, 265–272.
Pereira, D.S., Garcia, D.M., Narciso, F.M., Santos, M.L., Dias, J.M., Queiroz, B.Z., Souza, Snejdrlova, M., Kalvach, Z., Topinkova, E., Vrablik, M., Prochazkova, R., Kvasilova,
E.R., Nobrega, O.T., Pereira, L.S., 2011. Effects of 174 G/C polymorphism in the M., Lanska, V., Zlatohlavek, L., Prusikova, M., Ceska, R., 2011. APOE polymor-
promoter region of the interleukin-6 gene on plasma IL-6 levels and muscle phism as a potential determinant of functional fitness in the elderly regardless
strength in elderly women. Braz. J. Med. Biol. Res. 44, 123–129. of nutritional status. Neuro. Endocrinol. Lett. 32, 51–54.
Perez, M., Martin, M.A., Canete, S., Rubio, J.C., Fernandez-Moreira, D., San Juan, A.F., Sood, S., Hanson, E.D., Delmonico, M.J., Kostek, M.C., Hand, B.D., Roth, S.M., Hurley,
Gomez-Gallego, F., Santiago, C., Arenas, J., Lucia, A., 2006. Does the C34 T muta- B.F., 2012. Does insulin-like growth factor 1 genotype influence muscle power
tion in AMPD1 alter exercise capacity in the elderly? Int. J. Sports Med. 27, response to strength training in older men and women? Eur. J. Appl. Physiol.
429–435. 112, 743–753.
Plomin, R., DeFries, J.C., McClearn, G.E., McGuffin, P., 2001. Behavioral Genetics, Stathokostas, L., Jacob-Johnson, S., Petrella, R.J., Paterson, D.H., 2004. Longitudinal
fourth ed. Worth, New York. changes in aerobic power in older men and women. J. Appl. Physiol. 97, 781–789.
Proctor, D.N., Joyner, M.J., 1997. Skeletal muscle mass and the reduction of VO2max Sternberg, S.A., Wershof Schwartz, A., Karunananthan, S., Bergman, H., Mark
in trained older subjects. J. Appl. Physiol. 82, 1411–1415. Clarfield, A., 2011. The identification of frailty: a systematic literature review.
Quyyumi, A.A., Dakak, N., Andrews, N.P., Gilligan, D.M., Panza, J.A., Cannon 3rd, R.O., J. Am. Geriatr. Soc. 59, 2129–2138.
1995. Contribution of nitric oxide to metabolic coronary vasodilation in the Stratton, J.R., Levy, W.C., Cerqueira, M.D., Schwartz, R.S., Abrass, I.B., 1994. Cardio-
human heart. Circulation 92, 320–326. vascular responses to exercise. Effects of aging and exercise training in healthy
Reed, T., Fabsitz, R.R., Selby, J.V., Carmelli, D., 1991. Genetic influences and grip men. Circulation 89, 1648–1655.
strength norms in the NHLBI twin study males aged 59-69. Ann. Hum. Biol. 18, Tiainen, K.M., Perola, M., Kovanen, V.M., Sipila, S., Tuononen, K.A., Rikalainen, K.,
425–432. Kauppinen, M.A., Widen, E.I., Kaprio, J., Rantanen, T., Kujala, U.M., 2008. Genetics
Rigat, B., Hubert, C., Alhenc-Gelas, F., Cambien, F., Corvol, P., Soubrier, F., 1990. of maximal walking speed and skeletal muscle characteristics in older women.
An insertion/deletion polymorphism in the angiotensin I-converting enzyme Twin Res. Hum. Genet. 11, 321–334.
gene accounting for half the variance of serum enzyme levels. J. Clin. Invest. 86, Tiret, L., Rigat, B., Visvikis, S., Breda, C., Corvol, P., Cambien, F., Soubrier, F., 1992.
1343–1346. Evidence, from combined segregation and linkage analysis, that a variant of the
Risch, N., 1997. Evolving methods in genetic epidemiology. II. Genetic linkage from angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am. J.
an epidemiologic perspective. Epidemiol. Rev. 19, 24–32. Hum. Genet. 51, 197–205.
Rivera, A.M., Pels 3rd, A.E., Sady, S.P., Sady, M.A., Cullinane, E.M., Thompson, P.D., Toth, M.J., Gardner, A.W., Ades, P.A., Poehlman, E.T., 1994. Contribution of body com-
1989. Physiological factors associated with the lower maximal oxygen consump- position and physical activity to age-related decline in peak VO2 in men and
tion of master runners. J. Appl. Physiol. 66, 949–954. women. J. Appl. Physiol. 77, 647–652.
Robine, J.M., Paccaud, F., 2005. Nonagenarians and centenarians in Switzerland, Travison, T.G., Shackelton, R., Araujo, A.B., Morley, J.E., Williams, R.E., Clark, R.V.,
1860–2001: a demographic analysis. J. Epidemiol. Commun. Health 59, 31–37. McKinlay, J.B., 2010. Frailty, serum androgens, and the CAG repeat polymor-
Rockwood, K., Nassar, B., Mitnitski, A., 2008. Apolipoprotein E-polymorphism, frailty phism: results from the Massachusetts Male Aging Study. J. Clin. Endocrinol.
and mortality in older adults. J. Cell Mol. Med. 12, 2754–2761. Metab. 95, 2746–2754.
Rolland, Y., Lauwers-Cances, V., Cournot, M., Nourhashemi, F., Reynish, W., Riviere, United-Nations, 2011. World Population Prospects: The 2010 Revision. Dept. of Eco-
D., Vellas, B., Grandjean, H., 2003. Sarcopenia, calf circumference, and physi- nomic and Social Affairs, United Nations, New York.
cal function of elderly women: a cross-sectional study. J. Am. Geriatr. Soc. 51, Van Pottelbergh, I., Goemaere, S., Nuytinck, L., De Paepe, A., Kaufman, J.M., 2001.
1120–1124. Association of the type I collagen alpha1 Sp1 polymorphism, bone density and
Roth, S.M., Schrager, M.A., Ferrell, R.E., Riechman, S.E., Metter, E.J., Lynch, N.A., Lindle, upper limb muscle strength in community-dwelling elderly men. Osteoporos.
R.S., Hurley, B.F., 2001. CNTF genotype is associated with muscular strength and Int. 12, 895–901.
quality in humans across the adult age span. J. Appl. Physiol. 90, 1205–1210. Verdijk, L.B., Koopman, R., Schaart, G., Meijer, K., Savelberg, H.H., van Loon, L.J., 2007.
Roth, S.M., Zmuda, J.M., Cauley, J.A., Shea, P.R., Ferrell, R.E., 2004. Vitamin D recep- Satellite cell content is specifically reduced in type II skeletal muscle fibers in
tor genotype is associated with fat-free mass and sarcopenia in elderly men. J. the elderly. Am. J. Physiol. Endocrinol. Metab. 292, E151–E157.
Gerontol. A Biol. Sci. Med. Sci. 59, 10–15. Vigano, A., Trutschnigg, B., Kilgour, R.D., Hamel, N., Hornby, L., Lucar, E., Foulkes, W.,
Sabina, R.L., 2000. Myoadenylate deaminase deficiency. A common inherited defect Tremblay, M.L., Morais, J.A., 2009. Relationship between angiotensin-converting
with heterogeneous clinical presentation. Neurol. Clin. 18, 185–194. enzyme gene polymorphism and body composition, functional performance,
Sachidanandam, R., Weissman, D., Schmidt, S.C., Kakol, J.M., Stein, L.D., Marth, G., and blood biomarkers in advanced cancer patients. Clin. Cancer Res. 15,
Sherry, S., Mullikin, J.C., Mortimore, B.J., Willey, D.L., Hunt, S.E., Cole, C.G., Coggill, 2442–2447.
P.C., Rice, C.M., Ning, Z., Rogers, J., Bentley, D.R., Kwok, P.Y., Mardis, E.R., Yeh, R.T., Visscher, P.M., Hill, W.G., Wray, N.R., 2008. Heritability in the genomics
Schultz, B., Cook, L., Davenport, R., Dante, M., Fulton, L., Hillier, L., Waterston, R.H., era—concepts and misconceptions. Nat. Rev. Genet. 9, 255–266.
McPherson, J.D., Gilman, B., Schaffner, S., Van Etten, W.J., Reich, D., Higgins, J., Volpi, E., Nazemi, R., Fujita, S., 2004. Muscle tissue changes with aging. Curr. Opin.
Daly, M.J., Blumenstiel, B., Baldwin, J., Stange-Thomann, N., Zody, M.C., Linton, Clin. Nutr. Metab. Care 7, 405–410.
L., Lander, E.S., Altshuler, D., 2001. A map of human genome sequence variation von Haehling, S., Morley, J.E., Anker, S.D., 2010. An overview of sarcopenia: facts and
containing 1.42 million single nucleotide polymorphisms. Nature 409, 928–933. numbers on prevalence and clinical impact. J. Cachexia Sarcopenia Muscle 1,
Sadoshima, J., Xu, Y., Slayter, H.S., Izumo, S., 1993. Autocrine release of angiotensin 129–133.
II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 75, Wagner, K.R., Fleckenstein, J.L., Amato, A.A., Barohn, R.J., Bushby, K., Escolar, D.M.,
977–984. Flanigan, K.M., Pestronk, A., Tawil, R., Wolfe, G.I., Eagle, M., Florence, J.M., King,
Saini, A., Faulkner, S., Al-Shanti, N., Stewart, C., 2009. Powerful signals for weak W.M., Pandya, S., Straub, V., Juneau, P., Meyers, K., Csimma, C., Araujo, T.,
muscles. Age. Res. Rev. 8, 251–267. Allen, R., Parsons, S.A., Wozney, J.M., Lavallie, E.R., Mendell, J.R., 2008. A phase
San Juan, A.F., Gomez-Gallego, F., Canete, S., Santiago, C., Perez, M., Lucia, A., 2006. I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann. Neurol. 63,
Does complete deficiency of muscle alpha actinin 3 alter functional capacity in 561–571.
elderly women? A preliminary report. Br. J. Sports Med. 40, e1. Waite, L.J., 2004. The demographic faces of the elderly. Popul. Dev. Rev. 30, 3–16.
Sayer, A.A., Syddall, H., O’Dell, S.D., Chen, X.H., Briggs, P.J., Briggs, R., Day, I.N., Cooper, Wallace, D.C., Ruiz-Pesini, E., Mishmar, D., 2003. mtDNA variation, climatic adapta-
C., 2002. Polymorphism of the IGF2 gene, birth weight and grip strength in adult tion, degenerative diseases, and longevity. Cold Spring Harb. Symp. Quant. Biol.
men. Age Ageing 31, 468–470. 68, 479–486.
Schrage, W.G., Eisenach, J.H., Joyner, M.J., 2007. Ageing reduces nitric-oxide- and Walsh, S., Liu, D., Metter, E.J., Ferrucci, L., Roth, S.M., 2008. ACTN3 genotype is asso-
prostaglandin-mediated vasodilatation in exercising humans. J. Physiol. 579, ciated with muscle phenotypes in women across the adult age span. J. Appl.
227–236. Physiol. 105, 1486–1491.
102 N. Garatachea, A. Lucia / Ageing Research Reviews 12 (2013) 90–102

Walsh, S., Metter, E.J., Ferrucci, L., Roth, S.M., 2007. Activin-type II receptor B Windelinckx, A., De Mars, G., Huygens, W., Peeters, M.W., Vincent, B., Wij-
(ACVR2B) and follistatin haplotype associations with muscle mass and strength menga, C., Lambrechts, D., Delecluse, C., Roth, S.M., Metter, E.J., Ferrucci, L.,
in humans. J. Appl. Physiol. 102, 2142–2148. Aerssens, J., Vlietinck, R., Beunen, G.P., Thomis, M.A., 2011. Comprehensive
Walsh, S., Zmuda, J.M., Cauley, J.A., Shea, P.R., Metter, E.J., Hurley, B.F., Ferrell, R.E., fine mapping of chr12q12-14 and follow-up replication identify activin recep-
Roth, S.M., 2005. Androgen receptor CAG repeat polymorphism is associated tor 1B (ACVR1B) as a muscle strength gene. Eur. J. Hum. Genet.: EJHG 19,
with fat-free mass in men. J. Appl. Physiol. 98, 132–137. 208–215.
Walston, J., Arking, D.E., Fallin, D., Li, T., Beamer, B., Xue, Q., Ferrucci, L., Fried, L.P., Yang, N., MacArthur, D.G., Gulbin, J.P., Hahn, A.G., Beggs, A.H., Easteal, S., North, K.,
Chakravarti, A., 2005. IL-6 gene variation is not associated with increased serum 2003. ACTN3 genotype is associated with human elite athletic performance. Am.
levels of IL-6, muscle, weakness, or frailty in older women. Exp. Gerontol. 40, J. Hum. Genet. 73, 627–631.
344–352. Yao, L., Delmonico, M.J., Roth, S.M., Hand, B.D., Johns, J., Conway, J., Douglass, L.,
Wang, X.L., Sim, A.S., Wang, M.X., Murrell, G.A., Trudinger, B., Wang, J., 2000. Hurley, B.F., 2007. Adrenergic receptor genotype influence on midthigh inter-
Genotype dependent and cigarette specific effects on endothelial nitric oxide muscular fat response to strength training in middle-aged and older adults. J.
synthase gene expression and enzyme activity. FEBS Lett. 471, 45–50. Gerontol. A Biol. Sci. Med. Sci. 62, 658–663.
Wang, Y., DeLuca, H.F., 2011. Is the vitamin d receptor found in muscle? Endocrinol- Yoshihara, A., Tobina, T., Yamaga, T., Ayabe, M., Yoshitake, Y., Kimura, Y., Shi-
ogy 152, 354–363. mada, M., Nishimuta, M., Nakagawa, N., Ohashi, M., Hanada, N., Tanaka, H.,
Westerkamp, C.M., Gordon, S.E., 2005. Angiotensin-converting enzyme inhibition Kiyonaga, A., Miyazaki, H., 2009. Physical function is weakly associated with
attenuates myonuclear addition in overloaded slow-twitch skeletal muscle. Am. angiotensin-converting enzyme gene I/D polymorphism in elderly Japanese sub-
J. Physiol. Regul. Integr. Comp. Physiol. 289, R1223–R1231. jects. Gerontology 55, 387–392.
Wiebe, C.G., Gledhill, N., Jamnik, V.K., Ferguson, S., 1999. Exercise cardiac function Yoshimura, M., Yasue, H., Nakayama, M., Shimasaki, Y., Sumida, H., Sugiyama,
in young through elderly endurance trained women. Med. Sci. Sports Exerc. 31, S., Kugiyama, K., Ogawa, H., Ogawa, Y., Saito, Y., Miyamoto, Y., Nakao, K.,
684–691. 1998. A missense Glu298Asp variant in the endothelial nitric oxide synthase
Williams, A.D., Anderson, M.J., Selig, S., Carey, M.F., Febbraio, M.A., Hayes, A., Toia, gene is associated with coronary spasm in the Japanese. Hum. Genet. 103,
D., Harrap, S.B., Hare, D.L., 2011. Differential response to resistance training in 65–69.
CHF according to ACE genotype. Int. J. Cardiol. 149, 330–334. Zempo, H., Tanabe, K., Murakami, H., Iemitsu, M., Maeda, S., Kuno, S., 2010.
Williams, A.G., Day, S.H., Folland, J.P., Gohlke, P., Dhamrait, S., Montgomery, H.E., ACTN3 polymorphism affects thigh muscle area. Int. J. Sports Med. 31,
2005. Circulating angiotensin converting enzyme activity is correlated with 138–142.
muscle strength. Med. Sci. Sports Exerc. 37, 944–948.