Content uploaded by Francesco Landi
Author content
All content in this area was uploaded by Francesco Landi on Jan 08, 2016
Content may be subject to copyright.
Send Orders for Reprints to reprints@benthamscience.ae
Current Pharmaceutical Design, 2015, 21, 000-000 1
1381-6128/15 $58.00+.00 © 2015 Bentham Science Publishers
Treating Sarcopenia in Older and Oldest Old
Anna Maria Martone
1
*, Fabrizia Lattanzio
2
, Angela Marie Abbatecola
2
, Domenico La Carpia
1
*, Matteo
Tosato
1
, Emanuele Marzetti
1
, Riccardo Calvani
1
, Graziano Onder
1
and Francesco Landi
1#
1
Department of Geriatric, Neurosciences and Orthopaedics, Università Cattolica del Sacro Cuore, Rome, Italy;
2
Scientific
Direction, Italian National Research Center on Aging (INRCA), Ancona, Italy
Abstract: The presence of sarcopenia is not only rapidly rising in geriatric clinical practice and research, but is also becom-
ing a significant concept in numerous medical specialties. This rapidly rising concept has encouraged the need to identify
methods for treating sarcopenia. Physical activity measures using resistance training exercise, combined with nutritional in-
terventions (protein and amino acid supplementation) have shown to significantly improve muscle mass and strength in
older persons. Moreover, resistance training may improve muscle strength and mass by improving protein synthesis in skele-
tal muscle cells. Aerobic exercise has also shown to hold beneficial impacts on sarcopenia by improving insulin sensitivity.
At the moment, the literature indicates that most significant improvement in sarcopenia is based on exercise programs. Thus,
this type of intervention should be implemented in a persistent manner over time in elders, with or at risk of muscle loss. At
the same time, physical training exercise should include correcting nutritional deficits with supplementation methods. For example, in
older sarcopenic patients with adequate renal function, daily protein intake should be increased to >1. 0 grams of protein per kilogram of
body weight. In particular, leucine, -hydroxy -methylbutyrate (HMB), creatine and some milk-based proteins have been shown to im-
prove skeletal muscle protein balance. In addition, it is also recommended for adjustment of for vitamin D deficiency, if present, consid-
ering the crucial role of vitamin D in the skeletal muscle. In this review, we provide evidence regarding the effects of different physical
exercise protocols, specific nutritional intervention, and some new metabolic agents (HMB, citrulline malate, ornithine, and others) on
clinical outcomes related to sarcopenia in older adults.
Keywords: Aging, sarcopenia, physical exercise, nutritional intervention, medications.
INTRODUCTION
During the aging process, there is a significant loss in spinal
motor neurons (MNs) which is mainly as a result of apoptosis, im-
paired insulin-like growth factor 1 (IGF-1) signaling, increased pro-
inflammatory cytokines, especially tumor necrosis factor (TNF)-,
TNF-, interleukin (IL)-6, as well as high concentrations of oxida-
tive stress end products [1-2]. These physiological changes over the
aging process greatly contribute to the progressive decline in skele-
tal muscle mass and consequently muscle strength (sarcopenia).
The most significant decline is observed over the age of 60 years.
From a clinical point of view, sarcopenia leads to functional im-
pairment including poor endurance, slower gait speed and reduced
mobility [3]. In addition, sarcopenia can predict falls, poor quality
of life, disability and mortality [4]. There is now also evidence to
propose that lack of muscle strength, or dynapenia, is an important
factor in compromised well being in old age [3]. This demands
recognition of the concept of muscle quality that is the strength
produced per capacity per unit cross-sectional area. An understand-
ing of the influence of aging on skeletal muscle mass requires atten-
tion to both the changes in muscle size and the changes in muscle
quality. This is particularly important considering the potential
effects of treatments suggested, in term of not only muscle mass
improvement but also functional and physical performance.
PATHOPHYSIOLOGY OF SARCOPENIA
Sarcopenia is caused by a reduction in the number and atrophy
of skeletal muscle fibers [5]. There is a significant loss in both type
I and II muscle fibers with a significant decrease in the cross-
sectional area of skeletal muscle fibers, which may be due to re-
duced muscle protein synthesis in old age. These findings indeed,
#
Address correspondence to this author at the Department of Geriatric,
Neurosciences and Orthopaedics, Università Cattolica del Sacro Cuore,
Rome, Italy; Tel:/Fax: +39063051911;
E-mail: francesco.landi@rm.unicatt.it
*These authors contributed equally to this paper.
reflect an imbalance between anabolic and catabolic mechanisms
accompanying reduced muscle regeneration during advanced aging.
Dual energy x-ray absorptiometry of aging muscle also shows in-
creased collagen and fat deposits [6]. Besides the aging process
itself, many factors may play a significant role in skeletal muscle
decline over aging such as genetic susceptibility, lifestyle, chronic
comorbidities and diverse drug treatments [7-9]. Progressive mus-
cle atrophy leads to impaired mechanical muscle performance, es-
pecially a non-linear loss of maximum muscle strength. The ability
to produce muscular power is significantly reduced compared to
muscle strength [10]. An impairment in mechanical muscle function
leads to reduced functional performance for daily tasks, including
habitual walking, stair climbing and rising from a chair [4]. This
explains why sarcopenia can predict negative outcomes related to
disability (poor balance, walking speed, falls, and fractures). An-
other factor that is responsible for the loss in motor performance is
the physiological change in the neuromuscular and central nervous
system (CNS) that manifests during aging [11].
Neural functional alterations due to apoptosis can be observed
at the peripheral level (losses in axons and motor end plates) as well
as at the spinal level (loss in MNs). In particular, there is a signifi-
cant reduction in both the number and width of large myelinated
MN axons. Interestingly, it has been demonstrated that partially
denervated muscle fibers can be reinnervated by the sprouting of
surrounding surviving motor axons or motor end plates, which
cause extremely large motor units (MUs) [12]. As previously men-
tioned, there is also an age-related alteration in neuromuscular func-
tion which in turn, leads to deficits in MN frequency firing, muscle
agonist activation and antagonist co-activation. All of these factors
account not only for the loss in muscle strength, but also for balance
and coordination impairment. The formation of large MUs affects
fine motor control and force steadiness. Finally, the literature
strongly suggests that age-related decline in muscle IGF-1 may also
play a significant role in developing sarcopenia [13]. IGF-1 pro-
motes myoblast proliferation and differentiation, as well as in-
Francesco Landi
2 Current Pharmaceutical Design, 2015, Vol. 21, No. 00 Martone et al.
creased production in the skeletal muscle through signaling path-
ways including phosphatidylinositol 3 (PI3) and MAP kinases
along with calcineurin.
NON-PHARMACOLOGICAL TREATMENT
Physical Activity
Sarcopenia can have serious clinical consequences, thus its
natural course and identifying safe treatment strategies is a crucial
and necessary challenge. Lifestyle interventions including physical
activity programs and specific nutritional supplementations are
currently considered to hold the strongest and safest impact on im-
proving sarcopenia [14-17]. Since the 1980s, several studies have
confirmed that physical exercise is an effective countermeasure
against sarcopenia. Regular physical activity has been shown to
improve overall life expectancy, reduce the risk for physical dis-
abilities and chronic disease progression by improving the physio-
logical effects related to a sedentary lifestyle [18]. However, the
type of physical exercise to be applied in older adults needs to be
clearly defined in order to reduce any type of risk associated with
physical exercise programs in elders. At the moment, the Institute
of Medicine has defined “Physical activity” as all body movements
produced through contraction of skeletal muscles [19].
Physical exercise can be distinguished in: 1) baseline activity;
2) leisure-time physical activity; 3) moderate-intensity physical
activity; and 4) exercise. Baseline activity is defined as light-intense
energy expenditure just above sedentary behavior such as walking
slowly, standing and lifting lightweight objects [19]. According to
this definition, even though individuals with a baseline physical
activity level are above a sedentary lifestyle per se, they are consid-
ered inactive. Any type of physical activity above baseline activity
is considered health enhancing. Leisure-time physical activity is
generally considered aerobic and encompasses all popular leisure
activities such as biking, golfing, etc. Moderate-intensity physical
activity causes a significant rise in the heart rate and respiration. It
requires reaching a moderate level of physical energy related to
one’s personal aerobic capacity [20]. Examples of moderate-
intensity physical activities include brisk walking, dancing and
swimming. Indeed, physical activities have clearly shown to be
associated with beneficial impacts on comorbidities. Lastly, exer-
cise is considered a physical activity that creates specific adapta-
tions in a given physiological system. Exercise is generally planned,
structured and repetitive. It is typically performed to achieve weight
loss, improve health and/or physical fitness.
Types of Exercise
There are different forms of exercise: i) aerobic (endurance), ii)
resistance (strength) training and iii) combined aerobic and resis-
tance [1]. Other forms of exercise also include stretching and bal-
ance exercises. Aerobic exercise is a form of exercise performed
over a lengthy time span (>20 minutes) characterized by repeated
low-force muscle contractions with a low frequency in muscle fiber
activation. Aerobic activity depends primarily on oxygen consump-
tion to meet the energy demands and it enhances body composition,
cardio-respiratory fitness and/or cardio-metabolic health. Resis-
tance exercise is a form of exercise over intermittent time intervals
(< 2-4 min of total work per muscle group) and is characterized by
small high-force muscle contractions working against an applied
load that cause high frequency muscle activation. Resistance train-
ing involves the use of weight machines, dumbbells, and barbells as
resistance sources for improving muscle strength [21]. From a
metabolic point of view, resistance training (also defined as
strength training) relies on anaerobic metabolism, thus it mostly
stimulates glycolytic metabolism and lowers mitochondria density
in muscle cells, while aerobic training increases oxidative metabo-
lism and mitochondrial density. In older persons, strength training
may hold some advantages for improving neuromuscular function
as compared to endurance training by increasing muscle strength
and power [21-25]. Aerobic exercise (walking, jogging or biking)
has a small impact on improving muscle mass and strength [26].
For example, using cross-sectional data, Klitgaard et al., [27] found
that in a large sample of elderly men in different exercise training
programs, elderly weightlifters maintained better muscle mass and
strength as compared to swimmers. Even though the importance of
aerobic exercise in cardio-respiratory capacity is widely recognized,
its use in older patients with sarcopenia may not hold clear evidence
in the presence of chronic comorbidities.
Resistance exercise is designed to improve muscle strength and
mass. Thus, resistance exercise may hold more specific indications
(primary preventive or treatment) for sarcopenia in order to protect
against physical functional declines, disability and early all-cause
mortality in older adults [28-29]. At the moment, low to moderate
intensity physical activity programs on protecting or reducing dis-
ability remain unclear. Moderate-intensity resistance training seems
to lack the significant impact on lean skeletal muscle mass and
reduction in functional decline may manifest only when a high
intensity exercise training program is proposed. Fielding et al., [29]
showed that a training stimulus of a suitable intensity (70-90% of 1-
Repetition Maximum, 1 -RM) produced significant gains in muscle
mass and strength in healthy older individuals [29]. Frontera et al.,
[15] (observed an increase in cross-sectional area muscle of the
mid-thigh of 11. 4% and muscle strength (>100%) at the end of 12
weeks of high intensity training in older men. These authors also
showed that following 12 weeks of progressive resistance training,
a group of adult men (aging 60-72 years) had a 2-3 fold increase in
1-RM leg strength, with an 11% increase in muscle mass [16].
Other authors have investigated if these benefits could be found in
low to moderate physical activity exercise programs. However,
uptile now only a limited number of studies have been able to sup-
port this hypothesis. Resistance training in elderly persons has
shown to produce significant improvements in muscle strength [15-
16, 24, 29]. Even though such improvement is smaller in absolute
terms, percentage increases are similar as compared to younger
adults. In regards to the specific types of resistance training exercise
activities, the use of a standard concentric exercise protocol, which
allows for muscle loads of >1-RM, holds greater potential for mus-
cle strength gains.
Physical Activity: Benefits
Improved clinical outcomes obtained from physical activity
programs are widely known. Many studies have demonstrated how
specific programs of physical activity can improve muscle mass and
muscle strength associated with aging and sarcopenia [17-18, 30].
Their final effect indeed, is to reduce the risk of physical disability.
In the Established Populations for Epidemiologic Studies of the
Elderly (EPESE studies), routine physical activity was associated
with a 3 year reduced risk of mortality [31]. In addition, moderate
to vigorous leisure-time physical activity has been shown to lower
the risk of poor physical functioning and, thus the onset of disabil-
ity [32]. Using data from a standardized geriatric assessment tool, a
moderate physical activity program was an independent prognostic
indicator for community-dwelling elders [33]. Similarly, a cohort of
older Finnish adults undergoing a high level of everyday physical
activity (household chores, walking and gardening) were found to
be associated with significantly smaller reductions in knee exten-
sion strength and grip strength after five years as compared to older
adults in a sedentary lifestyle [34]. The efficacy of physical activity
in preventing disability and/or functional worsening has also been
found in randomized clinical trials (RCT). RCTs have demonstrated
a positive effect of physical activity programs in frail elders. For
example, in the FAST study, a randomized trial conducted among
439 community-dwelling older adults with knee osteoarthritis, self-
reported physical function was associated with a significant en-
hancement in objective physical performance, walking speed and
balance as compared to those in a health education program group
[35].
Treating Sarcopenia in Older and Oldest Old Current Pharmaceutical Design, 2015, Vol. 21, No. 00 3
Longitudinal studies have also indicated that regular physical
activity is associated with extended longevity [36-37]. Participating
in a physical activity program even late in the life has shown to
improve functional autonomy and reduce mortality [37]. Physical
exercise encompasses different factors that can stimulate aerobic
metabolism, increase muscle strength, power and mass. Aerobic
exercise training can significantly decrease resting heart rate, in-
crease VO2 max, improve endothelial and baroreflex function, and
reduce the arterial stiffness. Resistance exercise training can im-
prove muscle strength, power and endurance and has shown to im-
prove physical performance tasks related to everyday activities such
as walking, standing from a chair and balance. Indeed, the combina-
tion of aerobic and resistance training should be considered funda-
mental for preventing and managing numerous chronic comorbid-
ities often present in sarcopenic elders [32]. Progressive resistance
training is considered effective and safe against sarcopenia even in
very old geriatric patients. Binder et al., studied the effects of resis-
tance training on 91 community-dwelling subjects with frailty syn-
drome (greater than 78 years of age) in a RCT [38]. These authors
observed that after 3 months of supervised progressive resistance
training, there were significant improvements in maximal voluntary
thigh muscle strength and whole body fat-free mass. Muscle
strength enhancements (up to >50% strength gain) usually manifest
after 6 weeks of resistance training at a rhythm of 2-3 sessions per
week [32]. Therefore, age should not be considered a barrier to the
improvements in muscle mass and function following resistance
exercise. Specific resistance exercise programs from RCT have
proven to be relatively safe even in the presence of comorbidities,
and can protect against falls, disability and losses in personal inde-
pendence [38-39].
Considering the confirmatory findings from these reports, spe-
cific exercise programs are needed for elderly patients. However,
the type of exercise program for disease prevention and treatment
needs to be clearly defined, especially in frail elders. For example,
even though most studies suggest that resistance training can be
performed safely in an elderly population, it does not hold indica-
tions for use in patients with congestive heart failure because of a
potential negative impact on left ventricular function [28]. Stretch-
ing and balance exercises are indicated in elderly people at high risk
for falls and/or with mobility disability. Positive effects of exercise
on physical function may be mediated by a direct effect on muscle
strength, cardio-respiratory function and balance [40]. From a
physiological point of view, regular exercise improves aerobic ca-
pacity of the patient, his muscle strength and endurance. The down-
regulation of inflammatory system during physical activity may
also play an important role in preventing physical impairment and
disability. Regular physical activity programs have shown to lower
C-reactive protein (CRP) and IL-6 in both younger adult and eld-
erly population studies [41]. For example, the Lifestyle Interven-
tions and Independence for Elders (LIFE) trial showed that greater
physical activity was associated with a significant reduction in pro-
inflammatory cytokine, IL-6, in elderly individuals, and this reduc-
tion was particularly found in those at a greater risk of disability
[42]. In addition, several smaller trials have shown a positive effect
of aerobic exercise training on reducing CRP and IL-6 in adults and
older persons [43-44]. Therefore, even though the effect of physical
activity on reducing pro-inflammatory biomarkers seems obvious,
whether this reduction could protect against negative outcomes
related to health conditions associated with inflammation was not
tested.
Physical Activity: Guidelines
The main modifiable risk factor for sarcopenia is sedentary
lifestyle behavior. Sedentary behavior is defined as a range of ac-
tivities with energy expenditure 1. 5 times the energy expenditure
at rest [45]. In other terms, sedentary behavior (essentially time
spent sitting or lying down) increases with advancing age. It has
been shown that the effects of a sedentary lifestyle are a loss of
muscle mass and muscle strength results in muscle weakness and a
vicious cycle begins with a further reduction in activity levels. Sed-
entary behavior is a risk factor for numerous chronic diseases and
mortality among older adults [46-47]. Recommendations for adult
and older people include combined endurance and strength exer-
cises, performed on a regular schedule (at least 3 days per week). It
is important to underline that individual targets should be analyzed
to provide the best type of exercise program necessary, especially in
the presence of pre-existing medical conditions.
General Recommendations
Start slowly: Start any type of activity should be initiated using
a short time span with low intensity to gradually increase in order to
minimize the risk of injury. In addition, if any changes in health
status occur, activity plans should be re-evaluated [19].
Warm-Up And Cool Down: These activities are considered of
extreme importance before (warm-up) and after physical activity
(cool down) especially for older persons. They typically differ from
the real training for slower speed or lower intensity. These exercises
allow to gradually modify an individual’s heart rate and/or breath-
ing. For example, a warm-up with aerobic activity consists of short
intervals of low-intensity movements (for example, walking for 5
minutes) [19]. Any type of training program should be individual-
ized according to the presence of pre-existing chronic conditions,
fall risk, individual abilities and fitness. Muscle strengthening pro-
grams and/or balance training should be considered before aerobic
training in older persons with frailty syndrome.
Recommendations For Aerobic Exercise
ACSM/AHA recommendations [20, 48] for aerobic exercise in
older adults place a great emphasis on general health promotion.
The main suggestions are achieving routine aerobic physical activ-
ity and exercise patterns. Older adults are encouraged to perform
30-60 minutes of moderate-intensity physical activity per day (150-
300 minutes per week), or at least 20-30 min per day (75-150 min
per week) of vigorous intensity. Exercise should be performed at
least three days/week. Exercise sessions should last a minimum of
10 minutes for intermittent aerobic activity. Every session should
reach at least a total energy expenditure of 150/250 Kcal. Activities
such as fast walking, swimming and biking are usually well toler-
ated in older individuals without frailty.
Recommendations For Resistance Exercise
The current ACSM/AHA guidelines suggest to perform resis-
tance training on two or more non-consecutive days per week, using
a single set of 8-10 exercises and at a moderate (5-6 of the rating of
perceived exertion out of 10) to vigorous (7-8 of the rating of per-
ceived exertion out of 10) level of effort that allows 8-12 repetitions
[20, 48]. Prescription of resistance exercise should include a train-
ing period (1-2 times per week) in order to allow older adults to
safely learn at low dosage with minimal sets. Following this period,
a gradual increase in training dosage allows improvements in
strength and mass. Progression in resistance exercise should be
done according to the following: i) gradual intensity increase from
moderate to vigorous; ii) gradual increase in the number of sets
from a single set to as many as three or four sets per muscle group;
iii) gradual decrease in the number of repetitions performed with a
progressively heavier loading. Lower extremity functioning has
shown to be strongly associated with clinical outcomes and mortal-
ity, which may be explained by loss in muscle mass and strength.
Thus, it is essential to identify a training program with specific
focus on improvements of lower extremity mass and strength to
enhance overall functional abilities. In regard to flexibility and
stretching, the ACSM recommends that flexibility exercises should
be performed at least two days per week, ten minutes per day from
moderate to intense including exercises involving areas of the neck,
shoulder, elbow, wrist, hip, knee and ankle [48].
4 Current Pharmaceutical Design, 2015, Vol. 21, No. 00 Martone et al.
Nutritional Supplementation
Anorexia of aging, defined as loss of appetite and/or reduction
of food intake, can lead to muscle wasting, decreased immuno-
competence, depression and an increased rate of disease complica-
tions. In particular, a reduction in food intake along with an exer-
cise decline leads to significant losses in muscle mass and strength
[49]. Anorexia is strongly associated with a higher risk of quantita-
tive malnutrition due to low-calorie intake. On the other hand, ano-
rexia - especially in the early stage - may be correlated with a high
risk of qualitative low intake of single nutrients, in particular, pro-
tein and vitamins [49]. It could be hypothesized that this selective
malnutrition - for example, in terms of single macro- or micronutri-
ents - is directly correlated with the onset of sarcopenia. Sarcopenia
is mainly associated with atrophy of type II skeletal muscle fibers,
which are mainly involved in producing strength. Muscle composi-
tion and function are regulated by muscle protein turnover rate. A
loss in muscle protein synthesis may be due to many factors includ-
ing an inadequate nutritional intake, a deficit in post-absorptive
protein synthesis and due to an erroneous response to nutrients,
especially amino acids [50]. It has been shown that physical exer-
cise and oral nutritional supplementation may improve muscle mass
through different mechanisms (Fig. 1).
Amino Acids
Many studies investigated muscle anabolic responses following
an oral or intravenous intake of amino acid mixtures in the adult
and elderly persons [51-52]. These duties reported, in view of un-
changed protein breakdown, a large increase in muscle protein syn-
thesis with an associated reduction in protein turnover rate inde-
pendently of the type of mixture. These findings suggest that mus-
cle protein anabolism may be increased by a high amino acid dis-
posal, thus underlining the importance related to the quantity of
amino acids intake. This finding confirms that low doses of protein
intake do not stimulate muscle protein synthesis as compared to
higher doses [53], which may also be influenced by an impaired
response to insulin [54]. These data indicate that a threshold exists
for protein synthesis production. In addition, this threshold in-
creases over the aging process and in the presence of pro-
inflammation. In light of this, many authors have investigated if the
dietary protein requirement differs between the young and older
adults in order to identify the needed amount of protein intake in
elderly persons [55]. These studies demonstrate that the protein
requirement is increased in aged individuals, especially during bed
rest. Currently, it is suggested to maintain a daily protein intake of
0. 89 g/kg/d and 1. 3-1. 6 g/kg/d in case of bed rest to a maximum
of 2. 2 g/Kg/d in order to avoid renal function reduction [56]. Be-
sides the quantity of protein, it seems important to reach the great-
est protein availability through the best protein digestion rate which
depends on the daily protein feeding pattern and on the quality of
proteins (in particular, the content in essential amino acids). With
regard to the first concept, it has been shown that an intermittent
protein intake pattern may improve protein retention in elderly pa-
tients and that this effect persists several days after the end of diet
[57]. This persistent effect may be due to the combination of high
carbohydrates and low protein meals, which reduces protein break-
down because they induce postprandial hyperinsulinemia. Consid-
ering that the ingestion of a large quantity of proteins (90 grams) in
a single meal is not able to enhance the anabolic response more
than a moderate quantity (30 grams), most experts suggest a daily
protein distribution of 30 g at each meal. Furthermore, in order to
stimulate muscle protein anabolism, it is important to consume
protein mixtures that are rapidly absorbed. Whey proteins have a
high and fast absorption as compared to casein, which is considered
a “slow” protein. Bovine milk contains a mixture of whey and ca-
sein proteins and this combination has been hypothesized to pro-
mote both rapid and sustained muscle protein synthesis as well as
muscle breakdown reduction. Interestingly, milk ingestion increases
muscle protein synthesis [58], especially during resistance exercise
training.
Leucine
Leucine, a branched chain amino acid, is an essential amino
acid and modulates muscle metabolism. Leucine stimulates muscle
anabolism through the mammalian target of rapamycin (mTOR)
which is a regulator of leucine effects on mRNA translation needed
for skeletal muscle protein synthesis. Leucine also interacts with
proteolytic mechanisms by attenuating skeletal muscle breakdown.
Katsanos et al. [59] compared the effects of a single dose of
branched chain amino acid with different amount of leucine on
postprandial protein synthesis in elderly subjects. These authors
found that subjects supplemented with higher dose had a signifi-
cantly higher protein synthesis as compared to the subjects supple-
mented with lower doses. These data suggested that leucine sup-
plementation could be an effective approach for treating sarcopenia,
but further studies are still required needed. Recently, there is in-
creasing interest on the impact of other amino acids or their me-
tabolites on muscle protein synthesis, such as HMB, citrulline
malate, ornithine alpha - ketoglutarate.
eta Hydroxy eta Methylbutyrate (HMB)
HMB is an amino acid metabolite, which modulates protein
degradation through the inhibition of caspase-8, a protein impli-
cated in cellular apoptosis. HMB has also been shown to directly
upregulate protein synthesis by activating the mTOR signaling
pathway and promote muscle tissue response to endogenous growth
hormones such as IGF-1 [60]. It has been demonstrated that HMB
alone or in combination with other amino acids, increased protein
rates by approximately 20% [61]. Such increase was associated
with improved muscle mass and strength, as well as physical per-
formance at 3 grams per day. These data suggest that HMB repre-
sents a safe and useful oral nutritional supplement for elderly sar-
copenic patients.
Citrulline Malate
Citrulline malate supplementation, a combination of an amino
acid implicated in urea cycle and a tricarboxylic acid that incre-
ments arginine levels. Arginine produces nitric oxide which, in
turn, controls many skeletal muscle physiological functions, such as
mitochondriogenesis, muscle repair through satellite cell activation,
contractile functions, glucose uptake and oxidation [62]. Recently,
study was conducted to assess the benefits of citrulline malate sup-
plementation in high intensity anaerobic performance (flat barbell
bench press), which showed a significant improvement in physical
performance (increased number of repetitions) in the citrulline
malate group compared with placebo [62]. Even though these find-
ings are encouraging for oral supplementation with citrulline malate
in improving physical performance, additional studies in older frail
persons are needed.
Ornithine Alpha-Ketoglutarate
Ornithine alpha-ketoglutarate (OAK), a precursor of amino
acids such as glutamine and arginine, could represent an effective
nutritional supplement in sarcopenia because OAK stimulates insu-
lin secretion. A recent study testing the impact of OAK supplemen-
tation in malnourished elderly participants found positive effects on
weight and body mass index [63]. Further studies are needed to
assess potential effects on elderly without nutritional problems.
Essential Fatty Acids
The role of essential fatty acids (omega- 3 and omega- 6) in
muscle metabolism has been recently reported. In particular omega-
6 fatty acids, such as linoleic acid found in corn and sunflower oils,
may promote the development of sarcopenia because they are the
precursor for eicosanoids [64]. Recent studies have demonstrated
Treating Sarcopenia in Older and Oldest Old Current Pharmaceutical Design, 2015, Vol. 21, No. 00 5
that a high ratio of omega-6/omega-3 can cause higher levels of IL-
6, which interferes with IGF-1 mediated processes by blocking the
protein p70s60k phosphorylation necessary for protein synthesis
activation [65]. On the contrary, omega-3 fatty acids including lino-
lenic acid and its metabolic products, such as eicosapentaenoic acid
and docosahexaenic acid found in fish oil, promote muscle anabo-
lism. In a recent study conducted in 3000 older adults, higher con-
sumptions of fish oil were found to be associated with stronger grip
strength [66].
Vitamin D
Vitamin D deficiency is a very common condition among older
adults caused by reduced sunshine exposure, decreased kidney ab-
sorption and a reduced expression of Vitamin D receptors. Vitamin
D is considered to play a pivotal role both in bone and skeletal
muscle metabolism. In muscle tissue, vitamin D modulates: i) gene
expression of IGF-1 factor-binding protein-3, ii) calcium channels
of muscle membrane fibers, and iii) holds a neurotrophic effect on
nerve conduction [67]. Vitamin D deficiency is associated with
muscle atrophy, reduced muscular strength and power, impaired
balance and consequent increased risk of recurrent falls and frac-
tures [68]. Many studies have explored the effects of vitamin D
supplementation on muscle mass and function. Sato et al., [69]
investigated the impact of a period of vitamin D prolonged supple-
mentation of 1000 UI (3-6 months) and found that such a supple-
mentation was associated with an increase in the size of type II
muscle fibers. Interestingly, other authors have also shown benefi-
cial effects of vitamin D supplementation on muscle strength and
falls [70-71]. Therefore, vitamin D supplementation should be con-
sidered an effective approach toward preventing and treating sarco-
penia in older persons. Currently, there are strong recommendations
to measure vitamin D plasma levels in elderly people, especially
nursing home residents, and to begin daily oral supplementation
(700-1000 UI) in patients with levels < 40nmol/l [72]. Considering
the strong role played by both vitamin D and physical activity in
muscle mass and strength, their use in combination may represent
an ideal strategy for treating sarcopenia.
DRUG TREATMENTS
Angiotensin-Converting-Enzyme inhibitors (ACE inhibitors)
There is a strong evidence that ACE-inhibitors have positive
direct effects on muscle composition and function. For example,
their use in patients with congestive heart failure promoted the shift
from type I to type II muscle fibers [73]. ACE inhibitors also hold
an anti-inflammatory effect, as seen by lower levels of IL-6 and
TNF- plasma concentrations during treatment [74]. Furthermore,
ACE-inhibitors can modulate the GH/IGF-1 pathway, which re-
duces angiotensin-II induced muscle loss [75]. The effects of ACE-
inhibitors on muscle performance measures have been tested by
various studies. Di Bari et al., [76] conducted a study in over 2000
older persons and found that muscle mass was preserved in those
using ACE-inhibitors. Another report demonstrated a significant
improvement in physical performance measures (including the 6-
minute walking test) in older patients using ACE-inhibitors com-
pared to placebo [77]. In conclusion, ACE-inhibitors seem to repre-
sent a promising approach in order to reduce muscle loss but further
evidence is required.
Statins
There is substantial literature that statins may hold a positive
effect on skeletal muscle and physical performance. Statins may
improve muscle weakness and fatigue by improving endothelial
function through nitric oxide release, thus preventing muscle wast-
ing [78]. Statins may also prevent sarcopenia by reducing inflam-
mation. Indeed there is evidence of cholesterol-independent actions,
namely "pleiotropic effects" of statin use on endothelial function
including anti-oxidation and anti-inflammatory effects, modulation
of immune activation and atherosclerotic plaque stabilization, de-
creased platelet activation, cytokine-mediated vascular smooth
muscle cell proliferation [79]. In any case, it is important to under-
line that statin use has been associated with adverse effects on
skeletal muscle mass [80]. These effects may be related to lower
aerobic exercise tolerance caused by impaired mitochondrial func-
tion, decreased mitochondrial content and apoptotic pathways. In a
longitudinal study performed in community-dwelling older adults,
treatment with statins was associated with greater decline in
strength and increases the risk of falls [81]. Therefore, statin use in
sarcopenia older persons seems to remain limited.
Testosterone
It is widely known that testosterone levels gradually decline in
aging men and such decline has been observed to be associated with
losses in muscle mass, strength and function. Basic research con-
firms that testosterone administration prevents sarcopenia in hy-
pogonadic men. The anabolic effects of testosterone include reduc-
ing protein breakdown [82] and increasing size of both types I and
II fibers. Testosterone also holds positive effects on motor neurons
by promoting nerve regeneration following traumatic damage. A
recent study tested the effects of testosterone administration in frail
older men and found a significant increase in lean muscle mass,
strength and physical performance measures [83]. Unfortunately,
use of testosterone in clinical practice is limited due to common
side effects, such as prostate cancer, increased cardiovascular
events, peripheral edema, gynecomastia, polycythemia and sleep
apnea. Recent evidence suggests the use of testosterone in men with
low serum testosterone levels to improve muscle strength [84].
Dehydroepiandrosterone (DHEA)
Studies have found variable results regarding the effects of
DHEA supplementation on muscle mass and function in older
adults. For example, some investigations conducted in aged men
and women found that DHEA supplementation increased bone
density, testosterone and estradiol levels, but it did not affect mus-
cle size, strength, or function [85]. Improvements in strength and
function may require a combination of DHEA and exercise, al-
though this result was not observed in all studies. A recent review
by Baker et al., [86] showed that the benefits of DHEA on muscle
strength and physical function in older adults remain uncertain.
Significant impact of DHEA on physical function or performance
measures was not observed. Even though DHEA supplementation
has shown to improve bone mineral density and sex hormone lev-
els, it has not shown to significantly impact markers of sarcopenia
(mass and strength).
Ghrelin
Ghrelin is a gastric peptide hormone in response to fasting and
it regulates the sensation of hunger through melanocortin receptor
antagonism. It stimulates the release of GH through the activation
of GH secretagogue receptor. Ghrelin concentrations have been
reported to be related with muscle mass [87], but very few studies
had been conducted in older people. Therefore, it is not currently a
valid option for sarcopenia prevention or treatment in older persons.
Creatine
The use of creatine has been recently proposed for the preven-
tion and treatment of sarcopenia [88]. Even though there is evi-
dence for the impact of creatine supplementation on sarcopenia in
middle-aged and older adults, there are conflicting results. For ex-
ample, improved muscle mass and strength in older adults were
found in those using creatine supplementation in combination with
resistance training [89]. However, another recent report did not find
any enhancements with creatine supplementation on mass, total
body mass, or upper extremity strength [90]. Based on these con-
flicting results, creatine supplementation is not recommended for
treating sarcopenia in older adults [91].
6 Current Pharmaceutical Design, 2015, Vol. 21, No. 00 Martone et al.
Selective Androgen Receptor Modulators
Synthetic androgen modulators such as Selective Androgen
Receptor Modulators (SARMs) are potential alternatives to testos-
terone treatment. SARMs have the same anabolic effect on muscle
tissue as testosterone, but they do not have the same side effects
because of their improved tissue selectivity [92-93]. The first trials
testing SARMs for physical performance outcomes have shown
promising results. Treatment with Enobosarm has been associated
with increases in lean body mass and stair climbing ability, without
virilizing effects, in healthy older men and women and in patients
with cancer cachexia [94]. However, another trial testing 6 month
treatment with MK-0773 was found to be associated with increases
in lean body mass, but not in muscle strength or physical perform-
ance in older women with sarcopenia and mobility limitations [95].
Another trial testing SARM, LGD-4033, showed increased lean
body mass without affecting PSA levels in healthy young men [96].
As suggested by these initial trials, these agents may offer an im-
portant potential for future clinical indications in sarcopenia.
CONCLUSION
Combination of a specific physical exercise protocol and an
adequate intake of amino acids may represent the best strategy to
prevent and treat sarcopenia in older persons. Furthermore, even
though several promising pharmacological approaches are currently
under investigation, there are not any uses they are not yet available
for treating sarcopenia in older frail persons in the clinical practice.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
The study was partly supported by grants of the Italian Ministry
for Education, Universities and Research (MIUR – linea D1 2012
and MIUR – linea D3 2014).
REFERENCES
[1] Evans WJ. Skeletal muscle loss: cachexia, sarcopenia, and inactiv-
ity. Am J Clin Nutr 2010; 91: 1123S-7S.
[2] Morley JE. Anorexia, sarcopenia, and aging. Nutrition 2001; 17:
660-3.
[3] Morley JE, Abbatecola AM, Argiles JM, et al. Society on Sarco-
penia, Cachexia and Wasting Disorders Trialist Workshop. Sarco-
penia with limited mobility: an international consensus. J Am Med
Dir Assoc 2011; 12: 403-9
[4] Landi F, Liperoti R, Russo A, et al. Sarcopenia
as a risk factor for
falls in elderly individuals: Results from the ilSIRENTE study. Clin
Nutr 2012; 31: 652-8
[5] Evans WJ, Cyr-Campbell D. Nutrition, exercise, and healthy aging.
J Am Diet Assoc 1997; 97: 632-8
[6] Madsen OR, Lauridsen UB, Hartkopp A, Sørensen OH. Muscle
strength and soft tissue composition as measured by dual energy x-
ray absorptiometry in women aged 18-87 years. Eur J Appl Physiol
Occup Physiol 1997; 75(3): 239-45.
[7] Cesari M, Pedone C, Incalzi RA, Pahor M. ACE-inhibition and
physical function: results from the Trial of Angiotensin-Converting
Enzyme Inhibition and Novel Cardiovascular Risk Factors
(TRAIN) study. J Am Med Dir Assoc 2010; 11: 26-32.
[8] Montgomery HE, Marshall R, Hemingway H, et al. Human gene
for physical performance. Nature 1998; 393: 221-2.
[9] Abbatecola AM, Ferrucci L, Ceda G, et al. Insulin resistance and
muscle strength in older persons. J Gerontol A Biol Sci Med Sci
2005; 60: 1278-82.
Fig. (1). Potential pathways related to nutritional interventions and specific drugs that may influence cellular events implicated in the regulation of muscle
mass mTOR: mammalian target of rapamycin HMB: -hydroxy -methylbutyrate.
Treating Sarcopenia in Older and Oldest Old Current Pharmaceutical Design, 2015, Vol. 21, No. 00 7
[10]
Bean JF, Leveille SG, Kiely DK, et al. A comparison of leg power
and leg strength within the InCHIANTI study: which influences
mobility more? J Gerontol A Biol Sci Med Sci 2003; 58: 728-33.
[11]
Erim Z, Beg MF, Burke DT, de Luca CJ. Effects of aging on mo-
tor-unit control properties. Am Physiol Soc 1999; 82: 2081-91.
[12]
Marzetti E, Calvani R, Cesari M, et al. Mitochondrial dysfunction
and sarcopenia of aging: from signaling pathways to clinical trials.
Int J Biochem Cell Biol 2013; 45: 2288-301.
Barbieri M, Ferrrucci L, Emilia R, et al. Chronic inflammation and
the effect of IGF-1 on muscle strength and power in older persons.
Am J Physiol Metab 2003; 284: E481-7.
[14] Landi F, Abbatecola AM, Provinciali M, et al. Moving against
frailty: does physical activity matter? Biogerontology 2010; 11:
537-45.
[15] Frontera WR, Bigard X. The benefits of strength training in the
elderly. Sci Sports 2002; 17: 109-116.
[16] Frontera WR, Meredith CN, O’Reilly KP, Knuttgen HG, Evans
WJ. Strength conditioning in older men: skeletal muscle hypertro-
phy and improved function. J Appl Physiol 1988; 64: 1038-44.
[17] Landi F, Onder G, Carpenter I, Cesari M, Soldato M, Bernabei R.
Physical activity prevented functional decline among frail commu-
nity-living elderly subjects in an international observational study.
J Clin Epidemiol 2007; 60: 518-24.
[18] Landi F, Russo A, Cesari M, et al. Walking one hour or more per
day prevented mortality among older persons: results from ilSI-
RENTE study. Prev Med 2008; 47: 422-6.
[19] http: //www. health. gov/paguidelines/pdf/paguide. pdf accessed
November 28th, 2014.
[20] Nelson ME, Rejeski WJ, Blair SN, et al. Physical activity and
public health in older adults: recommendation from the American
College of Sports Medicine and the American Heart Association.
Med Sci Sports Exerc 2007; 39: 1435-45.
[21] Sundell J. Resistance Training Is an Effective Tool against Meta-
bolic and Frailty Syndromes. Adv Prev Med 2011: 984683.
[22] Frontera WR, Bigard X. The benefits of strength training in the
elderly. Sci Sports 2002; 17: 109-116. 21.
[23] Frontera WR, Meredith CN, O’Reilly KP, Knuttgen HG, Evans
WJ. Strength conditioning in older men: skeletal muscle hypertro-
phy and improved function. J Appl Physiol 1988; 64: 1038-44.
[24] Fiatarone MA, O'Neill EF, Ryan ND, et al. Exercise training and
nutritional supplementation for physical frailty in very elderly peo-
ple. N Engl J Med 1994; 330: 1769-75
[25] Reid KF, Martin KI, Doros G, et al. Comparative Effects of Light
or Heavy Resistance Power Training for Improving Lower Extrem-
ity Power and Physical Performance in Mobility-Limited Older
Adults. J Gerontol A Biol Sci Med Sci 2014 [Epub ahead of print]
[26] Russell B, Motlagh D, Ashley WW. Form follows function: how
muscle shape is regulated by work. J Appl Physiol 2000; 88: 1127-
32.
[27] Klitgaard H, Mantoni M, Schiaffino S, et al. Function, morphology
and protein expression of ageing skeletal muscle: a cross-sectional
study of elderly men with different training backgrounds. Acta
Physiol Scand 1990; 140(1): 41-5416.
[28] Borst, SE Interventions for sarcopenia and muscle weakness in
older people. Age Ageing 2004; 33: 548-55
[29] Fielding RA, LeBrasseur NK, Cuoco A, Bean J, Mizer K, Fiatarone
Singh MA. High-velocity resistance training increases skeletal
muscle peak power in older women. J Am Geriatr Soc 2002; 50:
655-62.
[30] Fielding RA, Rejeski WJ, Blair S, et al. LIFE Research Group. The
Lifestyle Interventions and Independence for Elders Study: design
and methods. J Gerontol A Biol Sci Med Sci 2011; 66: 1226-37.
[31] Ottenbacher AJ, Snih SA, Karmarkar A, et al. Routine physical
activity and mortality in Mexican Americans aged 75 and older. J
Am Geriatr Soc 2012; 60: 1085-91.
[32] Binder EF, Yarasheski KE, Steger-May K, et al. Effects of progres-
sive resistance training on body composition in frail older adults:
results of a randomized, controlled trial. J Gerontol A Biol Sci Med
Sci 2005; 60: 1425-31.
[33] Landi F, Cesari M, Onder G, et al. Physical activity and mortality
in frail, community-living elderly patients. J Gerontol A Biol Sci
Med Sci 2004; 59: 833-7.
[34] Rantanen T, Era P, Heikkinen E. Physical activity and the changes
in maximal isometric strength in men and women from the age of
75 to 80 years. J Am Geriatr Soc 1997; 45: 1439-45.
[35]
Ettinger WH, Burns R, Messier SP, et al. The Fitness Arthritis and
Seniors Trial (FAST): a randomized trial comparing aerobic exer-
cise and resistance exercise to a health education program on
physical disability in older people with knee osteoarthritis. JAMA
1997; 277: 25-31.
[36]
Leveille SG, Guralnik JM, Ferrucci L, Langlois JA. Aging success-
fully until death in old age: opportunities for increasing active life
expectancy. Am J Epidemiol 1999; 149: 654-664
[37]
Blair SN, Kohl HW, Barlow CE, et al. Changes in physical fitness
and all-cause mortality. A prospective study of healthy and un-
healthy men. JAMA 1995; 273: 1093-8.
[38] Gillespie LD, Gillespie WJ, Robertson MC, Lamb SE, Cumming
RG, Rowe BH. Interventions for preventing falls in elderly people.
Cochrane Database Syst Rev 2003; (4): CD000340
[39] Penninx B, Messier SP, Rejeski WJ, et al. Physical exercise and the
prevention of disability in activities of daily living in older persons
with osetoarthrits. Arch Intern Med 2001; 161: 2309-16.
[40] Gauchard GC, Gangloff P, Jeandel C, Perrin PP. Influence of regu-
lar proprioceptive and bioenergetic physical activities on balance
control in elderly women. J Gerontol A Biol Sci Med Sci 2003; 58:
M846-50.
[41] Geffken D, Cushman M, Burke G et al. Association between
physical activity and markers of inflammation in a healthy elderly
population. Am J Epidemiol 2001; 153: 242-50
[42] Nicklas BJ, Hsu FC, Brinkley TJ, et al. Exercise training and
plasma C-reactive protein and interleukin-6 in elderly people. J Am
Geriatr Soc 2008; 56: 2045-52.
[43] Brinkley TE, Leng X, Miller ME, et al. Chronic inflammation is
associated with low physical function in older adults across multi-
ple comorbidities. J Gerontol A Biol Sci Med Sci 2009; 64: 455-61.
[44] Lakka TA, Lakka HM, Rankinen T, et al. Effect of exercise train-
ing on plasma levels of C-reactive protein in healthy adults: the
HERITAGE Family Study. Eur Heart J 2005; 26: 2018-25.
[45] Owen N, Leslie E, Salmon J, Fotheringham MJ. Environmental
determinants of physical activity and sedentary behavior. Exerc
Sport Sci Rev 2000; 28: 153-8
[46] Katzmarzyk PT, Church TS, Craig CL, Bouchard C. Sitting time
and mortality from all causes, cardiovascular disease, and cancer.
Med Sci Sports Exerc 2009; 41: 998-1005
[47] Hamilton MT, Hamilton DG, Zderic TW. The role of low energy
expenditure and sitting on obesity, metabolic syndrome, Type 2
diabetes, and cardiovascular disease. Diabetes 2007; 56: 2655-67.
[48] Chodzko-zajko WJ, Proctor DN, Fiatarone Singh MA, Minson CT,
Salem GJ, Skinner JS. American College of Sports Medicine posi-
tion stand. Exercise and physical activity for older adults. Med Sci
Sports Exer 2009; 41: 1510-30.
[49] Morley JE. Anorexia and weight loss in older persons. J Gerontol
A Biol Sci Med Sci 2003; 58: 131-7.
[50] Short KR, Nair KS. The effect of age on protein metabolism. Curr
Opin Clin Nutr Metab Care 2000; 8: 89-94.
[51] Volpi E, Ferrando A, Yeckel CW, Tipton KD, Wolfe RR. Exoge-
nous aminoacids stimulate net muscle protein synthesis in the
erderly. J Clin Invest 1998 1; 101: 2000-7.
[52] Volpi E, Mittendorfer B, Wolf SE, Wolfe RR. Oral amino acids
stimulate muscle protein anabolism in the elderly despite higher
first-pass splanchnic extraction. Am J Physiol 1999; 277: E513-20.
[53] Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A,
Wolfe RR. Aging is associated with diminished accretion of muscle
proteins after the ingestion of a small bolus of essential amino ac-
ids. Am J Clin Nutr 2005; 82: 1065-73. 56.
[54] Rasmussen BB, Fujita S, Wolfe RR, et al. Insulin resistance of
muscle protein metabolism in aging. FASEB J 2006; 20: 768-9.
[55] Campbell WW, Crim MC, Dallal GE, Young VR, Evans WJ. In-
creased protein requirements in elderly people: new data and retro-
spective reassessments. Am J Clin Nutr 1994; 60: 501-9.
[56] Landi F, Marzetti E, Bernabei R. Perspective: Protein: what kind,
how much, when? J Am Med Dir Assoc 2013; 14: 66-7.
[57] Arnal MA, Mosoni L, Boirie Y, et al. Protein turnover modifica-
tions induced by the protein feeding pattern still persist after the
end of the diets. Am J Physiol Endocrinol Metab 2000; 278: E902-
9.
[58] Elliot TA, Cree MG, Sanford AP, Wolfe RR, Tipton KD. Milk
ingestion stimulates net muscle protein synthesis following resis-
tance exercise. Med Sci Sports Exerc 2006; 38: 667-74.
[59] Katsanos CS, Kobayashi H, Sheffield-Moore M, Aarsland A,
Wolfe RR. A high proportion of leucine is required for optimal
8 Current Pharmaceutical Design, 2015, Vol. 21, No. 00 Martone et al.
stimulation of the rate of muscle protein synthesis by essential
amino acids in the elderly. Am J Physiol Endocrinol Metab 2006;
291: E381-7
[60]
Holecek M, Muthny T, Kovarik M, Sispera L. Effect of beta-
hydroxy-beta-methylbutyrate (HMB) on protein metabolism in
whole body and in selected tissues. Food Chem Toxicol 2009; 47:
255-9 67.
[61]
Eley HL, Russell ST, Tisdale MJ. Mechanism of attenuation of
muscle protein degradation induced by tumor necrosis factor-alpha
and angiotensin II by beta-hydroxy-beta-methylbutyrate. Am J
Physiol Endocrinol Metab 2008; 295: E1417-26
[62] Petrovic V, Buzadic B, Korac A, et al. Antioxidative defence al-
terations in skeletal muscle during prolonged acclimation to cold:
role of L-arginine/NO producing pathway. J Exp Biol 2008; 211:
114-20.
[63] Walrand S. Ornthine alpha-ketoglutarate: colud it be a new thera-
peutic option for sarcopania? J Nutr Health Aging 2010; 14: 570-7.
[64] Roubenoff R. Catabolism of aging: is it an inflammatory process?
Curr Opin Clin Nutr Metab Care 2003; 6: 295-9.
[65] Simopoulos AP. The importance of the ratio of omega-6/omega-3
essential fatty acids. Biomed Pharmacother 2002; 56: 365-79.
[66] Robinson SM, Jameson KA, Batelaan SF, et al. Hertfordshire Co-
hort Study Group. Diet and its relationship with grip strength in
community-dwelling older men and women: the Hertfordshire co-
hort study. J Am Geriatr Soc 2008; 56(1): 84-90.
[67] Montero-Odasso M, Duque G. Vitamin D in the aging muscu-
loskeletal system: an authentic strength preserving hormone. Mol
Aspects Med 2005; 26: 203-19.
[68] Janssen HC, Samson MM, Verhaar HJ. Vitamin D deficiency,
muscle function, and falls in elderly people. Am J Clin Nutr 2002;
75: 611-5.
[69] Sato Y, Iwamoto J, Kanoko T, Satoh K. Low-dose vitamin D pre-
vents muscular atrophy and reduces falls and hip fractures in
women after stroke: a randomized controlled trial. Cerebrovasc Dis
2005; 20: 187-92.
[70] Bischoff HA, Stähelin HB, Dick W, et al. Effects of vitamin D and
calcium supplementation on falls: a randomized controlled trial. J
Bone Miner Res 2003; 18: 343-51
[71] Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall
prevention with supplemental and active forms of vitamin D: a
meta-analysis of randomised controlled trials. BMJ 2009; 339:
b3692
[72] Landi F, Liperoti R, Fusco D, et al. Prevalence and risk factors of
sarcopenia among nursing home older residents. J Gerontol A Biol
Sci Med Sci 2012; 67: 48-55.
[73] Vescovo G, Dalla Libera L, Serafini F, et al. Improved exercise
tolerance after losartan and enalapril in heart failure: correlation
with changes in skeletal muscle myosin heavy chain composition.
Circulation 1998; 98: 1742-9.
[74] Kranzhöfer R, Schmidt J, Pfeiffer CA, Hagl S, Libby P, Kübler W.
Angiotensin induces inflammatory activation of human vascular
smooth muscle cells. Arterioscler Thromb Vasc Biol 1999; 19:
1623-9.
[75] Giovannini S, Marzetti E, Borst SE, Leeuwenburgh C. Modulation
of GH/IGF-1 axis: potential strategies to counteract sarcopenia in
older adults. Mech Ageing Dev 2008; 129: 593-601.
[76] Di Bari M, van de Poll-Franse LV, Onder G, et al; Health, Aging
and Body Composition Study. Antihypertensive medications and
differences in muscle mass in older persons: the Health, Aging and
Body Composition Study. J Am Geriatr Soc 2004; 52: 961-6.
[77]
Sumukadas D, Witham MD, Struthers AD, McMurdo ME. Effect
of perindopril on physical function in elderly people with func-
tional impairment: a randomized controlled trial. CMAJ 2007; 177:
867-74.
[78] Aoki C, Nakano A, Tanaka S, et al. Fluvastatin upregulates endo-
thelial nitric oxide synthase activity via enhancement of its phos-
phorylation and expression and via an increase in tetrahydrobiop-
terin in vascular endothelial cells. Int J Cardiol 2012; 156: 55-6193.
[79]
Olivieri F, Mazzanti I, Abbatecola AM, et al. Telomere/Telomerase
system: a new target of statins pleiotropic effect? Curr Vasc Phar-
macol 2012; 10: 216-24.
[80]
Armitage J, Bowman L, Collins R, Parish S, Tobert J. MRC/BHF
Heart Protection Study Collaborative Group. Effects of simvastatin
40 mg daily on muscle and liver adverse effects in a 5-year ran-
domized placebo-controlled trial in 20, 536 high-risk people. BMC
Clin Pharmacol 2009; 31; 9: 6
[81]
Scott D, Blizzard L, Fell J, Jones G. Statin therapy, muscle function
and falls risk in community-dwelling older adults. QJM 2009; 102:
625-3399.
[82] Ferrando AA, Sheffield-Moore M, Paddon-Jones D, Wolfe RR,
Urban RJ. Differential anabolic effects of testosterone and amino
acid feeding in older men. J Clin Endocrinol Metab 2003; 88: 358-
62.
[83] Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of
testosterone on muscle strength, physical function, body composi-
tion, and quality of life in intermediate-frail and frail elderly men: a
randomized, double-blind, placebo-controlled study. J Clin Endo-
crinol Metab 2010; 95: 639-50.
[84] Borst SE, Yarrow JF, Conover CF, et al. Musculoskeletal and
prostate effects of combined testosterone and finasteride admini-
stration in older hypogonadal men: a randomized, controlled trial.
Am J Physiol Endocrinol Metab 2014 15; 306: E433-42.
[85] Baulieu EE, Thomas G, Legrain S, et al. Dehydroepiandrosterone
(DHEA), DHEA sulfate, and aging: contribution of the DHEAge
Study to a sociobiomedical issue. Proc Natl Acad Sci USA 2000;
97: 4279-84
[86] Baker WL, Karan S, Kenny AM. Effect of dehydroepiandrosterone
on muscle strength and physical function in older adults: a system-
atic review. J Am Geriatr Soc 2011; 59: 997-1002.
[87] Tai K, Visvanathan R, Hammond AJ, Wishart JM, Horowitz M,
Chapman IM. Fasting ghrelin is related to skeletal muscle mass in
healthy adults. Eur J Nutr 2009; 48: 176-83 108.
[88] Morley JE, Argiles JM, Evans WJ, et al; Society for Sarcopenia,
Cachexia, and Wasting Disease. Nutritional recommendations for
the management of sarcopenia. J Am Med Dir Assoc 2010; 11:
391-6.
[89] Aguiar AF, Januário RS, Junior RP, et al. Long-term creatine sup-
plementation improves muscular performance during resistance
training in older women. Eur J Appl Physiol 2013; 113: 987-96.
[90] Cooke MB, Brabham B, Buford TW, S et al. Creatine supplemen-
tation post-exercise does not enhance training-induced adaptations
in middle to older aged males. Eur J Appl Physiol 2014; 114: 1321-
32.
[91] Onder G, Della Vedova C, Landi F. Validated treatments and
therapeutics prospectives regarding pharmacological products for
sarcopenia. J Nutr Health Aging 2009; 13: 746-56.
[92] Bhasin S, Jasuja R. Selective androgen receptor modulators as
function promoting therapies. Curr Opin Clin Nutr Metab Care
2009; 12: 232-40.
[93] Mohler ML, Bohl CE, Jones A, et al. Nonsteroidal selective andro-
gen receptor modulators (SARMs): dissociating the anabolic and
androgenic activities of the androgen receptor for therapeutic bene-
fit. J Med Chem 2009; 52: 3597-617.
[94] Dalton J, Barnette K, Bohl C, et al. The selective androgen receptor
modulator GTx-024 (enobosarm) improves lean body mass and
physical function in healthy elderly men and postmenopausal
women: results of a double-blind, placebo-controlled phase II trial.
J Cachexia Sarcopenia Muscle 2011; 2: 153-61.
[95] Papanicolaou DA, Ather SN, Zhu H, et al. A phase IIA random-
ized, placebo-controlled clinical trial to study the efficacy and
safety of the selective androgen receptor modulator (SARM), MK-
0773 in female participants with sarcopenia. J Nutr Health Aging
2013; 17: 533-43.
[96] Basaria S, Collins L, Dillon EL, et al. The safety, pharmacokinet-
ics, and effects of LGD-4033, a novel nonsteroidal oral, selective
androgen receptor modulator, in healthy young men. J Gerontol A
Biol Sci Med Sci 2013; 68: 87-95).
Received: October 31, 2014 Accepted: January 26, 2015
