Clinical Section / Mini-Review

Gerontology 2014;60:294–305 Received: May 15, 2013

DOI: 10.1159/000356760 Accepted: October 21, 2013
Published online: April 8, 2014

Sarcopenia, Cachexia and Aging:

Diagnosis, Mechanisms and
Therapeutic Options – A Mini-Review
Sumbul Alia Jose M. Garciaa, b
a
Division of Diabetes, Endocrinology and Metabolism, MCL, Center for Translational Research in Inflammatory
Diseases, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, and b Department of
Molecular and Cell Biology and Huffington Center on Aging, Baylor College of Medicine, Houston, Tex., USA

Key Words Introduction

Cachexia · Anorexia · Aging · Sarcopenia · Inflammation ·
Ghrelin · Testosterone During the 20th century, overall survival
dramatically increased as a result of advances in
medicine, particularly in the treatment of infectious and
Abstract cardiovascular diseases. Consequently, at the beginning of
By the year 2050, individuals over the age of 65 years the 21st century, we are looking at a rising percentage of
will comprise 20% of the US population. Loss of muscle mass an aging population. According to the US Census
and strength is common in this age group and it is Bureau’s projections, it is estimated that by the year
associated with increased dependence, frailty and 2050 the number of individuals over the age of 65 years
mortality. Sarcopenia, defined as the loss of muscle mass will increase to approximately 80 million, comprising
and function associated with aging, and cachexia, defined 20% of the US population, and 4.3% will be ≥85 years
as weight loss due to an underlying illness, are muscle of age [1]. Similar trends are recognized in other
wasting disorders of particular relevance in the aging developed countries across the world. Ten percent of
population, but they go largely unrecognized. In this community-dwelling people aged 65 years or older
review we highlight the common pathophysiological require some assistance with activities of daily living.
mechanisms underlying muscle loss in sarcopenia and This number rises to 50% in those >85 years of age [1].
cachexia, the factors unique to each condition and means Given the disproportionate rise in the aged population,
of diagnosing and differentiating them clinically. efforts to promote independence and decrease frailty in
Therapeutic options including exercise, nutritional this demographic group are major challenges faced by
therapy, androgens and growth hormone as well as the healthcare system looking ahead.
their practical limitations are discussed. We also shed As the human body ages, there is a gradual decrease
light on newer agents being developed as potential in muscle mass accompanied by gains in fat mass and
therapeutic options for wasting diseases. © 2014 S. Karger AG, Basel abdominal circumference. This age-related loss of
muscle mass and strength is often referred to as
‘sarcopenia’. Weight loss due to an underlying disease
is called ‘ca-

E-Mail [email protected] www.karger.com/ger

© 2014 S. Karger AG, Jose M. Garcia, MD, PhD
Basel Divi
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chexia’, and it usually involves a loss of fat and muscle Sarcopenia Working
mass. This review reflects on the similarities and differ-
ences of the two conditions and the tools for managing
them in the elderly.

Mechanisms Regulating Skeletal Muscle Mass

Muscle mass is determined by the balance between

pathways favoring protein synthesis and breakdown.
The best-defined anabolic pathway leading to protein
synthesis in muscle involves activation of the
serine/threonine kinase Akt, resulting in downstream
amplification of mammalian target of rapamycin
(mTOR), which leads to increased muscle protein
synthesis [2]. Most muscle anabolic stimuli, especially
insulin-like growth factor 1 (IGF-1), and also branched-
chain amino acids (e.g. leucine), exercise and
testosterone upregulate this pathway [3]. Skeletal
muscle atrophy involves muscle protein breakdown by
activation of the ubiquitin proteasome pathway and
caspases under transcriptional control of the tran-
scription factors forkhead box O (Fox-O) and nuclear
factor (NF)-κB (fig. 1). Another important pathway
leading to muscle atrophy is the myostatin pathway.
Myostatin is a member of the transforming growth
factor-β family that is secreted by muscle cells,
circulates in the blood and acts locally as a negative
muscle mass regulator by downregulating the Akt/mTOR
pathway and by decreasing the number of satellite cells
[3]. The role of myostatin in muscle wasting in humans
has not been well delineated, but it is emerging as a
promising therapeutic target for muscle disorders. There
is considerable cross-communication between these
synthetic and degradation pathways, and when the
balance between these components is altered, muscle
mass atrophy (as in sarcopenia and cachexia) or
hypertrophy ensues (fig. 1). Other pathways that have
been shown to contribute to cachexia and sarcopenia
include an increase in muscle apoptosis [4, 5] and
autophagy/lysosomal activity [6], and a decrease in
mitochondrial function [7, 8] and satellite cells, which
are essential for muscle repair [9, 10].

Sarcopenia

Sarcopenia (from Greek sarx, ‘flesh’, and penia,

‘pov-erty’) has been defined as the ‘progressive loss of
muscle mass and strength with a risk of adverse
outcomes such as disability, poor quality of life and
death’ by the Special Interest Group of the European
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Aging DOI: 10.1159/000356760
Group in 2010 [11]. The term is used specifically to motor neurons all play a role in tipping the balance
denote loss of muscle mass and strength associated toward muscle breakdown in the elderly [11, 20]. Also,
with aging and distinguishes muscle loss from aging muscle autophagy is
from other causes such as immobility or neurological
damage.
Sarcopenia is increasingly being recognized as a
geriatric syndrome and a key public health issue.
Starting at the age of 30 years, individuals lose 1–2%
of muscle per year, and by the age of 80 years, 30% of
the muscle mass is lost [12, 13]. The prevalence of low
muscle mass is estimated to be between 10 and 25%
depending on the population and method used to
identify sarcopenia. In octo-genarians the prevalence
increases to 50% [11]. Reduced muscle function is
independently associated with increased risk of
functional impairment, falls, disability and mortality in
the elderly [14]. The direct cost attributed to sarcopenia
in the year 2000 was 1.5% of the total healthcare
expenditure. It is estimated that a 10% reduction in
prevalence of sarcopenia would save USD 1.1 billion
in health-related costs [15].

Pathophysiologic Mechanisms Contributing to

Sarcopenia
Sarcopenia is characterized by atrophy of muscle fi-
bers, especially type II fibers (fast), by a decreased
number of motor units and by accumulation of fat
within muscle [16]. There are multiple reasons for
declining muscle mass with aging (fig. 2); however,
their relative contribution to the process of normal
aging has not been well characterized. Immobility
seems to be an important driver of the
pathophysiological changes leading to muscle loss.
However, muscle loss can lead to immobility as well.
There is also decreased synthetic capacity of the
muscle with age, termed ‘anabolic resistance’ [17]. As
mentioned earlier, testosterone, insulin and IGF-1 are
potent activators of the Akt pathway, resulting in
increased muscle protein synthesis and decreased
degradation by inhibiting Fox-O (fig. 1). Testosterone
also stimulates myo-blasts, inhibits myostatin and
increases satellite cells, which help in the repair of
myocytes [18]. Aging is associated with lower
testosterone levels, IGF-1 and insulin resistance,
leading to decreased protein synthesis. Although there is
an increase in circulating markers of inflammation
such as interleukin (IL)-6 with advancing age, it is
debatable whether such elevation is due to age alone or
to underlying comorbidities that accompany old age
[19]. Moreover, inflammatory pathways involving NF-
κB are typically not activated in sarcopenia. Genetic
potential, nutritional deficiencies and loss of lower

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 IGF-1, Inactivity, inflammation
Exercise testosterone
Insulin, BCAA Myostatin

Fig. 1. Simplified cellular pathways for

muscle protein synthesis and degradation.
Blue: synthesis pathways. Red:
PI-3K/Akt Fox-O NF-kB
proteolytic pathways. Dotted lines:
pathways that are not well characterized.
Anabolic signals activate the
phosphatidylinositol 3-kinase mTOR Ubiquitin proteasome activation
(PI-3K)/Akt/mTOR pathway, resulting in Other atrophy related genes
protein synthesis. Inactivity and
inflammatory cytokines result in Caspases
activation of NF-κB- and Fox-O-mediated
induction of genes, resulting in muscle
atrophy. Fox-O activates transcription of Protein synthesis Protein degradation
ubiquitin proteasome ligases, resulting in
protein degradation. PI-3K/Akt
phosphorylates Fox-O, preventing its
nuclear translocation and inhibiting its
activity. Fox-O, when active, can inhibit
the mTOR pathway. Also, mTOR Muscle mass
pathway activation inhibits protein
degradation by lysosomal caspases. Myo-
statin causes muscle atrophy via
activating Fox-O and inhibiting PI-3K.
BCAA = Branched-chain amino acids.

Endocrine factors
↓ GH, IGF-1 Muscle fiber atrophy
↓ sex steroids Insulin resistance
Other mechanisms:
Autophagy
Apoptosis
Mitochondria Neurodegenerative processes
dysfunction

Decreased protein synthesis

Immobility*

Genetic influence SARCOPENIA Nutritional status (↓ Protein & energy intake)

↓ Muscle mass
↓ Muscle strength

Fig. 2. Pathophysiology of sarcopenia. GH = Growth hormone. * Immobility may also be considered part of disuse atrophy rather than
sarcopenia.

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impaired and apoptosis increased in animal models of Cochrane review in 2009, looking at 121 trials,
sarcopenia. Interestingly, these changes are prevented
by caloric restriction [4, 6]. Lastly, mitochondrial
function and content is decreased in aged muscles, and
this is prevented by exercise [7].

Diagnosis
Sarcopenia is an underdiagnosed entity, partly due to
lack of consensus regarding the optimal approach to di-
agnosis. Although targeted screening of at-risk patients
has been proposed, this is not widely practiced (table 1).
It has been recommended that elderly subjects who are
chronically bedbound, are nonambulatory, have a
history of recent significant weight loss and appear
malnourished (including alcoholics), and those with
chronic medical conditions associated with loss of
muscle (e.g. diabetes and chronic heart, lung, kidney
and liver disorders) should be assessed for the presence
of muscle wasting [11], although some of these
conditions are more likely to induce cachexia rather than
sarcopenia.
Sarcopenia includes both a reduction in muscle mass
as well as function. It has been suggested that the
diagnosis can be made in subjects with muscle mass ≥2
standard deviations (SD) below that of sex- and
ethnicity-matched young adults along with slow
walking speed (<0.8 m/s over 4 m), or with reduced
performance on any other commonly used test as part of
a comprehensive geriatric assessment. In 2010 the
European Working Group on Sarcopenia in Older
People published guidelines in order to aid clinicians
and researchers to assess muscle mass, which can vary
depending on affordability and clinical settings (table 2)
[21].

Treatment
Exercise
Both resistance and aerobic training have been
shown to increase muscle strength and improve
function. Progressive resistance training (PRT) is the
best-studied form of exercise in this context and should
be considered the primary intervention for sarcopenia.
In PRT participants exercise their muscles against an
increasing external force; it is performed at least 2–3
times a week for 8–12 weeks. The duration of sessions
and number of exercises increase gradually over time
based on each individual’s capability and improvement.
Yarasheski et al. [22] demonstrated that whole body
muscle mass was increased by 1 kg in women and by
2.2 kg in men with 3 months of PRT. Fiatarone et al.
[23] demonstrated not only improved muscle mass but
also strength and gait speed with resistance training. A
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Table 1. Sarcopenia screening apparent benefits
Bedbound Targeted screening at:
Nonambulatory
Unable to rise from a sitting position unassisted
History of weight loss (>5%)
Noted or reported decline in function/strength
History of recurrent falls
After hospitalization
Comorbidities associated with loss of muscle mass (e.g. diabetes
mellitus, CHF, chronic kidney disease, COPD, rheumatoid
arthritis)
Gait speed <0.8 m/s over 4 m

CHF = Congestive heart failure; COPD = chronic

obstructive pulmonary disease. Adapted from Fielding et al.
[11].

concluded that PRT results in improved muscle

strength as well as functional measures of physical
performance including gait speed and getting up from a
chair [24]. No intervention in the field so far has shown
results superior to exercise – although a combination of
exercise and other therapies could potentially surpass
the benefits of exercise alone. Nevertheless, major
barriers exist to the universal implementation of this
simple tool. Community-dwelling elderly may lack
access to and motivation for embarking on a strenuous
exercise training program. PRT requires trained
therapists and special equipment which are not
routinely available to everyone. Other exercise options
that are less intensive and do not require as many
resources could be useful as well, although they may be
less effective. Hence there remains a continued need
for alternatives to address the growing problem of
sarcopenia.

Nutrition
There is a considerable wealth of literature on nutri-
tional interventions, including antioxidants, specific
amino acids, combinations of amino acids, compounds
like creatine and fatty acids, for the use of muscle
building. However, the evidence is not conclusive and
universal recommendations are not possible at this
time. For a detailed overview refer to the review by
Calvani et al. [25].
Of all the proposed dietary agents, protein supple-
ments and vitamin D optimization seem to be the most
promising. Supplementation of diets with additional
calories, protein concentrates (such as whey) or,
specifically, branched-chain amino acids (e.g. leucine)
have been shown to have beneficial effects on mixed
muscle protein synthesis in young adults. But these
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 Table 2. Diagnostic criteria for sarcopenia

Reference range

Muscle mass
Anthropometry Calf circumference <31 cm
(not recommended as it is very variable) Mid-upper arm circumference –
men: <32 cm; women: <18 cm
Bioimpedance analysis Predicted skeletal muscle mass (SM) equation
(SM/height2; based on 2 SD below the mean of
young adults in the study, n = 200) – men: 8.87
kg/m2; women: 6.42 kg/m2
Skeletal Muscle Index using absolute muscle mass, not
appendicular muscle mass [absolute muscle mass/
height2; based on statistical analysis of NHANES III
data on older (≥60 years) men and women] –
men: severe sarcopenia, ≤8.50 kg/m2; moderate
sarcopenia, 8.51–10.75 kg/m2; normal muscle,
≥10.76 kg/m2
women: severe sarcopenia, ≤5.75 kg/m2; moderate
sarcopenia, 5.76–6.75 kg/m2; normal muscle,
≥6.76 kg/m2
Dual energy X-ray absorptiometry Skeletal muscle mass index = appendicular skeletal muscle
mass/height2 (2 SD below mean of young adults) –
men: 7.26 kg/m2; women: 5.5 kg/m2
Muscle strength
Handgrip strength (using dynamometer) Men: <30 kg; women: <20 kg
Muscle function
Short Physical Performance Battery ≤8
Usual gait speed over 6 m <1 m/s
Get-up-and-go test >10 s

NHANES III = Third National Health and Nutrition Examination Survey. Adapted from: Cruz-Jentoft et al.
[21].

have not translated into improved functional perfor- Androgens/Selective Androgen Receptor Modulators
mance or muscle mass in the elderly. Forty percent of Testosterone levels gradually decline with age. Ap-
the elderly do not meet the recommended 0.8 g/kg proximately 20% of healthy men have testosterone lev-
protein intake requirement in their diet; and although els in the hypogonadal range at the age of 60 years, and
experts propose at least a protein intake of 1.5 g/kg/day 50% after the age of 80 years [28]. Although
comprising 15–20% of the total caloric intake for testosterone has been shown to increase weight and
sarcopenic elderly [26], this may be difficult to achieve muscle mass and to decrease fat mass in hypogonadal
in certain scenarios. elderly men, studies of testosterone treatment in healthy
There is ongoing controversy regarding the utility of populations are divisive. A study on 207 community-
supplementation with calcium and vitamin D, despite dwelling older males revealed that oral testosterone
considerable observational evidence linking low supplementation was beneficial in increasing lean body
vitamin D levels to poor functional performance and mass but did not demonstrate improved muscle function
frailty. A 2009 meta-analysis showed a 19% risk or strength [29]. On the other hand, Srinivas-Shankar et
reduction in falls in elderly people taking at least 700 IU al. [30] demonstrated improved knee extensor
of supplemental vitamin D a day [27]. The Society on functioning and physical functional improvement with
Sarcopenia, Cachexia and Wasting Diseases transdermal testosterone supplementation in frail
recommends checking 25-hy-droxy-vitamin D levels elderly. A 2010 trial of testosterone replacement in
and replacing, if low, in all sarcopenic patients [26]. elderly men with a high burden of comorbidities and
limited mobility was stopped early

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due to concerns of increased cardiovascular morbidity relin demonstrated not only increases in body weight
in the testosterone arm [31]. This group showed im- and fat-free mass but also improved tandem gait, and
provement in muscle strength and function with testos- by 12 months, stair climbing also improved [36]. More
terone as compared with placebo. In summary, due to trials are needed to establish the efficacy and safety of
safety concerns, testosterone replacement or supple- these agents in the long-term treatment of sarcopenia.
mentation in the elderly frail population presently re-
mains debatable, and guidelines recommend testoster- Other Agents
one therapy for hypogonadal men after careful risk-ben- Certain drugs that are known to improve functional
efit assessment [32]. performance and prognosis in heart failure patients,
Selective androgen receptor modulators (SARM) are such as inhibitors of the renin-angiotensin system, are
agents with desirable androgenic effects in certain tis- being investigated as agents for skeletal muscle
sues (e.g. muscle and bone), but without effects on other preservation. Observational studies have shown
organs like the prostate or skin, thereby limiting the improved skeletal muscle performance in subjects using
adverse effects typically associated with androgens these agents. In the Health ABC study there was an
(prostate growth or androgenization). These agents association seen between angiotensin-converting
have been shown to increase lean body mass and bone enzyme inhibitor (ACEI) users and lower-extremity
density in animal models. Recently, a phase II study of muscle mass [37]. In the Women’s Health and Aging
enobosarm in 120 healthy elderly showed an increase in Study, ACEI use was associated with a lower rate of
lean body mass as well as improvement in stair decline in walking speed and lower-extrem-ity muscle
climbing that was dose dependent. Enobosarm also strength as compared with people who used ACEI
decreased insulin resistance with a favorable safety intermittently or subjects taking other antihyper-
profile [33]. These agents are not available on the tensives [38]. Prospective randomized studies assessing
market yet, and further studies are awaited to establish the effect of ACEI on measures of physical performance
their role in muscle wasting disorders. yielded mixed results, with one trial showing improve-
ment in walking distance after 20 weeks of treatment,
Growth Hormone/IGF-1 but others showing no change [39]. Inhibition of the
Growth hormone (GH), primarily through IGF-1, is renin-angiotensin system leads to improved oxygen
a potent regulator of muscle growth and differentiation. delivery to muscle tissue, and this is thought to be
GH administration to healthy older men increases lean primarily responsible for the proposed beneficial effects
body mass but induces no change in muscle functional of ACEI in this setting [40].
parameters in addition to that seen with exercise. There
was an increased incidence of adverse events, mainly
fluid retention, edema, arthralgia and increased insulin Cachexia
resistance [34].
Cachexia (from the Greek cacos, ‘bad’, and hexis, ‘hav-
Ghrelin Mimetics (GH Secretagogues) ing’) is defined as a multifactorial syndrome character-
Ghrelin, an endogenous GH secretagogue (GHS) and ized by severe body weight, fat and muscle loss due to
appetite stimulant, has triggered much interest as a ther- an underlying illness [41]. Typically, it is associated with
apeutic option for wasting syndromes due to its action increased catabolism which cannot be reversed by mere
profile. Several studies involving ghrelin have demon- nutritional support. Table 3 highlights the features
strated increased appetite, food intake and weight gain distinguishing between cachexia and sarcopenia.
in healthy volunteers with no major adverse effects. Between 10 and 40% of patients with chronic condi-
Trials using oral GHS for ease of administration are tions including heart failure, chronic obstructive pulmo-
also showing considerable promise. A randomized, nary disease (COPD), cancer, HIV, and renal and liver
blinded, placebo-controlled trial using the oral ghrelin failure suffer from cachexia. This comprises more than
mimetic MK-677 for 1 year in healthy elderly men and 5 million people in the USA or approximately 2% of the
women resulted in restoration of pulsatile GH secretion population [42]. Table 4 lists the common causes of ca-
and IGF-1 levels to those seen in young healthy adults, chexia and its relevance in various diseases. Reliable
and increased fat-free mass by 1.6 kg with no estimates for cachexia in the elderly are not available,
significant change in strength or function [35]. Another but the interplay between chronic illness and elements
study using the GHS capromo- such as sarcopenia, malnutrition and immobility, all

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Aging DOI: 10.1159/000356760
prevalent in

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 Table 3. Differences between sarcopenia and cachexia

SarcopeniaCachexia

Definition Muscle mass <2 SD of young healthy Weight loss >5%

population, decreased muscle function in 6 months
Mechanism Aging Pathologic
Comorbid condition +/– +++
Functional limitation ++ +++
Inflammation – ++
Fat mass Increased Decreased
Protein degradation –/+ +++
Resting energy expenditure Decreased Increased
Anorexia + ++

Table 4. Leading causes of cachexia

Condition Prevalence Impact of cachexia

of cachexia

COPD 25–35% Mortality 10–15%/year in cachectic patients;

impaired mobility and worsened response to treatment
CHF 16–42% 50% mortality in 18 months as compared with 17% in
non-cachectic individuals in an unselected population
Cancer Approx. Up to 20% of deaths of cancer patients due to cachexia and
30–60% its associated morbidity; impacts mobility, quality of life and
treatment response
Advanced chronic 30–60% 20–30% mortality/year; blunted response to treatment
kidney disease
Rheumatoid arthritis 67% Lean body mass loss with fat mass gain
Chronic liver disease Approx. 50% Cachexia more common in males than in females with
cirrhosis

CHF = Congestive heart failure. Adapted from Morley et al. [43].

old age, makes this age group particularly vulnerable to -independent mechanisms. As mentioned before, down-
cachexia. The importance of recognizing cachexia lies
in the fact that it is an independent predictor of
mortality, response to treatment as well as quality-of-
life measures in different settings [42].

Pathophysiologic Mechanisms Contributing to

Cachexia
Inflammation is purported to play an important role
in the pathogenesis of cachexia (fig. 3). Inflammatory
cytokines including IL-1, IL-6 and tumor necrosis
factor-α induce myofibrillar breakdown by activation of
the ubiquitin proteasome pathway, via NF-κB-
dependent and

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regulation of anabolic factors/pathways including IGF-
1, androgens and satellite cell proliferation [10], and
increases in catabolic pathways/processes such as
apoptosis [5], autophagy [6], mitochondrial dysfunction
[7, 8] and the myostatin pathway [3] all contribute to
muscle mass and function loss in this setting.
Cytokine-mediated release of cortisol and
adrenergic hormones can also lead to increased fat
oxidation and fat atrophy, insulin resistance,
hypermetabolism, anemia and fatigue. Numerous
disease-, therapy- and patient-re-lated factors such as
pain, gastrointestinal obstruction, nausea, fatigue and
depression also cause a paradoxical reduction in
appetite in these patients, further aggravating their
hypercatabolic state.

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 DISEASE/ TREATMENT RELATED FACTORS

Inflammation

BRAIN MUSCLE FAT LIVER

↓ Synthesis
ଭ Breakdown
ଭ Lipolysis ଭ Acute phase reactants
ଭ DŽ-oxidation ଭ CRP, ↓ Albumin

↓ Testosterone Fatigue immobility Insulin

Anorexia
resistance
Anemia

CACHEXIA

Fig. 3. Pathophysiology of cachexia. Various disease- or treatment-

tigue, and ultimately leading to cachexia. These factors are inter-
related factors lead to inflammation, hypogonadism, anorexia
dependent and altered by disease type, stage and treatment. CRP
and insulin resistance, resulting in muscle and fat loss, anemia
= C-reactive protein.
and fa-

The elderly, with their comorbidities, limited IL-6 or C-reactive protein) [41]. Further studies will be
mobility, reduced nutrition, low IGF-1 and testosterone needed to validate this and other definitions in different
levels and low muscle mass, are especially vulnerable to settings.
cachexia even at earlier stages of the disease. Moreover,
they are more likely to suffer from the consequences of Treatment
increased dependence, increased utilization of care, Despite a clear association of cachexia with adverse
poor response to therapy and worse prognosis as outcomes, there is currently no approved treatment for
compared with the nonelderly population [43]. cachexia. However, there are some promising agents in
trials underway and expected to be on the market in the
Diagnosis future.
There is no unanimous consensus about diagnosing
cachexia. Most studies have used different weight loss Exercise and Nutrition
cutoffs or symptoms to define cachexia. In 2008, Evans Nutrition therapy coupled with exercise training is
et al. [41] proposed a systematic approach to diagnosing thought to be beneficial from a pathophysiological per-
cachexia for research as well as clinical purposes. This spective in terms of decreasing protein breakdown and
multidimensional model incorporates documenting improving muscle function. Though cachectic patients
weight loss of >5% in the preceding year or BMI <20 may not feel motivated to exercise, evidence indicates
along with the presence of any 3 of the following: fa- that resistance training improves muscle strength and
tigue, anorexia, decreased muscle strength, laboratory lean body mass, attenuates inflammatory markers and
evidence of anemia (Hb <12 g/dl), hypoalbuminemia improves fatigue [44]. Cachexia is a hypercatabolic
(<3.2 g/dl) or elevated markers of inflammation (e.g. state and a diet containing 1.5 g/kg/day of protein

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constituting

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15–20% of total caloric intake is recommended to counter wasting syndrome, pediatric chronic
catabolism [45]. However, studies aimed at supplement-
ing caloric intake or adding specific nutritional elements
like whey protein supplements, branched-chain amino
acids or creatine have not shown consistent benefit [46].

Appetite Stimulants
Appetite stimulants, including steroids,
progestational agents such as megestrol acetate (MPA)
and cannabinoids, are the oldest and best-studied drugs
for cachexia, and hence maybe the only agents with
which clinicians have some familiarity. Corticosteroids
may result in subjective improvements in appetite and
quality of life, but they are not recommended due to
their side effects. MPA can increase appetite and body
weight primarily through fat accrual, but side effects
include venous thromboem-bolism, hypogonadism,
adrenal insufficiency and possibly increased mortality
in the elderly [47]. Cannabinoids like dronabinol are
another option but are usually considered inferior in
terms of efficacy as compared with steroi-dal agents
[48].

Androgens/SARM
Oxandrolone, an oral synthetic testosterone deriva-
tive with minimal androgenic effects, has been
approved for use in men and women with weight loss
associated with catabolic conditions including surgery,
burns and chronic infections. It has been shown to
increase lean body mass and body weight in HIV- and
COPD-related weight loss. It is, in general, well
tolerated, but may cause hypogonadism in men [49].
SARM are tissue-specific nonsteroidal androgenic
agents expected to have minimal androgenic and
prostatic side effects and greater anabolic potency
compared with testosterone. Recently, a phase II,
randomized controlled trial of enobosarm in 159
patients with cancer and 2% weight loss showed sig-
nificant weight gain when compared with placebo (me-
dian lean body mass gain: 1–1.5 kg) with up to 113 days
of treatment. No adverse effects related to the drug were
reported [50]. Further phase III studies are taking place
in cancer-cachexia to test the safety and efficacy of this
agent.

Growth Hormone
Recombinant GH has shown consistently favorable
results in various catabolic states including AIDS,
congestive heart failure (CHF), COPD and
hemodialysis as well as in postsurgical patients.
Recombinant GH has been approved by the US Food
and Drug Administration for the treatment of HIV
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kidney disease and parenteral nutrition-dependent heterogeneity between groups, preventing any
short-bowel patients to treat cachexia. However, it is meaningful conclusions
costly, requires daily subcutaneous injections, and its
side effects include arthralgia, edema, insulin
resistance, paresthesia and sodium retention [34]. It is
also contraindicated in individuals with active tumors,
although the evidence linking GH and cancer is weak.

Ghrelin and Ghrelin Mimetics

Ghrelin as an infusion, or its synthetic analogues as
oral agents, have been studied in weight loss in
conditions including cancer, CHF, end-stage renal
disease, COPD and anorexia nervosa. Acylated ghrelin
infusions have been shown to increase appetite and food
intake in healthy subjects and in cancer, COPD and
CHF patients. Ghrelin demonstrated an excellent short-
term safety profile with no major adverse effects
reported. Ghrelin mimetics (also known as GHS) are
orally administered, small molecules with a longer
half-life, making them easier to use in clinical settings.
In a randomized, double-blinded crossover study, 16
patients with cancer cachexia were randomized to
receive placebo or the GHS anamorelin for 3 days. Ana-
morelin significantly increased body weight by 0.77 kg
as well as appetite [51]. Adverse events were mild and
included hyperglycemia, nausea and dizziness. Ghrelin
mimetics show considerable potential as a future
therapy against cachexia. Larger studies are ongoing to
test the safety and efficacy of this intervention in
cancer subjects.

Anti-Inflammatory Agents (Nonsteroidal

Anti-Inflammatory Drugs, Omega–3 Fatty
Acids, Thalidomide)
Since inflammation is an important underlying
mechanism for cachexia, drugs targeting inflammatory
cytokines are of particular interest to the field, but none
have shown beneficial effects consistently. Studies
looking at ω–3 fatty acids like eicosapentaenoic acid,
both nonselec-tive and selective COX inhibitors, anti-
tumor necrosis factor agents and thalidomide have
reported variable efficacy and inconsistent results [40].
Thalidomide, an im-munomodulatory, antineoplastic
and anti-inflammatory agent, seemed to ameliorate the
weight loss seen in certain cancers, but a Cochrane
review conducted in 2012 concluded that there is a
paucity of evidence to recommend thalidomide for
such use [52]. One randomized controlled trial
evaluating a multimodal cachexia treatment approach
showed a benefit of using thalidomide, MPA,
eicosapentaenoic acid, L-carnitine and nutritional
support together, but there was significant

3 Gerontology 2014;60:294– Ali/

305 DOI:
about each individual arm. These studies suggest that myostatin antagonists. Trials are underway to assess
since cachexia is a multifactorial entity, an approach their effects on muscle disorders such as wasting or
targeting different underlying mechanisms including in- muscular dystrophies [54].
flammation, appetite stimulation and muscle anabolic
agents may prove more efficacious than targeting Anti-IL-6 Antibodies
inflammation alone. In preclinical and phase I and II studies of non-small-
cell lung cancer, a monoclonal antibody to IL-6, ALD518,
Beta Blockers seemed to be of benefit in ameliorating cancer-related
Beta blockers may also have a beneficial effect on cachexia and anemia in humans [55]. Further studies are
preserving body weight as they inhibit catecholamine- needed to confirm this observation.
de-pendent lipolysis, decrease resting energy
expenditure and induce vasodilation and enhanced
oxygenation. In a rat model of cachexia they have Conclusion
shown improved survival and decreased weight loss
[40]. Further research is needed to establish the role of There is ample evidence showing that weight and
these agents in muscle preservation in the elderly. muscle loss are associated with frailty, loss of
independence, poor prognosis and increased mortality.
Future Therapies The elderly are particularly prone to the spectrum of
Melanocortin Receptor Inhibition wasting diseases and their unfavorable consequences.
Mutations in the melanocortin 4 receptor, a receptor Despite this, we fail to identify sarcopenia and cachexia
for α-melanocyte-stimulating hormone, have been in the majority of patients until the disease is advanced.
linked to obesity. The α-melanocyte-stimulating Currently, we have limited options to counter the effects
hormone/mel-anocortin 4 receptor binding leads to of muscle loss as part of aging or a disease process
widespread effects, ultimately culminating in appetite except for lifestyle therapies like healthy nutrition and
control and decreased body mass, while antagonism of exercise training. Nonetheless, the future looks bright
this pathway leads to increased appetite and weight with some promising new therapies on the horizon.
gain. These compounds have shown promising results
in mouse models of cachexia, and trials in human
subjects are awaited [53]. Acknowledgements

Myostatin Inhibitors J.M.G. receives research support from the Department of

Myostatin inhibits muscle protein synthesis and pro- Veterans Affairs (MERIT grants: I01-BX000507 and I01-
motes fibrosis, while myostatin inhibition leads to CX000174) and the National Institute on Aging (T32AG000183
and AG040583).
muscle hypertrophy. Hence, ways to inhibit its activity
are of immense interest in the prevention of muscle loss.
Several agents are in development, including hormones
such as follistatin (a natural myostatin-binding protein), Disclosure Statement
recombinant myostatin antibodies and soluble activin
J.M.G. is a consultant for and receives research support from
type IIB receptors (myostatin binds to activin type I, IIA Æterna Zentaris Inc. and Helsinn Therapeutics Inc.
and IIB receptors for its action), all of which are
mechanistic

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