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Med Clin N Am 90 (2006) 837847

John E. Morley, MD, BCha,b,*,
Matthew T. Haren, PhDa,b,
Yves Rolland, MDc, Moon Jong Kim, MDd

Division of Geriatric Medicine, Saint Louis University School of Medicine, 1402 South Grand
Boulevard, M238, St. Louis, MO 63104, USA
Veterans Aairs Medical Center, GRECC, #1 Jeerson Barracks Dr., St. Louis,
MO 63125, USA
Department of Internal Medicine and Geriatrics, Hopital La Grave-Casselardit,
31300 Toulouse, France
Department of Family Medicine, Pochon CHA University, 351 Yatap-dong, Bundang-gu,
Sungnam-si, Kyonggi-do, 463-712, Seoul, South Korea

The concept of older people becoming frail is not a new one. The ability
to dene frailty in a clinically meaningful manner has remained elusive,
however. Frailty can be considered to occur when under stressful conditions
an individual has diminished ability to carry out important practiced social
activities of daily living. It represents a form of predisability and, as such,
needs to be distinguished from functional impairment [1,2]. Recently, Linda
Fried and her colleagues at Johns Hopkins University have developed objective criteria for the diagnosis of frailty [3,4]. These are: weight loss of more
than 10 lb in one year, physical exhaustion by self report, weakness as measured by grip strength, decline in walking speed, and low physical activity.
The importance of the recognition of frailty is that frail people are more
likely to be precipitated into disability by exposure to a stressor (eg, inuenza or death of a spouse). Early intervention to reverse some of the aspects
of frailty may delay the onset of disability in an older person (Fig. 1).
The development of frailty depends on the interaction of disease
processes with the normal physiologic processes of aging. Genes, environment, and lifestyle all play a role in the pathway to frailty. In the nal analysis, frail people usually have an excess loss of functional muscle associated
* Corresponding author. Division of Geriatric Medicine, Saint Louis University School
of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104.
E-mail address: morley@slu.edu (J.E. Morley).
0025-7125/06/$ - see front matter 2006 Elsevier Inc. All rights reserved.



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Age Related Physiological Deterioration

- Exercise


- Adequate Nutrition

Mental Activity

Disease Processes
e.g., anemia, heart failure


Stressful Event


e.g. influenza
death of a spouse

Functional Decline





Fig. 1. The frailty cascade.

with some decline in executive function. Pain, by limiting a persons ability

to exercise, is often an important precipitant of frailty. Diseases that limit
a persons cardiopulmonary function (eg, congestive heart failure, anemia,
or chronic obstructive pulmonary disease), those that interfere with muscle
function (eg, diabetes, peripheral vascular disease, and polymyalgia rheumatica), weight loss, and impaired executive function (eg, depression and
cognitive deterioration) all interact to produce frailty.

Sarcopenia: a central factor in the pathophysiology of frailty

Sarcopenia is the age-related loss of muscle mass [5]. It is derived from
the Greek sarx for esh and penia for loss. It has become conventional



to consider an older person to be sarcopenic when the lean body mass is less
than two standard deviations of the sex-specic mean in a young healthy
sample. Operationally, this can be dened using the following formula derived from measurements using dual-energy x-ray absorptiometry: Appendicular skeletal mass/height2.
These measurements fail to take into account the quality of muscle and
with aging there can be a marked uncoupling of muscle cross-sectional
area and muscle ber strength. Also, there has been increased awareness recently that with aging there is fat accumulation in muscle (myosteatosis),
which results in a decline in muscle function. Using this denition, the prevalence of sarcopenia is approximately 12% for adults 60 to 70 years of age
rising to 30% by 80 years of age. In most studies, the development of sarcopenia is associated strongly with increased disability, gait and balance disorders, and mortality [6,7]. Muscle strength also declines with aging [8].
A second concept is that whereas obese people often have a larger lean
body mass than normal weight people, a small subset actually are sarcopenic. This group has been called the sarcopenic obese or the fat frail.
In the New Mexico Aging Process Study obese sarcopenia was found to
be the best predictor of future disability and mortality [9]. The risk for developing disability in this prospective study was 2.63. Obesity, in the absence
of adequate exercise, is a cause of frailty [10].
There are multiple causes of sarcopenia (Fig. 2). Genes and early life environment clearly play a role. Several genes have been demonstrated to relate clearly to muscle quality in sports stars. An example that can be
extended to older people is the angiotensin converting enzyme (ACE) alleles.
Emerging evidence suggests the ACE inhibitors may retard the loss of

Fig. 2. The causes of sarcopenia.



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muscle strength in some individuals [11]. People with a single or double I allele for ACE can generate more power when exercising regularly than people
with the D allele. The Hartfordshire cohort study demonstrated that grip
strength at 70 years of age is predicted by birth weight [12]. Epidemiologic
studies have demonstrated that predictors of muscle mass and strength with
aging include testosterone, insulinlike growth factor (IGF)-1, physical activity, energy intake, and age [1214].
Muscle is continuously undergoing a process of rejuvenation (Fig. 3).
Muscle proteins are degraded as they become unfolded leading to atrophy,
and cells also can undergo apoptosis (cell death). Rejuvenation occurs because of incorporation of amino acids to drive protein synthesis leading
to muscle hypertrophy and stimulation of stem cells to produce satellite cells
that repair damaged muscle. It needs to be recognized that each time muscle
contracts damage occurs and mechanoreceptors in muscle, such as titin,
stimulate the rejuvenation process. The hypertrophy/atrophy process is regulated by the activation of the PI3K-AKT pathway, which leads to muscle
hypertrophy. This pathway also inhibits muscle atrophy by phosphorylating
forkhead transcription factors (FOXOs) and thus inhibiting the action of
Atrogin I, which carries ubiquitin-tagged proteins to the proteasome (the
cellular death chamber) where they are degraded into small peptides
and amino acids.
The PI3K-AKT pathway is driven by anabolic factors, such as growth
hormone and testosterone, that activate the IGF genes within muscle. There
are three IGF genes. IGF-1 stimulates protein synthesis and muscle hypertrophy. This gene is regulated by growth hormone [15]. Mechanogrowth factor (MGF) is responsible for activating the production of satellite cells and
stimulating the ring of motor unit cells. MGF is stimulated in the rst instance by resistance exercise [16]. Growth hormone can then synergistically
increase this process further but is not eective in the absence of resistance
exercise. This ineectiveness explains why the studies giving growth hormone to older people result in an increase in muscle mass but not in muscle
strength [17,18]. Ghrelin, a growth hormone secretagogue, also increases

Fig. 3. The yin and yang of muscle death and rejuvenation.



muscle mass and food intake [19]. The transgene for MGF, when inserted
into muscle of older rats, has been shown to rejuvenate the muscle [20].
Testosterone is an anabolic hormone that has been demonstrated to increase muscle mass and strength in older hypogonadal men when given at
high doses [2129]. A small number of studies suggest similar eects in
women [30,31]. Testosterone levels decline with aging at the rate of about
1% per year [32,33]. Low testosterone levels are associated with a decrease
in muscle strength and function [34,35]. Androgen deprivation leads to
a loss of muscle mass [36]. In animal models testosterone improves function
in a stroke model [37]. Testosterone replacement results in improved function over a 3-year period in older men [38]. At the cellular level testosterone
stimulates protein synthesis, inhibits the ubiquitin-proteasome pathway, and
most importantly stimulates satellite cell production [3941]. At present, testosterone would appear to be the best pharmacologic agent to treat sarcopenia, but as we have pointed out elsewhere, there are only a limited number of
studies in support of this viewpoint [42]. Dehydroepiandrosterone, a weak
androgen, failed in a well-controlled study to increase muscle mass or
strength at a dose of 50 mg daily given for one year [43].
Myostatin is an inhibitor of muscle regeneration. It has a direct eect inhibiting satellite cell production. A double deletion of the myostatin gene
leads to muscle hypertrophy in mice, cows, and in a single human [44].
Amgen has developed peptobodies to myostatin, which in animal studies
appear to cause muscle hypertrophy.
People who are vitamin D decient have poor muscle function, which is
improved with vitamin D administration [45]. In vitamin Ddecient people
vitamin D supplementation decreases falls and reduces functional impairment [46,47]. Vitamin D levels have been shown to decline throughout the
lifetime in a longitudinal study [48].
Adequate food intake is essential for the maintenance of muscle quality.
Creatine is essential to maintenance of muscle quality [49]. With aging,
many people experience an associated anorexia, which can lead to inadequate protein intake for muscle maintenance [50,51].
Motor unit ring, an important component of muscle maintenance, decreases in people more than 80 years of age [52]. Ciliary neurotrophic factor
(CNTF) levels decline with aging and correlate with the decline in muscle
strength that occurs with aging [53]. CNTF replacement leads to an increase
in muscle mass in animals [54].
The increase in cytokines that occurs with agingdcytokine-related aging
processdis associated with a decline in muscle strength and frailty [55]. Cesari and colleagues [56] showed that high levels of tumor necrosis factora and interleukin-6 are associated with a decline in hand grip strength
and physical performance.
Diabetes mellitus is associated with a decline in muscle strength,
increased falls, and a decrease in function [57]. Diabetes is associated with
an increase in angiotensin II, which stimulates caspase 3 to produce cleavage



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of actomyosin to actin and myosin. In addition, insulin resistance leads to

fat inltration within muscle cells (myosteatosis). This phenomenon seems
to be associated with mitochondrial abnormalities [58]. Neuropathy leads
to decreased motor unit ring. Atherosclerosis results in a decline in blood
ow to muscle and, therefore, decreased muscle rejuvenation.
Sarcopenia represents a major cause of frailty and functional impairment.
Its causes are multifactorial. At present, the primary treatment is resistance
exercise. In hypogonadal men testosterone may play a role. Nandrolone, an
anabolic steroid, has been shown to produce positive eects in women [59].
The development of selective androgen receptor molecules represents an exciting research area for the future treatment of sarcopenia.
Weight loss and frailty
Most frail people have some degree of weight loss. This weight loss may
be not only because of sarcopenia but also secondary to cachexia, dehydration, or anorexia. A physiologic anorexia of aging places older people at
major risk for developing severe weight loss when they develop a disease
[60,61]. The most common disease leading to weight loss in older people
is depression [62,63]. Side eects of medication and therapeutic diets are
common iatrogenic causes of weight loss [64].
Cachexia occurs when there is an excess of cytokines and usually is
associated with major depletion of muscle and fat [65]. Cachexia commonly
is associated with diseases such as cancer, congestive heart failure, AIDS,
chronic obstructive pulmonary disease, chronic infections such as tuberculosis, and renal failure.
Weight loss is associated with hip fracture, increased disability, and death
[66,67]. Reversal of weight loss is associated with improved outcomes [68].
Disease and frailty
Numerous diseases lead to frailty. Diabetes mellitus is a particular example of this [69]. Diabetes leads to a decline in functional status to a greater
degree than other diseases [70,71]. Diabetes is associated with an increase in
injurious falls [70]. The reasons people who have diabetes are at increased
risk for frailty are multifactorial and include peripheral neuropathy, autonomic neuropathy leading to orthostasis and postprandial hypotension,
peripheral vascular disease, cognitive dysfunction, and a decreased pain
threshold [7276]. People who have diabetes mellitus also have an increased
rate of male hypogonadism [77].
Pain is a major precipitant of frailty. People who have pain have limitation of their activity. This limitation leads to muscle atrophy and eventually
decreased function [78].
Anemia represents another cause of frailty. People who have anemia have
increased syncope, disability, depression, cognitive dysfunction, and mortality



[79,80]. Modern treatment of anemia (caused by chronic disease and

chronic kidney failure) with erythropoietin or darbepoetin-alfa represents
a major advance in limiting the onset of frailty in older people.
Depression commonly is associated with frailty and functional deterioration [81,82]. Depression is often undertreated, especially in minority and
low-level socioeconomic populations [81]. Although a minority of people
who have cognitive dysfunction do not become frail, the majority eventually
develop functional decline often associated with weight loss [83,84]. Frail
people are particularly prone to develop delirium, which can lead to a cascade of increasing frailty.
Hip fracture is an important precipitant of frailty. Several studies have
shown that physicians often fail to treat osteoporosis [85].
Frailty is a common condition in older people. It now can be objectively dened by the Fried criteria [3]. When recognized, early intervention should begin with the institution of endurance, resistance, and balance exercises [86]. In
men with testosterone deciency a trial of testosterone replacement should be
considered [87]. Vitamin D deciency needs to be recognized and treated. Appropriate treatment of underlying diseases, such as anemia, diabetes mellitus,
and congestive heart failure, are a key management principle. In people who
have frailty aggressive health promotion and disease prevention techniques
can lead to an inhibition of the downward spiral to disability [88].
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