The American Journal of Medicine (2007) 120, 748-753

REVIEW

Frailty: An Emerging Geriatric Syndrome

Nasiya Ahmed, MD,a,b Richard Mandel, MD,a Mindy J. Fain, MDa,b
a
Southern Arizona VA Health Care System, Tucson and bUniversity of Arizona, College of Medicine, Tucson

ABSTRACT

Frailty is a new and emerging syndrome in the field of geriatrics. The study of frailty may provide an
explanation for the downward spiral of many elderly patients after an acute illness and hospitalization. The
fact that frailty is not present in all elderly persons suggests that it is associated with aging but not an
inevitable process of aging and may be prevented or treated. The purpose of this article is to review what
is known about frailty, including the definition, epidemiology, and pathophysiology, and to examine
potential areas of future research. © 2007 Elsevier Inc. All rights reserved.

KEYWORDS: Aging; Frailty; Geriatrics

The relentless path to old age, frailty, and death has been a
hopeless enigma of medicine. In Ptolemy’s treatise, the last
age of life from 68 years to death was described as “dispir-
ited, weak, easily offended, and hard to please.” Aristotle
further explained this stage as a period when the body’s heat
dissipates and is no longer able to provide energy and
balance; the loss of inward heat depressed the spirit, caused
illness, and decreased strength, and eventually human be-
ings lost their passion for life and succumbed to death.1 In
1908, Eli Metchnikoff asked, “How can we transform to a
normal and physiological condition, old age, at present
utterly pathological, unless we first understand the most
intimate details of its mechanism?”2 This question is just
beginning to be answered almost a century later as geriatri-
cians struggle to define frailty. This article will review the
definition, epidemiology, pathophysiology, and treatment of
frailty, and examine potential areas of future research.
FRAILTY DEFINED
Frailty, a fairly common biological syndrome in the elderly,
is identified by decreased reserves in multiple organ sys-
tems. It may be initiated by disease, lack of activity, inad-
equate nutritional intake, stress, and/or the physiologic
changes of aging. Frailty develops slowly in a stepwise
Requests for reprints should be addressed to Mindy J. Fain, MD,
University of Arizona, College of Medicine, Section of Geriatrics and
Gerontology, PO Box 245069, Tucson, AZ 85724-5069.
E-mail address: mfain@aging.arizona.edu
process, with increments of decline precipitated by acute
events. It is manifested as loss of skeletal muscle mass
(sarcopenia), abnormal function in inflammatory and neu-
roendocrine systems, and poor energy regulation. In the frail
elderly, there is homeostenosis, or a decreased ability in the
body’s physiologic response to maintain homeostasis in
times of acute stress. In essence, frailty is a product of
“excess demand imposed upon reduced capacity.”3 Once
the elderly become frail, there is often a rapid, progressive,
and self-perpetuating downward spiral toward failure to
thrive and death.4
BACKGROUND
Contrary to popular belief, not all elderly are frail.5 Only
3% to 7% of elderly persons between the ages of 65 to 75
years are frail.6 The incidence of frailty increases with age,
reaching more than 32% in those aged more than 90 years.7
Furthermore, once a person is pre-frail, he or she is more
likely to progress to frailty, thus emphasizing the downward
spiral affect of this syndrome.8
Frailty can be a primary or secondary diagnosis. Notably,
7% of the frail elderly have no illness, and 25% have only
1 comorbid diagnosis.6 Researchers have demonstrated that
even when individuals with acute and chronic medical con-
ditions were excluded, 7% of the population aged more than
65 years and 20% of the population aged more than 80 years
were frail.5 On the other hand, frailty may occur as a result
of an acute event or the end stage of many chronic condi-
tions, including atherosclerosis, infection, malignancy, and

0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2006.10.018
Ahmed et al Frailty 749

depression.5 For example, severe congestive heart failure aged more than 85 years. The incidence of frailty increases
can lead to decreased activity, decreased nutritional intake, with age and will become more prevalent as our population
and increased inflammation and circulating cytokines. The continues to grow old.13 Studies show that 3% to 7% of
combination of these factors eventually leads to cardiac people aged more than 65 years are frail6; this percentage
cachexia and frailty. increases to 20% to 26% for elderly persons in their 80s5,6
The phenotypic picture of frailty and to 32% for those in their 90s.7
can be confused easily with disabil- The 4-year incidence of frailty in
ity; however, investigators have the elderly is 7%10; a similar study
CLINICAL SIGNIFICANCE
sought to differentiate them. Dis- in the Hispanic population showed
ability, defined as the inability to ● When compared with non-frail elderly, the 7-year incidence to be 7.9%.8
perform activities of daily living pre-frail elderly have an increased risk of In general, the elderly population
(ADL), instrumental activities of falls, institutionalization, and mortality has a greater percentage of fe-
daily living (IADL), or difficulty males and frailty is considerably
but not as high as the frail elderly.
with mobility, does not affect the higher in women.14 After adjust-
body across multiple organ sys- ● During the pre-frail stage, the frailty ment for age, race, sex, smoking,
tems.9 Among frail elderly persons, syndrome may be reversed. and comorbid illness, frail patients
only 60% have difficulty complet- have 1.2- to 2.5-fold increase in
ing IADL, and 27% cannot com- ● Multiple studies have shown the benefit their risk for falls, decreased mo-
plete ADL; furthermore, only 28% of exercise, stretching, resistance train- bility, worsening ADL, institution-
of disabled elderly persons are ing, and tai chi on frailty. Frailty markers alization, and death.10 A separate,
10
frail. Even when adjustments are have been shown to improve after 30 to cross-sectional observational study
made for disability and comorbid- 60 minutes of exercise, done 3 times a reported that frail patients had a sig-
ity, elderly persons with a diagnosis week. nificantly increased risk of cardio-
of frailty continue to have a higher vascular disease, hypertension, can-
mortality rate.11 Although disability ● By recognizing the frailty syndrome and cer, and death, even after adjusting
may contribute to frailty and vice suggesting lifestyle changes, physicians for chronic conditions.15 As the
versa, the 2 diagnoses are distinct may help patients prevent comorbidities elderly population continues to
from each other. later in life. grow, the impact of frailty will be
Frailty has been described as felt throughout families and per-
having a continuum. The initial vade our economic, health care,
stage of frailty, in which patients and social systems.
demonstrate fewer than 3 of the characteristics diagnostic of
frailty, is referred to as the pre-frail stage. Studies show that A WORKING DIAGNOSIS OF FRAILTY
pre-frail elderly persons are more likely than non-frail el-
The diagnosis of frailty has taken time to evolve. Initial studies
derly persons to develop the full syndrome.10 Pre-frail el-
showed a decrease in strength and balance to be predictors of
derly persons also have an increased risk of falls, institu-
frailty.16,17 However, in the elderly, multiple causes can lead to
tionalization, and mortality, but not as high as frail elderly
such a state, including immobility, decreased appetite, poor
persons.10 It is at the pre-frail stage that investigators be-
nutrition, and chronic illness. On this basis, a “cycle of frailty”
lieve the frailty syndrome may be reversed. The end stage of
6 was hypothesized. The Figure helps conceptualize this cycle
the frailty continuum is failure to thrive. Elderly patients,
and highlights the interdependence of various factors that may
with or without comorbidity, eventually reach an irrevers-
cause patients to enter this cycle. For example, poor dentition
ible stage of functional decline, progressive apathy, and
12 itself cannot cause frailty; however, it can lead to chronic
decreased appetite that ultimately ends in death.
undernutrition and eventually sarcopenia, thus placing the pa-
A more recent study expands on the concept of a con-
tient in the cycle of frailty. Poor dentition can also lead to
tinuum of frailty, defining it as both a static and dynamic
infection and periodontal disease, which may cause an increase
diagnosis. Dynamic frailty is defined as a decline in the
in inflammatory markers and cytokines, once again placing the
measurement of frailty markers over a 3-year period, with or
patient in this cycle.
without a diagnosis of frailty. Dynamic frailty, even when
More recently, Fried10 conducted a detailed study ana-
adjusted for age, education, disability, chronic disease, and
lyzing multiple demographic, medical, and laboratory mark-
static frailty markers, was still associated with an increased
11 ers to statistically determine a definition of frailty. A diag-
mortality; this increase was greater in women than in men.
nosis of frailty requires 3 of the following 5 characteristics
(Table):
SIGNIFICANCE ● Decreased walk time, as defined by a 15-foot walk test.
Why is frailty important? Currently 20% of the population ● Decreased grip strength, measured by a dynamometer.
of the United States are aged more than 65 years, and the ● Decreased physical activity, measured by the Minnesota
most rapidly growing segment of our population are those Leisure Time Activity Questionnaire.18
750 The American Journal of Medicine, Vol 120, No 9, September 2007

Figure The frailty cycle.

● Exhaustion, measured by the Center for Epidemiologic
Studies Depression Scale.
● More than 10 pounds or 5% of weight loss in the last
1 year.
This set of criteria indirectly measures the manifestations
of frailty, most important, sarcopenia as measured by grip
strength, malnutrition as measured by weight loss, and fa-
tigue as measured by the Center for Epidemiologic Studies
Depression Scale. Recently, these criteria were applied to
data from the Women’s Health and Aging Studies. By using
this definition, a similar incidence and prevalence of frailty
were observed; in addition, statistical correlations between
the incidence of frailty and the development of disability,
falls, institutionalizations, and mortality mirrored the results
found in Fried’s study.19 Although Fried’s definition of
frailty is most widely accepted and will be the definition
referenced in this article, other indices of frailty have also
been published.20-22
Not all that appears to be frailty is frailty. The differential
diagnosis of frailty includes congestive heart failure, poly-
myalgia rheumatica, Parkinson disease, rheumatoid arthri-
tis, occult malignancy, and infection. A new onset or an

Table Criteria Used to Define Frailty

One Must Have 3 of the Following 5 Criteria to Be Frail

Male Female
Weight Loss Greater than 10 lbs or 5% of weight loss in the last year
15-Foot Walk Time Height ⱕ173 cm ⱖ7 seconds Height ⱕ159 cm ⱖ7 seconds
Height ⬎173 cm ⱖ6 seconds Height ⬎159 cm ⱖ6 seconds
Grip Strength BMI ⱕ24 ⱕ29 BMI ⱕ23 ⱕ17
BMI 24.1-26 ⱕ30 BMI 23.1-26 ⱕ17.3
BMI 26.1-28 ⱕ30 BMI 26.1-29 ⱕ18
BMI ⬎28 ⱕ32 BMI ⬎29 ⱕ21
Physical Activity (MLTA) ⬍383 kcal/wk ⬍270 kcal/wk
Exhaustion A score of 2 or 3 on either question on the CES-D*
*How often in the last week did you feel this way?
(a) I felt that everything I did was an effort.
(b) I could not get going.
0 ⫽ 1 day; 1 ⫽ 1-2 days; 2 ⫽ 3-4 days; 3 ⫽ more than 4 days.
BMI ⫽ body mass index; MLTA ⫽ Minnesota Leisure Time Activity Questionnaire; CES-D ⫽ Center for Epidemiologic Studies Depression Scale.
Ahmed et al Frailty
exacerbation of any of these diseases could present as frailty;
however, all of these illnesses are treatable and should be
excluded before attributing a decline to frailty.6
Other Markers of Frailty
Although not part of the definition, other demographic
and neuroendocrine markers also have been associated
with frailty. Demographic markers include female sex,
African-American race, lower education level, lower in-
come, chronic illness, and disability.10,23 In the previous
study, chronic illnesses associated with frailty included car-
diovascular disease, pulmonary disease, arthritis, and dia-
betes; cancer was an exclusion criteria. Cognitive limita-
tions and depression were also more prevalent, despite the
exclusion of patients taking antidepressants or having a
mini-mental status examination score of less than 18.
Researchers also have evaluated the inflammatory and
neuroendocrine changes in frailty. Walston and others7
looked extensively at frailty markers in the Cardiovascular
Health Study Cohort. When excluding patients with diabe-
tes or cardiovascular disease, frail patients had an increased
C-reactive protein (CRP) and fibrinogen (odds ratio 2.0-
3.0). CRP has been shown to activate the inflammation and
clotting cascade, including d-dimer and factor VIII, both of
which are elevated in frail patients. CRP also causes an
increase in circulating interleukin-6; Leng and others24 con-
firmed that frail patients have higher levels of interleukin-6.
Glucose intolerance also was noted; both fasting/post-
prandial glucose and insulin levels were elevated in frail
patients (odds ratio 1.5-2.6).25 Glucose intolerance is often
associated with sarcopenia. In addition, recent research
shows that hyperinsulinemia and hypertriglyceridemia may
be associated with cognitive decline and leptin resistance,
resulting in appetite suppression and decreased nutritional
intake.
Serum levels of insulin-like growth factor-1 and dehy-
droepiandrosterone were significantly lower in frail patients
as well.26 Dehydroepiandrosterone, a weak androgenic ste-
roid that is a precursor of testosterone, plays a role in
maintaining muscle mass and suppressing inflammation.
Insulin-like growth factor-1 stimulates growth hormone
release that regulates cell growth and development, and is
often decreased in patients with diabetes or malnutrition.
No relationship between frailty and lipid profiles or
albumin has been seen.21 It is important to note that it
remains unknown whether the above neuroendocrine
changes cause frailty or whether the reverse is true.
Markers of Aging
Before the formulation of Fried’s definition, researchers
using various criteria for frailty noted other demographic
trends in patients who appeared to be frail. Not all of
these markers have been validated using Fried’s defini-
tion. One study linked frailty in men to depression, in-
activity, weight loss, decreased peak flow, and decreased
cognition. Furthermore, a decline in peak flow, cognition,
751
vision, and physical activity over a 3-year period was
linked to frailty in women.11 Other studies have found
incontinence, poor hearing, and a feeling of loss of con-
trol over one’s life to be associated with frailty.11 A study
based in China found that social factors, such as limited
contact with relatives, blue-collar occupations, and ab-
sence of religious or community activities, were more
likely to be seen in the frail elderly.27
Many gerontologic studies have shown inflammatory
and neuroendocrine markers linked to aging, but these ex-
periments have not been reproduced in the frail popula-
tion.28,29 In times of stress, cortisol secretion and pituitary
reactivity are increased in older adults.30 Although in-
creased levels of cortisol have not been directly linked to
frailty, this can lead to the frailty phenotype, including
increased risk of infection, sarcopenia, and insulin resis-
tance. Tumor necrosis factor-␣ has also been linked to aging
and sarcopenia; studies attempting to link this cytokine to
frailty are currently under way.31 More recently, leptin, a
hormone that controls appetite and body fat stores, and
ghrelin, a hormone that inhibits leptin, have been shown to
be links in the endotoxin-induced cachexia suspected in
frailty.32 A recent study, using an alternative definition of
frailty, showed that elderly persons had lower 25(OH)D
levels (odds ratio 2.6).33
Frailty and Its Causes
What causes frailty? Although many studies have shown
associations between the incidence of frailty and factors that
may lead to the condition, a definitive correlation has not
been established. It also remains unclear why factors trigger
frailty in some individuals but not in others. Experts spec-
ulate that certain environments, medications, age-related
changes, and diseases make a particular genotype of people
vulnerable to frailty.5,34
Data from the Women’s Health Initiative study showed
that obesity, anorexia, smoking, and depression may lead to
the development of frailty.35 Multiple aging studies showed
that cumulative predictors over 3 decades, including heavy
drinking, cigarette smoking, physical inactivity, depression,
social isolation, poor perceived health, and chronic ill-
nesses, led to increased morbidity in the elderly but not
necessarily frailty.36
At the cellular level, Bortz37 proposed a theory referred
to as “the physics of frailty,” which postulates that a loss of
functional competence at a cellular level, along with ther-
modynamic decline and a loss of energy stores, leads to
physiologic decline. Walston38 further adds that the cause of
frailty might be at the molecular level; mechanisms related
to aging, such as oxidative damage, telomere shortening,
gene expression changes, and cellular senescence, may con-
tribute to the dysregulated inflammatory and neuroendo-
crine signaling that leads to frailty. Genetic research also
has been done linking Apo E to frailty as well.39
752 The American Journal of Medicine, Vol 120, No 9, September 2007
CLINICAL RESEARCH
Research also has begun in the clinical realm. Although a
detailed discussion of clinical research is beyond the scope
of this article, a general overview is provided.
Atherosclerosis contributes to frailty by decreasing blood
flow and oxygenation to muscles, leading to sarcopenia. It
indirectly contributes to cognitive impairment, through
strokes, and to decreased physical activity in congestive
heart failure and myocardial infarction.31 The Cardiovascu-
lar Health Study showed that cardiovascular disease, most
notably heart failure (odds ratio 7.5), was associated with an
increased likelihood of frailty.40 In elderly patients with no
history of cardiovascular disease, subclinical cardiovascular
disease, measured by carotid ultrasound, ankle-brachial in-
dex, and left ventricular hypertrophy, was also linked to
frailty.40 Obesity also carries a high risk of frailty.41,42
Anemia is increased in frail patients; researchers have
noted a direct correlation between decreased hemoglobin
and increased frailty.24,43 Furthermore, anemia in the frail
population has been linked to elevation of interleukin-6.44
Patients with chronic renal insufficiency, after adjustment
for other comorbidities, also have a higher risk of frailty.45
Research also has shown that frailty and concurrent in-
flammation affect the treatment of infectious diseases.46
Chronic cytomegalovirus infection has been associated with
frailty, but further studies are needed to establish a causal
relationship.47 Frailty is more often seen in both depressed
and cognitively impaired patients.48,49 Increased inflamma-
tion, but not necessarily frailty, has been shown to prevent
wound healing as well.
Treatment
There is limited treatment available for frailty. The goal of
initial treatment is the optimal management of all medical
illnesses that may cause frailty. The second step is to prevent
sarcopenia through muscle-strengthening exercises.50,51 Mul-
tiple studies have shown the benefit of exercise, stretching,
resistance training, and tai chi on frailty. Frailty markers have
been shown to improve after 30 to 60 minutes of exercise,
done 3 times per week, for 3 to 6 months. Exercise also has
been shown to decrease the level of inflammatory markers.
However, studies have not been done to show improvement
in mortality with exercise; it is known, however, that exer-
cise does not improve morbidity or mortality in the general
elderly population.
Nutritional research conducted on the elderly population
may shed some light on possible treatments for frailty. It has
been found that increased caloric intake has little benefit in
improving health status in the elderly; however, there does
seem to be some benefits gained from a nutritional program
when combined with an exercise program to increase ex-
penditures by 1000 kcal/week.6 The appetite stimulants
megestrol acetate and dronabinol have been of minimal
benefit in improving appetite in geriatric nursing home
patients; moreover, these drugs are associated with signifi-
cant adverse effects.12
It has been noted that as people age, levels of testoster-
one and DHEA, 2 hormones that have been shown to main-
tain muscle strength, decrease. However, investigators have
been unable to demonstrate any benefit from hormone re-
placement.25 Growth hormone replacement also has failed
to produce any positive effects in frail elderly persons,
although short-term treatment has improved malnutrition
and functional status.25 Last, a study done on frail elderly
persons showed that a positive attitude prevented both the
physical and mental decline of frailty.52
CONCLUSION
An understanding of what Eli Metchnikoff once referred to
as the “intimate details” of the mechanisms behind an “ut-
terly pathological” old age has just begun. It is now known
that old age is not synonymous with the frailty syndrome.
Still, frailty has only recently been defined, and frailty
research is in its early stages. Acceptance of a formalized set
of criteria for the diagnosis of frailty will facilitate studies.
Potential areas of investigation include the underlying
pathophysiology of primary frailty and the contributions of
other comorbid diagnoses to the clinical picture. Further
investigation may illuminate its symptoms and impact on
the body’s various organ systems, and how best to treat
those who are frail. By identifying the risk factors for
frailty, a window of prevention before the development of
frailty may be found. Last, the effect of frailty on other
organ systems may be elucidated.53 Successful investiga-
tions may lead to pharmacologic or other treatment modal-
ities to address the needs of frail and pre-frail patients, and
prevent both the development and the effects of this geri-
atric syndrome.
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