See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/252764592

Risk Factors for Frailty in the Older Adult

Article  in  Clinical Geriatrics · June 2007

CITATIONS READS
37 2,372

2 authors:

Sara E Espinoza Linda P Fried

University of Texas Health Science Center at San Antonio Columbia University
30 PUBLICATIONS   637 CITATIONS    597 PUBLICATIONS   58,436 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Immunologic changes in frail older adults View project

Schools of public health View project

All content following this page was uploaded by Sara E Espinoza on 06 March 2015.

The user has requested enhancement of the downloaded file.

CME_Fried.qxd 6/6/07 3:27 PM Page 37
GERIATRIC SYNDROMES
CME ARTICLE
Risk Factors for Frailty
in the Older Adult
Sara E. Espinoza, MD, and Linda P. Fried, MD, MPH
Dr. Espinoza is Assistant Professor of
Medicine, Division of Geriatrics and
Gerontology, The Sam and Ann
Barshop Institute for Longevity and Ag-
ing Studies, The University of Texas
Health Sciences Center at San Antonio,
and Geriatric Research Education and
Clinical Center, South Texas Veterans
Health Care System, San Antonio, TX.
Dr. Fried is Professor of Medicine, Epi-
demiology, Health Policy and Nursing,
Director of the Division of Geriatric
Medicine and Gerontology, Johns Hop-
kins University School of Medicine, and
Director of the Center on Aging and
Health, Baltimore, MD.
ACCREDITATION
The Johns Hopkins University School of Medi-
cine is accredited by the Accreditation Council
for Continuing Medical Education to provide
continuing medical education for physicians.
The Johns Hopkins University School of Medicine
takes responsibility for the content, quality, and
scientific integrity of this CME activity.
CREDIT DESIGNATION STATEMENT
The Johns Hopkins University School of Medicine
designates this educational activity for a maximum
of 1 AMA PRA Category 1 Credit™. Physicians
should only claim credit commensurate with the
extent of their participation in the activity.
Release Date: July 1, 2007
Expiration Date: September 30, 2007
Estimated Time to Complete: 1 hour
Clinical Geriatrics Volume 15, Number 6
At the conclusion of this activity, participants should be able to:
1. Describe the conceptualization that frailty represents a geriatric syndrome
associated with increased risk for adverse health outcomes.
2. Identify the physical characteristics of frailty.
3. Identify possible risk factors associated with frailty.
4. Discuss the current field of frailty research.
INTRODUCTION
Geriatricians and physicians caring for older adults recognize frailty in
older patients. There is now increasing evidence that such frailty is a
geriatric syndrome characterized by a clinical presentation of a critical
mass of identifiable components, thus syndromic, with progressive de-
cline, increased vulnerability to stressors, and increased risk for adverse
health outcomes. As the U.S. population of those over age 65 contin-
ues to grow, recognition of frail older adults is important so that tar-
geted intervention and prevention, medical care, and/or palliation, as
appropriate, can be implemented. This review focuses on specific fac-
FULL DISCLOSURE POLICY AFFECTING CME ACTIVITIES
As a provider accredited by the Accreditation Council for Continuing Medical Education (AC-
CME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure
of the existence of any significant financial interest or any other relationship a faculty member
or provider has with the manufacturer(s) of any commercial product(s) discussed in an educa-
tional presentation. The authors report no relevant financial relationships.
No faculty member has indicated that the presentation will include information on off-label
products.
DISCLAIMER STATEMENT
The opinions and recommendations expressed by faculty and other experts whose input
is included in this program are their own. This enduring material is produced for education-
al purposes only. Use of Johns Hopkins University School of Medicine name implies re-
view of educational format design and approach. Please review the complete prescribing
information of specific drugs or combination of drugs, including indications, contraindica-
tions, warnings and adverse effects before administering pharmacologic therapy to patients.
June 2007
37
CME_Fried.qxd 6/6/07 3:27 PM Page 38

RISK FACTORS FOR FRAILTY

tors that may put older adults at risk for the devel-
opment of frailty, complementing a previous dis-
cussion of specific interventions for frailty.1 By un-
derstanding and targeting key risk factors for
amelioration, it may be possible for clinicians to im-
prove the overall health of older patients.
FRAILTY DEFINITIONS
Most definitions of frailty describe a syndrome of
loss of muscle mass and strength, energy and exercise
tolerance, and decreased physiologic reserve with
associated increased vulnerability to physiologic
stressors, such as acute illness, hospitalization, or
extreme heat or cold. Most of these definitions
include measures of strength, low energy, low phys-
ical activity, inadequate nutrition and unintentional
weight loss, slowed performance, and decreased
Disease
Environment
Medications Chronic
undernutrition
Cycle of frailty
➞
mobility2-5; some have also included cognitive or
psychological components, such as cognitive impair-
ment and depression.6,7
Although frailty research is still in its infancy and
there is no one universally accepted gold-standard
definition,8-11 one of the most validated models of
frailty is one that was operationalized in the Car-
diovascular Health Study (CHS).3 Building on a
broad consensus that frailty is a “biologic syndrome
of decreased reserve and resistance to stressors, re-
sulting from cumulative declines across multiple sys-
tems, causing vulnerability to adverse outcomes,”3
these investigators proposed a standardized, phe-
notypic, clinical presentation of frailty consistent
with both geriatricians’4,12,13 and patients’ recog-
nition of markers. Fried et al3 characterized frailty
as the presence of three of five central components:
unintentional weight
loss, slow walking speed,
Disease
self-reported exhaustion,
Medications
Aging-related
low energy expenditure,
changes
and weakness. They the-
orized that the compo-

Total energy expenditure

Sarcopenia
nents of this phenotype
were etiologically related
➞

Insulin sensitivity

Resting Osteopenia
to each other in a “vi-
➞

cious” cycle of dysregu-

➞

Activity metabolic
rate

lated energetics that,

➞

Walking
speed
➞

Strength VO max
➞

2
and power when at least three were
Disability Immobilization Impaired balance
present, identified frailty
(Figure 1) and could be
Dependency
Falls and
injuries self-perpetuating. 3,9,13
Those identified as frail
Figure 1. Cycle of frailty.3,9,13 by these criteria were
shown to be at increased
Fried LP, Walston J. Frailty and failure to thrive. In: Hazzard WR, Blass JP, Ettinger WH Jr, et al, eds. Prin- risk for falls, hospitaliza-
ciples of Geriatric Medicine and Gerontology. 5th edition. New York, NY: The McGraw-Hill Companies;
2003;1487-1502. Adapted with permission of The McGraw-Hill Companies. Copyright © 2003.
tion, worsening mobili-
ty and activities of daily

Clinical Geriatrics Volume 15, Number 6 June 2007

38
CME_Fried.qxd 6/6/07 3:27 PM Page 39

RISK FACTORS FOR FRAILTY

living (ADLs) disability, and death.3,11,14 Further- in which no one of the five components carries more
more, these factors were additive in a dose-response weight than the others in terms of predicting these
fashion, such that those individuals with one or two adverse outcomes. It has been further cross-validat-
of these factors (considered intermediate frail) were ed in a study by Woods et al,14 which found that
at increased risk for the adverse health outcomes baseline frailty status was, again, strongly predic-
mentioned when compared with those without any tive of ADL disability, number of hospitalizations,
hip fracture, and death at 3 years in the Women’s
of these factors (non-frail), but were at less risk than
those with three or more (frail). Health Initiative (WHI) Observational Study.
This model has recently been cross-validated in It is important to note that individuals who are
a longitudinal cohort of older women, the Women’s classified as frail may certainly have disability, mul-
Health and Aging Studies (WHAS), in which this tiple comorbid illnesses, and advanced age, but
definition of frailty again strongly predicted ADLs frailty may be present in the absence of these.
and instrumental activities of daily living (IADLs) These factors may predispose one to the develop-
disability, permanent nursing home entry, and ment of frailty. This review shall examine several
death.11 This study also showed that this frailty potential risk factors of frailty. Beyond that, Fried
model is consistent with being a medical syndrome, et al3 have hypothesized that the clinical presen-
tation marks those at risk of adverse
outcomes because it results, itself,
Possible Risk Factors for Frailty
TA B L E

and Summary of Supporting References from dysregulation of multiple phys-

I. Physiologic
A. Activated inflammation15
B. Immune system dysfunction16,17
C. Anemia18
D. Endocrine system alteration19
E. Underweight or overweight14,15,21
F. Age14
II. Medical Illness/Comorbidity
A. Cardiovascular disease14,18,26
B. Diabetes14
C. Stroke14
D. Arthritis14
E. Chronic obstructive pulmonary disease14
F. Cognitive impairment/cerebral changes6,26
III. Sociodemographic and Psychological
A. Female gender3,14,30
B. Low socioeconomic status21,26
C. Race/ethnicity3,14,30
D. Depression3,14
IV. Disability
A. Activity of daily living disability3,14
iologic systems, leading to character-
istic clinical manifestations as well as
attendant vulnerability.
RISK FACTORS FOR FRAILTY
In order to identify risk factors for a
specific illness or syndrome (in the
case of frailty), observational studies,
especially prospective ones, provide
essential insight. Frailty research is an
emerging field, and much of what we
know about potential risk factors for
this syndrome must be obtained from
cross-sectional observational studies.
In this article, we will review the
findings from the study by Woods et
al14 described above, the largest and
most comprehensive study to date
that has examined potential risk fac-

Clinical Geriatrics Volume 15, Number 6 June 2007

39
CME_Fried.qxd 6/6/07 3:27 PM Page 40
RISK FACTORS FOR FRAILTY
tors for frailty in a prospective fashion, as well as
from other cross-sectional studies on potential risk
factors for frailty. This review is organized into cate-
gories of potential risk factors: physiologic, medical
illness/comorbidity, sociodemographic and psycho-
logical, and disability (Table).
Physiologic Factors
A number of physiologic alterations have been
associated with frailty. Continuing research suggests
that frailty is a distinct physiologic entity with char-
acteristic changes in physiology, including activat-
ed inflammation, decreased immune function,
anemia, endocrine system alterations, and muscu-
loskeletal alterations. Walston et al15 studied sever-
al markers of inflammation in the CHS in relation
to frail and non-frail status, and found that those
subjects classified as frail by the criteria described
above had increased mean levels of C-reactive pro-
tein, a reliable marker of inflammation, as well as
increased markers of coagulation, including factor
VIII and D-dimer. These findings suggest that frail
individuals are in a chronic state of upregulated in-
flammation and are perhaps more prone to coagu-
lation as a result.
Altered immune function is also associated with
frailty16; this may potentially lead to activated in-
flammation.17 Specifically, Leng et al17 found that
frail individuals, when compared with non-frail
controls, have decreased ability to proliferate their
peripheral blood mononuclear cells (PBMCs) when
stimulated with the endotoxin lipopolysaccharide,
as would occur with some acute bacterial infections,
and that the PBMCs of frail individuals have in-
creased production of interleukin-6, a marker of
inflammation.
Other studies have found that frail individuals
are more likely to be anemic,18 potentially also re-
Clinical Geriatrics Volume 15, Number 6
40
sulting from activated inflammation, and are
more likely to have endocrine system alterations,
including decreased levels of insulin-like growth fac-
tor-I (IGF-I) and dehydroepiandrosterone sulfate
(DHEAS).19 A decrease in both of these hormones
is associated with decreased lean muscle mass, or
sarcopenia, which has been hypothesized to be a
central component of frailty.9,20
Although weight loss is one of the components
of the frailty model proposed by Fried et al3 and
inadequate nutrition is commonly recognized
clinically as a marker of frailty, subjects in the
CHS categorized as frail included both a subset
who were underweight and a subset with higher
body mass index (BMI) consistent with obesi-
ty.15,21 This information suggests that decreased
lean body mass can predispose individuals to the
development of frailty even in the presence of
obesity. In fact, sarcopenic obesity is a term that
has been used to describe this mismatch between
lean muscle mass and fat and resulting metabol-
ic derangement. Research in this area shows that
it is a physiologic state with adverse consequences
such as physical disability, including disability in
ADLs.22 Obesity itself is thought to contribute
to altered glucose metabolism and insulin insen-
sitivity, as well as activation of inflammation,23
which are physiologic alterations that have been
associated with the development of sarcopenia and
the frailty syndrome.15 Consistent with these ob-
servations, the WHI study found that both un-
derweight and overweight women had increased
risk for the development of frailty, suggesting a
U-shaped relationship between BMI and frailty.14
The aging process itself has been characterized
by a decline in normally functioning physiologic
systems and loss of redundancy in normal feedback
mechanisms; it has been hypothesized that frailty
June 2007
CME_Fried.qxd 6/6/07 3:27 PM Page 41
RISK FACTORS FOR FRAILTY
results from reaching a threshold of decline result-
ing from an aggregate severity of dysregulation in
multiple systems.9,10 Aging itself could con-
tribute to this through many mechanisms, poten-
tially including such pathways as age-associated ac-
cumulation of oxidative stress and associated
cellular damage due to the generation of oxygen-
derived free radicals over time.10 Perhaps in sup-
port of these age-related mechanisms, increased
chronological age has been associated with frailty
cross-sectionally, even after adjustment for med-
ical comorbidities.21 The WHI frailty study found
that individuals age 70-79 years at the time of
screening were at increased risk for becoming frail
at 3-year follow-up when compared to those age
60-69 years14; similarly, the CHS evaluation in-
dicated a stepwise increase in prevalence with in-
creasing age over 90.3 These data may indicate that
increased age is a risk factor for frailty.
The physiologic alterations that have been asso-
ciated with frailty are complex, and there are like-
Figure 2. Physiology of frailty.
DHEAS = dehydroepiandrosterone sulfate; IGF-I = insulin-like growth factor-I; IL-6 = interleukin-6; CRP = C-reactive protein.
Espinoza S, Walston JD. Frailty in older adults: Insights and interventions. Cleve Clin J Med 2005;72(12):1105-1112. Adapted with
permission. Copyright © 2005. Cleveland Clinic Foundation. All rights reserved.
Clinical Geriatrics Volume 15, Number 6
41
ly interactions between specific systems that increase
the risk of frailty, such as inflammation and en-
docrine dysregulation10 (Figure 21). This is congru-
ent with the hypothesis that frailty is a physiolog-
ic syndrome of multisystem dysregulation and
decline, which leads to vulnerability to adverse
health outcomes and the clinically manifest syn-
drome itself.3,9,24 Although inadequate nutrition,
increasing age, and physiologic changes that occur
with age may lead to sarcopenia and resultant in-
creased risk for frailty, there is evidence that this is
modifiable. An innovative and landmark random-
ized, controlled trial by Fiatarone et al25 showed that
strength training increased lower-extremity strength,
gait velocity, and stair climbing power in frail old-
er adult residents of a nursing facility. Furthermore,
their finding that individuals randomized to
strength training also had improvements in mobil-
ity and spontaneous activity suggests that increased
muscle strength may break the cycle of frailty by
stimulating increased activity.
June 2007
CME_Fried.qxd 6/6/07 3:27 PM Page 42
RISK FACTORS FOR FRAILTY
Medical Illness/Comorbidity
Frailty has been associated with selected diseases
in cross-sectional studies, and cardiovascular disease,
in particular, has been shown to be related to frailty
cross-sectionally18,26 and longitudinally.14 The
frailty phenotype has been associated with both clin-
ically diagnosed cardiovascular disease, with dias-
tolic blood pressure, and with selected noninvasive
tests of cardiovascular function, such as carotid wall
thickness measured by ultrasound, infarct-like le-
sions on brain magnetic resonance imaging (MRI),
abnormal left ventricular wall motion measured by
echocardiography, and major electrocardiogram ab-
normalities.26
In addition to its findings that a prior diagno-
sis of cardiovascular disease was independently as-
sociated with baseline as well as incident frailty at
3 years, the WHI study found that prior diagno-
sis of stroke, diabetes, hypertension, arthritis, can-
cer, and chronic obstructive pulmonary disease were
predictive of incident frailty.14 Thus, specific
chronic diseases are risk factors for frailty. In fact,
some conceptions of frailty posit that the accumu-
lation of medical illnesses and other deficits, such
as geriatric syndromes, predispose to adverse
health outcomes with advancing age, and this pre-
disposing vulnerability is frailty.27,28 This is a dif-
ferent formulation of frailty, which does not con-
sider frailty as a syndrome with distinct clinical
presentation or etiologic factors. In contrast, a pri-
or survey of geriatricians led to the combined per-
spective that, while comorbidity may certainly pre-
dispose one to the development of frailty, it does
not appear to be synonymous with the distinct med-
ical syndrome of frailty.29
Central nervous system (CNS) function and cog-
nitive impairment have been hypothesized to be ei-
ther components of frailty or risk factors,5,6,10 but
Clinical Geriatrics Volume 15, Number 6
42
this has not been extensively studied. It is thought
that cognitive impairment could directly contribute
to the development of frailty as a result of decreased
food intake,6 which could then lead to weight loss
and sarcopenia, providing a means of entry into the
cycle of frailty.3 However, one study suggests, in-
ferentially, that CNS alterations present in frail in-
dividuals could result from cerebrovascular dis-
ease.26 Newman et al26 found that, when compared
to non-frail persons, frail individuals had a higher
prevalence of infarct-like lesions and white matter
changes, as examined by cerebral MRI. It is plau-
sible that these changes are the result of cerebrovas-
cular disease secondary to upregulated inflamma-
tion, either resulting from frailty or contributing
to frailty15; however, further studies are needed in
order to better characterize these relationships.
Sociodemographic and
Psychological Factors
Female gender has been associated with frailty,
as women have been more likely than men to be
characterized as frail in several studies.3,14,30 This
finding may be related to sarcopenia, with women
having less muscle mass than age-matched men,
which may confer an intrinsic risk for the devel-
opment of frailty.3
Lower socioeconomic status (SES), as measured
by low education and/or low annual income, has
been associated with frailty in several cross-section-
al studies.21,26 CHS studies found that higher ed-
ucational status and higher income were associat-
ed with disease-free survival at 3-6 years31 and with
lower mortality.32 It is likely that high SES does not
intrinsically confer less risk for frailty, but that this
relationship between SES and frailty is modified by
lifestyle factors that are likely to co-exist with low
SES. For example, it appears that low income and
June 2007
CME_Fried.qxd 6/6/07 3:27 PM Page 43
RISK FACTORS FOR FRAILTY
education are predictive of frailty at 3-year follow-
up, but this association is attenuated (although it
persists) after adjustment for BMI, ethnicity, tobac-
co use, alcohol use, self-reported health, and comor-
bid conditions, suggesting that differences in
health status and risk factors may explain at least
part of the increased risk for frailty.14 This may al-
so be operant in the case of race and ethnicity, as
several studies have shown a higher prevalence of
frailty in non-white individuals.3,14,26
While the contribution of psychologic factors has
not been extensively studied in relation to frailty
in older adults, psychological well-being has long
been associated with the idea of “successful aging,”33
and depressive symptoms have been shown to be
associated with the syndrome in cross-sectional
analyses.3 The WHI study found a strong prospec-
tive relationship between depressive symptoms
and the onset of frailty, suggesting that depression
may contribute to the etiology of frailty.14 The
hypothesis that depression or the presence of de-
pressive symptoms leads to frailty is biologically
plausible, given that individuals with depression of-
ten lose weight, become less active, and can there-
fore lose muscle mass, strength, and exercise toler-
ance, and may be more prone to acute illness. All
of these may, additionally, be related to an increase
in circulating inflammatory cytokines.34
Self-reported health has also been associated with
frailty. The WHI study found that the likelihood
of being frail increased in a step-wise fashion as self-
reported general health went from very good, good,
to fair/poor.14
Disability
The overlap of frailty with disability is similar
to its overlap with comorbidity.29 While it is clear
that many individuals who are frail are also disabled,
Clinical Geriatrics Volume 15, Number 6
43
whether frailty is theorized to be a distinct physi-
ologically-based clinical syndrome or as the aggre-
gation of comorbidities, it is not synonymous with
disability, which is the difficulty or dependency in
tasks of daily life. Consistent with this, only 27%
of individuals in the CHS who were disabled in
ADL tasks were also characterized as frail.3 Rather,
frailty is predictive of disability, as baseline frailty
was strongly associated with ADL disability at 3-
year follow-up in the WHI study,14 in the CHS
study,3 and in the WHAS study.11 Each of these
studies concluded that the frailty phenotype3 was
able to identify a group of older adults who were
at substantially increased risk for adverse health
events, death, and future ADL disability. These da-
ta support the hypothesis that frailty may be a phys-
iologic precursor to disability.3 It is also possible that
disability itself, through secondary decreased phys-
ical activity, could itself lead to frailty.
CONCLUSION
Frailty is a syndrome of physiologic vulnerability
and progressive decline that is likely multifactori-
al in etiology. The potential risk factors presented
in this review are meant to give an overview of the
state of frailty research and to aid clinicians in iden-
tifying frail patients so that appropriate interven-
tion and medical care can be identified. Potential
interventions span a large range, from exercise in-
tervention to specific geriatric assessment models
to end-of-life care for those with end-stage frailty,
and have been discussed in further detail elsewhere.
While some of the potential risk factors discussed
here, such as race and SES, may not be modifiable,
it may be possible to modify some of the factors
associated with frailty, including strength and ex-
ercise tolerance, as well as comorbid illness and dis-
ability. In the future, new research will provide in-
June 2007
CME_Fried.qxd 6/6/07 3:27 PM Page 44
RISK FACTORS FOR FRAILTY
sight into the utility of pharmacologic approaches
to addressing physiologic risk factors.
The research reported in this article is supported by
the National Institute on Aging T32AG000120.
Dr. Fried is a Cosner Scholar. Support comes through
the Johns Hopkins Center for Innovative Medicine.
REFERENCES
1. Espinoza S, Walston JD. Frailty in older adults: Insights and
interventions. Cleve Clin J Med 2005;72(12):1105-1112.
2. Chin A Paw MJ, Dekker JM, Feskens EJ, et al. How to select a
frail elderly population? A comparison of three working defi-
nitions. J Clin Epidemiol 1999;52(11):1015-1021.
3. Fried LP, Tangen CM, Walston J, et al; Cardiovascular Health
Study Collaborative Research Group. Frailty in older adults:
Evidence for a phenotype. J Gerontol A Biol Sci Med Sci
2001;56(3):M146-M156.
4. Ferrucci L, Guralnik JM, Studenski S, et al; Interventions on
Frailty Working Group. Designing randomized, controlled tri-
als aimed at preventing or delaying functional decline and
disability in frail, older persons: A consensus report. J Am
Geriatr Soc 2004;52(4):625-634.
5. Studenski S, Hayes RP, Leibowitz RQ, et al. Clinical Global
Impression of Change in Physical Frailty: Development of a
measure based on clinical judgment. J Am Geriatr Soc
2004;52(9):1560-1566.
6. Morley JE, Perry HM 3rd, Miller DK. Editorial: Something
about frailty. J Gerontol A-Biol Sci Med Sci
2002;57(11):M698-M704.
7. Rockwood K, Stadnyk K, MacKnight C, et al. A brief clinical
instrument to classify frailty in elderly people. Lancet
1999;353(9148):205-206.
8. Rockwood K. What would make a definition of frailty suc-
cessful? Age Ageing 2005;34(5):432-434.
9. Fried LP, Hadley EC, Walston JD, et al. From bedside to
bench: Research agenda for frailty. Sci Aging Knowledge En-
viron 2005;2005(31):pe24. [Erratum in: Sci Aging Knowl-
edge Environ 2005;2005(41):er24.]
10. Walston J, Hadley EC, Ferrucci L, et al. Research agenda for
frailty in older adults: Toward a better understanding of phys-
iology and etiology: Summary from the American Geriatrics
Society/National Institute on Aging Research Conference on
Frailty in Older Adults. J Am Geriatr Soc 2006;54(6):991-
1001.
11. Bandeen-Roche K, Xue QL, Ferrucci L, et al. Phenotype of
frailty: Characterization in the women's health and aging
studies. J Gerontol A Biol Sci Med Sci 2006;61(3):262-266.
12. Studenski S, Hayes RP, Leibowitz RQ, et al. Clinical Global
Impression of Change in Physical Frailty: Development of a
measure based on clinical judgment. J Am Geriatr Soc
2004;52(9):1560-1566.
13. Fried LP, Walston J. Frailty and failure to thrive. In: Hazzard
WR, Blass JP, Ettinger WH Jr, et al, eds. Principles of Geri-
atric Medicine and Gerontology. 5th edition. New York, NY:
The McGraw-Hill Companies; 2003;1487-1502.
14. Woods NF, LaCroix AZ, Gray SL, et al; Women’s Health Ini-
tiative. Frailty: Emergence and consequences in women aged
65 and older in the Women's Health Initiative Observational
Clinical Geriatrics Volume 15, Number 6
44
View publication stats
Study. J Am Geriatr Soc 2005;53(8):1321-1330.
15. Walston J, McBurnie MA, Newman A, et al; Cardiovascular
Health Study. Frailty and activation of the inflammation and
coagulation systems with and without clinical comorbidities:
Results from the Cardiovascular Health Study. Arch Intern
Med 2002;162(20):2333-2341.
16. Semba RD, Margolick JB, Leng S, et al. T cell subsets and
mortality in older community-dwelling women. Exp Gerontol
2005;40(1-2):81-87.
17. Leng SX, Yang H, Walston JD. Decreased cell proliferation
and altered cytokine production in frail older adults. Aging
Clin Exp Res 2004;16(3):249-252.
18. Chaves PH, Semba RD, Leng SX, et al. Impact of anemia and
cardiovascular disease on frailty status of community-dwelling
older women: The Women's Health and Aging Studies I and
II. J Gerontol A Biol Sci Med Sci 2005;60(6):729-735.
19. Leng SX, Cappola AR, Andersen RE, et al. Serum levels of in-
sulin-like growth factor-I (IGF-I) and dehydroepiandrosterone
sulfate (DHEA-S), and their relationships with serum inter-
leukin-6, in the geriatric syndrome of frailty. Aging Clin Exp
Res 2004;16(2):153-157.
20. Roubenoff R. Sarcopenia: A major modifiable cause of frailty
in the elderly. J Nutr Health Aging 2000;4(3):140-142.
21. Blaum CS, Xue QL, Michelon E, et al. The association be-
tween obesity and the frailty syndrome in older women: The
Women's Health and Aging Studies. J Am Geriatr Soc
2005;53(6):927-934.
22. Janssen I, Baumgartner RN, Ross R, et al. Skeletal muscle cut-
points associated with elevated physical disability risk in old-
er men and women. Am J Epidemiol 2004;159(4):413-421.
23. Roubenoff R. Sarcopenic obesity: The confluence of two epi-
demics. Obes Res 2004;12(6):887-888.
24. Walston J. Frailty--the search for underlying causes. Sci Aging
Knowledge Environ 2004;2004(4):pe4.
25. Fiatarone MA, O'Neill EF, Ryan ND, et al. Exercise training
and nutritional supplementation for physical frailty in very
elderly people. N Engl J Med 1994;330(25):1769-1775.
26. Newman AB, Gottdiener JS, Mcburnie MA, et al; Cardiovas-
cular Health Study Research Group. Associations of subclini-
cal cardiovascular disease with frailty. J Gerontol A Biol Sci
Med Sci 2001;56(3):M158-M166.
27. Mitnitski A, Song X, Skoog I, et al. Relative fitness and frailty
of elderly men and women in developed countries and their
relationship with mortality. J Am Geriatr Soc
2005;53(12):2184-2189.
28. Rockwood K, Song X, MacKnight C, et al. A global clinical
measure of fitness and frailty in elderly people. CMAJ
2005;173(5):489-495.
29. Fried LP, Ferrucci L, Darer J, et al. Untangling the concepts of
disability, frailty, and comorbidity: Implications for improved
targeting and care. J Gerontol A Biol Sci Med Sci
2004;59(3):255-263.
30. Ottenbacher KJ, Ostir GV, Peek MK, et al. Frailty in older Mexi-
can Americans. J Am Geriatr Soc 2005;53(9):1524-1531.
31. Burke GL, Arnold AM, Bild DE, et al; CHS Collaborative Re-
search Group. Factors associated with healthy aging: The
Cardiovascular Health Study. J Am Geriatr Soc
2001;49(3):254-262.
32. Fried LP, Kronmal RA, Newman AB, et al. Risk factors for 5-
year mortality in older adults: The Cardiovascular Health
Study. JAMA 1998;279(8):585-592.
33. Rowe JW, Kahn RL. Human aging: Usual and successful.
Science 1987;237(4811):143-149.
34. Hickie I, Lloyd A. Are cytokines associated with neuropsychi-
atric syndromes in humans? Int J Immunopharmacol
1995;17(8):677-683.
June 2007