Risk Factors for Frailty in the Older Adult
-
Sara E. Espinoza, MD, and Linda P. Fried, MD, MPH
Accreditation
The Johns Hopkins University School of Medicine is
accredited by the Accreditation Council for Continuing
Medical Education to provide continuing medical education
for physicians.
The Johns Hopkins 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 1AMA 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
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 decline,
increased vulnerability to stressors, and increased risk for
adverse health outcomes. As the U.S. population of those
over age 65 continues to grow, recognition of frail older
adults is important so that targeted intervention and
prevention, medical care, and/or palliation, as appropriate,
can be implemented. This review focuses on specific factors
that may put older adults at risk for the development of
frailty, complementing a previous discussion of specific
interventions for frailty.1 By understanding and targeting
key risk factors for amelioration, it may be possible for
clinicians to improve 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
physical activity, inadequate nutrition and unintentional
weight loss, slowed performance, and decreased mobility25; some have also included cognitive or psychological
components, such as cognitive impairment 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 Cardiovascular Health Study (CHS).3
Building on a broad consensus that frailty is a “biologic
syndrome of decreased reserve and resistance to stressors,
resulting from cumulative declines across multiple systems,
causing vulnerability to adverse outcomes,”3 these
investigators proposed a standardized, phenotypic, clinical
presentation of frailty consistent with both
geriatricians’4,12,13 and patients’ recognition of markers.
Fried et al3 characterized frailty as the presence of three of
five central components: unintentional weight loss, slow
walking speed, self-reported exhaustion, low energy
expenditure, and weakness. They theorized that the
components of this phenotype were etiologically related to
each other in a “vicious” cycle of dysregulated energetics
that, when at least three were present, identified frailty
(Figure 1) and could be self-perpetuating.3,9,13 Those
identified as frail by these criteria were shown to be at
increased risk for falls, hospitalization, worsening mobility
and activities of daily living (ADLs) disability, and
death.3,11,14 Furthermore, these factors were additive in a
dose-response fashion, such that those individuals with one
or two of these factors (considered intermediate frail) were
at increased risk for the adverse health outcomes mentioned
when compared with those without any of these factors
(non-frail), but were at less risk than those with three or
more (frail).
This model has recently been cross-validated in a
longitudinal cohort of older women, the Women’s Health and
Aging Studies (WHAS), in which this definition of frailty
again strongly predicted ADLs and instrumental activities of
daily living (IADLs) disability, permanent nursing home
entry, and death.11 This study also showed that this frailty
model is consistent with being a medical syndrome, in which
no one of the five components carries more weight than the
others in terms of predicting these adverse outcomes. It has
been further cross-validated in a study by Woods et al,14
which found that baseline frailty status was, again, strongly
predictive of ADL disability, number of hospitalizations, hip
fracture, and death at 3 years in the Women’s Health
Initiative (WHI) Observational Study.
It is important to note that individuals who are classified as
frail may certainly have disability, multiple comorbid
illnesses, and advanced age, but frailty may be present in
the absence of these. These factors may predispose one to
the development of frailty. This review shall examine several
potential risk factors of frailty. Beyond that, Fried et al3
have hypothesized that the clinical presentation marks those
at risk of adverse outcomes because it results, itself, from
dysregulation of multiple physiologic systems, leading to
characteristic 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
review, 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 factors 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 categories of
potential risk factors: physiologic, medical
illness/comorbidity, sociodemographic and psychological,
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 characteristic changes in
physiology, including activated inflammation, decreased
immune function, anemia, endocrine system alterations, and
musculoskeletal alterations. Walston et al15 studied several
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 protein, 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
inflammation and are perhaps more prone to coagulation as
a result.
Altered immune function is also associated with frailty16;
this may potentially lead to activated inflammation.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 increased production of
interleukin-6, a marker of inflammation.
Other studies have found that frail individuals are more
likely to be anemic,18 potentially also resulting from
activated inflammation, and are more likely to have
endocrine system alterations, including decreased levels of
insulin-like growth factor-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 obesity.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 metabolic 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 insensitivity, 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 observations, the WHI study found that both
underweight 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 results from reaching a threshold of
decline resulting from an aggregate severity of dysregulation
in multiple systems.9,10 Aging itself could contribute to this
through many mechanisms, potentially including such
pathways as age-associated accumulation of oxidative stress
and associated cellular damage due to the generation of
oxygen-derived free radicals over time.10 Perhaps in
support of these age-related mechanisms, increased
chronological age has been associated with frailty crosssectionally, even after adjustment for medical
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
indicated a stepwise increase in prevalence with increasing
age over 90.3 These data may indicate that increased age is
a risk factor for frailty.
The physiologic alterations that have been associated with
frailty are complex, and there are likely interactions between
specific systems that increase the risk of frailty, such as
inflammation and endocrine dysregulation10 (Figure 21).
This is congruent with the hypothesis that frailty is a
physiologic syndrome of multisystem dysregulation and
decline, which leads to vulnerability to adverse health
outcomes and the clinically manifest syndrome itself.3,9,24
Although inadequate nutrition, increasing age, and
physiologic changes that occur with age may lead to
sarcopenia and resultant increased risk for frailty, there is
evidence that this is modifiable. An innovative and landmark
randomized, controlled trial by Fiatarone et al25 showed
that strength training increased lower-extremity strength,
gait velocity, and stair climbing power in frail older adult
residents of a nursing facility. Furthermore, their finding that
individuals randomized to strength training also had
improvements in mobility and spontaneous activity suggests
that increased muscle strength may break the cycle of frailty
by stimulating increased activity.
Medical Illness/Comorbidity
Frailty has been associated with selected diseases in crosssectional studies, and cardiovascular disease, in particular,
has been shown to be related to frailty crosssectionally18,26 and longitudinally.14 The frailty phenotype
has been associated with both clinically diagnosed
cardiovascular disease, with diastolic blood pressure, and
with selected noninvasive tests of cardiovascular function,
such as carotid wall thickness measured by ultrasound,
infarct-like lesions on brain magnetic resonance imaging
(MRI), abnormal left ventricular wall motion measured by
echocardiography, and major electrocardiogram
abnormalities.26
In addition to its findings that a prior diagnosis of
cardiovascular disease was independently associated with
baseline as well as incident frailty at 3 years, the WHI study
found that prior diagnosis of stroke, diabetes, hypertension,
arthritis, cancer, 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 accumulation of medical illnesses and
other deficits, such as geriatric syndromes, predispose to
adverse health outcomes with advancing age, and this
predisposing vulnerability is frailty.27,28 This is a different
formulation of frailty, which does not consider frailty as a
syndrome with distinct clinical presentation or etiologic
factors. In contrast, a prior survey of geriatricians led to the
combined perspective that, while comorbidity may certainly
predispose one to the development of frailty, it does not
appear to be synonymous with the distinct medical
syndrome of frailty.29
Central nervous system (CNS) function and cognitive
impairment have been hypothesized to be either
components of frailty or risk factors,5,6,10 but 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, inferentially, that CNS alterations present in frail
individuals could result from cerebrovascular disease.26
Newman et al26 found that, when compared to non-frail
persons, frail individuals had a higher prevalence of infarctlike lesions and white matter changes, as examined by
cerebral MRI. It is plausible that these changes are the
result of cerebrovascular disease secondary to upregulated
inflammation, 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
development 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-sectional studies.21,26 CHS
studies found that higher educational status and higher
income were associated 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 education are predictive of
frailty at 3-year follow-up, but this association is attenuated
(although it persists) after adjustment for BMI, ethnicity,
tobacco use, alcohol use, self-reported health, and comorbid
conditions, suggesting that differences in health status and
risk factors may explain at least part of the increased risk for
frailty.14 This may also 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 crosssectional analyses.3 The WHI study found a strong
prospective 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 depressive symptoms leads to
frailty is biologically plausible, given that individuals with
depression often lose weight, become less active, and can
therefore lose muscle mass, strength, and exercise
tolerance, 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, whether frailty is theorized to
be a distinct physiologically-based clinical syndrome or as
the aggregation 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 data
support the hypothesis that frailty may be a physiologic
precursor to disability.3 It is also possible that disability
itself, through secondary decreased physical activity, could
itself lead to frailty.
Conclusion
Frailty is a syndrome of physiologic vulnerability and
progressive decline that is likely multifactorial 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 identifying frail patients so that appropriate
intervention and medical care can be identified. Potential
interventions span a large range, from exercise intervention
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 exercise
tolerance, as well as comorbid illness and disability. In the
future, new research will provide insight 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):11051112.
2. Chin A Paw MJ, Dekker JM, Feskens EJ, et al. How to
select a frail elderly population? A comparison of three
working definitions. J Clin Epidemiol 1999;52(11):10151021.
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
trials 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
successful? 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
Environ 2005;2005(31):pe24. [Erratum in: Sci Aging
Knowledge 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
physiology 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 Geriatric Medicine and Gerontology. 5th ed. New York,
NY: McGraw Hill Publisher; 2003:1487-1502.
14. Woods NF, LaCroix AZ, Gray SL, et al; Women’s Health
Initiative. Frailty: Emergence and consequences in women
aged 65 and older in the Women's Health Initiative
Observational Study. J Am Geriatr Soc 2005;53(8):13211330.
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 communitydwelling 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 insulin-like growth factor-I (IGF-I) and
dehydroepiandrosterone sulfate (DHEA-S), and their
relationships with serum interleukin-6, in the geriatric
syndrome of frailty. Aging Clin Exp Res 2004;16(2):153157.
20. Roubenoff R. Sarcopenia: A major modifiable cause of
frailty in the elderly. J Nutr Health Aging 2000;4(3):140142.
21. Blaum CS, Xue QL, Michelon E, et al. The association
between 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 cutpoints associated with elevated physical disability
risk in older men and women. Am J Epidemiol
2004;159(4):413-421.
23. Roubenoff R. Sarcopenic obesity: The confluence of two
epidemics. 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):17691775.
26. Newman AB, Gottdiener JS, Mcburnie MA, et al;
Cardiovascular Health Study Research Group. Associations of
subclinical 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
Mexican Americans. J Am Geriatr Soc 2005;53(9):15241531.
31. Burke GL, Arnold AM, Bild DE, et al; CHS Collaborative
Research 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
neuropsychiatric syndromes in humans? Int J
Immunopharmacol 1995;17(8):677-683.
Clinical Geriatrics - ISSN: 1070-1389 - Volume 15 - Issue 6
- June 2007 - Pages: 37 - 44