Article

Biological Research for Nursing

1-27
Biological Processes and Biomarkers ª The Author(s) 2018
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Related to Frailty in Older Adults: DOI: 10.1177/1099800418798047
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A State-of-the-Science Literature Review

Jinjiao Wang, PhD, RN1, Cathy A. Maxwell, PhD, RN2,

and Fang Yu, PhD, RN, GNP-BC, FGSA, FAAN3

Abstract
The objectives of this literature review were to (1) synthesize biological processes linked to frailty and their corresponding
biomarkers and (2) identify potential associations among these processes and biomarkers. In September 2016, PubMed,
Cumulative Index to Nursing and Allied Health, Cochrane Library, and Embase were searched. Studies examining biological
processes related to frailty in older adults (≥ 60 years) were included. Studies were excluded if they did not employ specific
measures of frailty, did not report the association between biomarkers and frailty, or focused on nonelderly samples (average
age < 60). Review articles, commentaries, editorials, and non-English articles were also excluded. Fifty-two articles were
reviewed, reporting six biological processes related to frailty and multiple associated biomarkers. The processes
(biomarkers) include brain changes (neurotrophic factor, gray matter volume), endocrine dysregulation (growth hormones
[insulin-like growth factor-1 and binding proteins], hormones related to glucose and insulin, the vitamin D axis, thyroid
function, reproductive axis, and hypothalamic–pituitary–adrenal axis), enhanced inflammation (C-reactive protein,
interleukin-6), immune dysfunction (neutrophils, monocytes, neopterin, CD8þCD28T cells, albumin), metabolic imbalance
(micronutrients, metabolites, enzyme-activity indices, metabolic end products), and oxidative stress (antioxidants, telomere
length, glutathione/oxidized glutathione ratio). Bidirectional interrelationships exist within and between these processes.
Biomarkers were associated with frailty in varied strengths, and the causality remains unclear. In conclusion, frailty is
related to multisystem physiological changes. Future research should examine the dynamic interactions among these
processes to inform causality of frailty. Given the multifactorial nature of frailty, a composite index of multisystem
biomarkers would likely be more informative than single biomarkers in early detection of frailty.

Keywords
frailty, frail elderly, older adults, biomarkers, biological phenomena

Frailty, a common geriatric syndrome affecting 7 million older
Americans (Bandeen-Roche et al., 2015; Mather, Jacobsen, &
Pollard, 2015), represents a state with reduced physiological
reserve for responding to stressors (El Assar et al., 2017; Fried
et al., 2001; Wang, Boehm, & Mion, 2017). Frailty has been
defined and measured in a number of ways (Buta et al., 2016).
The most commonly used definition considers frailty to be a
phenotype comprising five indicators: unintentional weight
loss of 5% or 10 pounds within 1 year, slow gait speed,
reduced grip strength, exhaustion, and physical inactivity
(Fried et al., 2001). Clinically, frailty is diagnosed by the pres-
ence of three or more of these indicators and is preceded by a
prodromal stage known as prefrailty, defined by having one or
two indicators (Fried et al., 2001). Other common measures
include the frailty index of deficits (Rockwood et al., 2005)
and the Vulnerable Elders Survey-13 (Saliba et al., 2001).
Frailty and prefrailty affect more than 10% and up to 50% of
community-dwelling older adults, respectively (Choi, Ahn,
Kim, & Won, 2015; Collard, Boter, Schoevers, & Oude
Voshaar, 2012), and increase the risk of multiple adverse out-
comes such as disability (Ehlenbach, Larson, Randall Curtis, &
Hough, 2015), falls and fractures (Ensrud et al., 2007), hospi-
talization (Joseph et al., 2014; Kahlon et al., 2015), and death
(Shamliyan, Talley, Ramakrishnan, & Kane, 2013).
The World Health Organization (2015) recognized frailty as
an emerging public health priority and urged early recognition
and intervention for frailty. A first step is to understand the
1
School of Nursing, University of Rochester, Rochester, NY, USA
2
School of Nursing, Vanderbilt University, Nashville, TN, USA
3
School of Nursing, University of Minnesota, Minneapolis, MN, USA
Corresponding Author:
Jinjiao Wang, PhD, RN, School of Nursing, University of Rochester, Room
2w.319, 255 Crittenden Blvd, Rochester, NY 14642, USA.
Email: jinjiao_wang@urmc.rochester.edu
2 Biological Research for Nursing XX(X)

biological processes from which frailty arises and their associ- independently conducted a secondary review of titles,
ated biomarkers. Biomarkers provide objective, measurable abstracts, and article content for inclusion. After consensus was
indices for normal and/or pathogenic states as well as responses reached, J.W. reviewed the full text of eligible studies to con-
to therapeutic interventions (Colburn et al., 2001). Since altera- firm adherence to eligibility criteria.
tions in biomarkers precede clinical manifestation of frailty
(Sanchis et al., 2015), they are useful for detecting subclinical
changes that lead to observable indicators of frailty. Biomar- Data Extraction
kers are also useful for tailoring and testing intervention pro-
J.W. and C.A.M. independently extracted the following infor-
tocols for frailty, as they reflect changes in biophysiological
mation from eligible studies: geographical region, data collec-
processes that underlie and/or relate to frailty (Corwin & Fer-
tion years, study objective, design, sampling method, sample
ranti, 2016). Studies have identified biological processes
size (and power calculation), sample characteristics (age, sex,
related to frailty, such as changes in brain structure; alterations
living arrangement, chronic conditions [e.g., dementia, cancer,
in endocrinal, immune, and skeletal muscle systems; and
cardiovascular disease]), retention rate (longitudinal studies),
chronic inflammation (Clegg, Young, Iliffe, Rikkert, & Rock-
frailty measure, examined biological process and biomarkers
wood, 2013; Fougere, Vellas, Van Kan, & Cesari, 2015; Moh-
and association with frailty, data analysis, strength of associa-
ler, Fain, Wertheimer, Najafi, & Nikolich-Žugich, 2014).
tions, control of confounders, and synthesis of results. They
Researchers have often studied these processes in isolation,
assigned this information to 11 fields (Table 1). The two
without considering the interconnectivity among them (Calvani
reviewers were blinded to each other’s screening results, and
et al., 2015; Zaslavsky et al., 2013). The objectives of the
the level of agreement on data extraction was 87.9% (i.e., per-
present state-of-the-science literature review were to (1)
centage of matched fields), with discrepancy resolved by con-
synthesize the biological processes and markers linked to
sensus with a third reviewer in weekly team meetings.
frailty and (2) identify potential associations between these
processes and frailty. In this review, we use the term biomar-
Quality assessment. We assessed the quality of the reviewed
kers to refer to general laboratory-measured markers of biolo-
studies using the “Strengthening the Reporting of Observa-
gical phenomena related to frailty.
tional Studies in Epidemiology (STROBE) Statement” (von
Elm et al., 2007). First, J.W., C.A.M., and a trained research
Method assistant independently evaluated a random sample of the eli-
gible studies (n ¼ 6); interrater agreement was 90%. After we
We conducted and reported this review in three steps: data discussed disagreements and resolved them by consensus, the
acquisition, data extraction, and quality assessment of identi- research assistant evaluated the quality of the remaining
fied studies. studies.

Data Acquisition
We conducted a comprehensive literature search in September Results
2016 in four major electronic databases (PubMed, Cumulative
The initial search strategy produced 272 articles. After we
Index to Nursing and Allied Health [CINAHL], Cochrane
removed 10 duplicates and 174 unsuitable articles during the
Library, and Embase) to identify studies on biological pro-
title, abstract, and content screening, 88 data-driven articles
cesses and biomarkers related to frailty in older adults (60
remained for further review. Full-text reviews led to the exclu-
years of age). We used text terms (i.e., frail*, biomarker*,
sion of 36 studies that did not utilize a specific frailty measure
biological, mechanism) and the following Medical Subject
(n ¼ 22), did not measure specific biomarkers (n ¼ 7), focused
Headings and CINAHL headings: Frailty, Frail Elderly, Older
on nonelderly samples (n ¼ 6), or did not report the association
Adults, Biomarkers, and Biological Phenomena. We reviewed
between biomarkers and frailty (n ¼ 1). In the end, 52 studies
references of extracted studies and relevant reviews to identify
met the eligibility criteria and were included in the review
additional studies and conducted a manual search of relevant
(Figure 1).
studies. We used no limitations on the publication years in the
search process. In the final selection of articles, we included
primary studies examining the biological processes and bio-
markers related to frailty and excluded studies that lacked a
Study Characteristics
specific definition or measure of frailty, those not reporting Years and region. The majority of the studies (n ¼ 33, 63%) were
associations between biomarkers and frailty, and those focused published after 2010; 23% (n ¼ 12) did not specify data col-
on nonelderly samples (average age < 60 years). We also lection years, 56% (n ¼ 29) utilized data collected before 2007.
excluded non-data-driven articles (reviews, commentaries, and The studies were conducted primarily in North America
editorials) and articles in languages other than English. Author (United States: n ¼ 25, 48%) and Europe (n ¼ 18, 35%), with
J.W. initially screened the titles and abstracts of identified six in Asia (Australia, China, and Japan; 12%) and one in South
studies for preliminary eligibility. Author C.A.M. America (Brazil, 2%).
 Table 1. Description of Reviewed Studies.
Study Design
Article: first (Longitudinal: Sample Characteristics: Size; Frailty: Measure; As
Author, Pub- Region* (Data- Follow-Up; Setting; Age; Sex; Race/ Exclusion Based on Health Exclusion Based Biomarkers (Association With Exposure or
lication Year Collection Year[s]) Retention) Sampling Method Ethnicity Conditions on Cognition Frailty) Outcome

Walston AM: United States Cross-sectional Population-based 4,735; community; average Parkinson’s disease, stroke, Dementia with 1. Inflammation: CRP (positive) Phenotype; outcome
et al. (1989–1990) sampling age: 72.7 years; biological depression under treatment MMSE < 18 2. Coagulation: Factor VIII, D
(2002) (CHS) sex: both; race: 95% dimer (positive)
Caucasian 3. Endocrine: glucose and insulin
(positive)
4. Immune: albumin (negative)
Leng et al. AM: United States Cross-sectional Convenience 326; community; average Parkinson’s disease, cerebral Cognitive deficit 1. Endocrine: serum IGF-I, Phenotype;
(2004)a (unspecified) sampling age:81.3–84.9 years; vascular accident with with MMSE < DHEA-S (negative) exposure
biological sex: both; residual hemiparesis, 18 2. Inflammatino: IL-6 (NS)
face: 100% Caucasian symptomatic rheumatoid
arthritis or any other
inflammatory conditions,
symptomatic congestive
heart failure or coronary
artery disease, malignancy,
current use of steroids, or
other immune-modulating
agents, chronic inflammatory
diseases or disability
conditions
Puts et al. EU: the Netherlands Longitudinal (3 Population- 885; community; average Baseline frailty N 1. Inflammation: CRP (positive) Researcher-
(2005) (1995–1996) years; based, age: 74.5 years; biological 2. Endocrine: 25(OH)D developed frailty
retention stratified sex: both; race: not (negative) indicators;
82%) random (from reported outcome
the LASA)
Semba et al. AM: United States Case–control Population-based 766; community; average 2/3 of least disabled older MMSE < 18 Immune: T cell subsets (CD8þ Phenotype; exposure
(2005)a (WHAS-I: 1993– (died vs. (WHAS I & II) age: 76.9–77.3 years (for women in the community CD28 lymphocyte counts:
1997; WHAS-II: surviving in a WHAS I and II, were excluded positive)
1994–1998) longitudinal respectively); biological
cohort study) sex: female; race: 69-77%
Caucasian
Semba et al. AM: United States Longitudinal (3 Population-based 766; community; 2/3 of least disabled older N 1. Endocrine: 25(OH)D Phenotype; outcome
(2006) (1992–1995) years; (WHAS I & II) average age: 76– 80.4 women in the community (negative)
retention years; biological sex: were excluded 2. Metabolic: serum
90%) female; carotenoids, a-tocopherol,
race: 70.4–72.7% nutritional deficiencies
Caucasian (independent of weight loss;
all negative)
Ble et al. EU: Italy (1998–2000) Cross-sectional Population- 827; community; average Cancer, disabilities in basic Dementia and Oxidative stress: plasma vitamin Phenotype; outcome
(2006) based(from age: 73.6 years; biological activities of daily living severe E (negative)
the sex: both; race: not cognitive
InCHIANTI reported impairment
study) with MMSE
< 18

(continued)

3
4
Table 1. (continued)

Study Design
Article: first (Longitudinal: Sample Characteristics: Size; Frailty: Measure; As
Author, Pub- Region* (Data- Follow-Up; Setting; Age; Sex; Race/ Exclusion Based on Health Exclusion Based Biomarkers (Association With Exposure or
lication Year Collection Year[s]) Retention) Sampling Method Ethnicity Conditions on Cognition Frailty) Outcome

Barzilay et al. AM: United States(1989/ Longitudinal (5– Population-based 3,141; community; average Having cancer under active MMSE < 18 1. Metabolic: metabolic Phenotype; outcome
(2007) 1990–1998/1999) 9 years, (from CHS age: 70.4–74.7 years; treatment, frailty, DM, syndrome total status
retention cohort) biological sex: both; race: coronary heart disease, (positive), HOMA-IR
90%) 94–97.4% Caucasian myocardial infarction, angina, (positive)
congestive heart failure, 2. Inflammation: CRP (positive),
stroke, transient ischemic Factor VIIc (positive)
attack, peripheral arterial 3. Endocrine: glucose (positive)
disease requiring
intervention, antidepressant
use, Parkinson’s disease at
baseline
Leng et al. AM: United States Cross-sectional Population-based 1,106; community; average Having disabilities in more than N 1. Inflammation: IL-6 (positive); Phenotype; outcome
(2007) (WHAS I: 1991–1994; (from the age: 67.3 years; biological one domain, acute bacterial 2. Immune: WBC count
WHAS II: 1994) WHAS I & II sex: female; race: 79.4% infection, hematological (positive)
cohorts) Caucasian cancer
Varadhan AM: United States Cross-sectional Population-based 214; community; average Having disabilities in more than N Endocrine: higher levels and Phenotype; outcome
et al. (2004–2005) (from WHAS age: 83.4–85.5 years; one domain blunted diurnal variation of
(2008) II) biological sex: female; cortisol (positive)
race: 76.1–90% Caucasian
Matteini AM: United States Cross-sectional Population-based 703; community; average N MMSE < 24 Metabolic & oxidative stress Phenotype; outcome
et al. (unspecified) (from WHAS I age:74.2–74.9 years; 1. Methylmalonic acid
(2008) & II) biological sex: female; (indicating vitamin B12
race: 79% Caucasian deficiency; positive)
2. Vitamin B12 (negative)
Hubbard EU: United Kingdom Cross-sectional Convenience 110; institution (continuing N N 1. Inflammation: TNF-a, IL-6, Phenotype; outcome
et al. (unspecified) care, day hospital, and CRP (all positive), albumin
(2008)a independent living); (negative)
average age: 82.7–84.9 2. Metabolic: drug metabolism
years; biological sex: both; (esterase activity; negative)
race: 100% Caucasian
Woo et al. Asia: China (Hong Kong; Cross-sectional Convenience 2,000; community; average N N Oxidative stress: telomere Index; outcome
(2008) unspecified) (a 4-year age: 72.02–72.75 years; length (NS)
longitudinal biological sex: both; race:
study focused all Chinese
on mortality)

(continued)
 Table 1. (continued)

Study Design
Article: first (Longitudinal: Sample Characteristics: Size; Frailty: Measure; As
Author, Pub- Region* (Data- Follow-Up; Setting; Age; Sex; Race/ Exclusion Based on Health Exclusion Based Biomarkers (Association With Exposure or
lication Year Collection Year[s]) Retention) Sampling Method Ethnicity Conditions on Cognition Frailty) Outcome

Gruenewald AM: United States Longitudinal (3 Population-based 803; community; average Manifest functional disability at Manifest Comprehensive: allostatic load Phenotype; outcome
et al. (1990–1993) years; age: 74.23 years; baseline cognitive index (positive), based on 13
(2009) retention biological sex: both; race: disability at biomarkers:
61%) 81.85% Caucasian baseline 1. Cardiovascular: systolic and
diastolic blood pressure,
HDL, total cholesterol/HDL
2. Metabolic: HbA1c, waist–hip
ratio
3. Hormonal: DHEA, urinary
cortisol, urinary epinephrine,
urinary norepinephrine
4. Inflammation: CRP, IL-6 &
fibrinogen (coagulation)
Hubbard EU: United Kingdom Cross-sectional Convenience 110; community;average age: N N Inflammation: TNF-a, IL-6, CRP Phenotype & index;
et al. (unspecified) 83.9 years; biological sex: (positive); albumin (negative) outcome
(2009) both; race: 100%
Caucasian
Leng et al., AM: United States Cross-sectional population-based 696; community; average Acute bacterial infection or N 1. Immune: WBC (positive) Phenotype; outcome
Hung (WHAS I: 1991–1994) (from WHS I) age: 77.6 years; biological hematologic malignancies 2. Endocrine: IGF-1 (negative)
et al. sex: female; race: 68.3–
(2009) 81.1% Caucasian
Leng et al. AM: United States Cross-sectional Population-based 1,106; community; average Acute bacterial infection or N 1. Inflammation: IL-6 (positive) Phenotype; outcome
(2009) (WHAS I: 1991–1994 (from WHAS age: 77.4 years; biological hematological cancer 2. Immune: neutrophil,
and Xue & 1994) I) sex: female; race: 72.6% monocyte count (positive
et al. Caucasian but NS)
(2009)
Reiner et al. AM: United States Case–control Population-based 900; community; minimal Having frailty at baseline, N 1. Inflammation: CRP (NS), IL-6 Phenotype; outcome
(2009) (1993–1998) (frail vs. (from the age: > 65 years (average Parkinson’s disease, severe (NS)
nonfrail) Women’s age not reported); autoimmune disease, 2. Coagulation: D-dimer
Health biological sex: female; multiple sclerosis, (positive), t-PA levels
Initiative race: 96.1% Caucasian amyotrophic lateral sclerosis, (positive), factor VIII (NS),
study) congestive heart failure, fibrinogen (NS)
coronary heart disease,
stroke, cancer, or use of
antidepressant medications
at baseline
Serviddioet EU: Italy (2007) Cross-sectional Convenience 62; community; average age: Physical impairment or disability Dementia with 1. Inflammation: TNF-a Phenotype; outcome
al. (2009) 76.7 years; biological sex: evaluated by MMSE < 18 (positive)
both; race: not reported Multidimensional Geriatric 2. Oxidative stress: GSH/GSSG
Assessment, disabilities in (positive), MDA (positive),
basic activity of daily living, HNE protein plasma adducts
cancer, taking antioxidant (positive)
supplementation

(continued)

5
6
Table 1. (continued)

Study Design
Article: first (Longitudinal: Sample Characteristics: Size; Frailty: Measure; As
Author, Pub- Region* (Data- Follow-Up; Setting; Age; Sex; Race/ Exclusion Based on Health Exclusion Based Biomarkers (Association With Exposure or
lication Year Collection Year[s]) Retention) Sampling Method Ethnicity Conditions on Cognition Frailty) Outcome

Szanton et al. AM: United States Cross-sectional Population-based 728; community; average N MMSE < 24 in Comprehensive: allostatic load Phenotype; outcome
(2009) (WHAS I &II: 1991– (from WHAS I age: 74.2 years; biological one sample, (positive)
1994 & 1994) & II) sex: female; race:76% MMSE < 18 in
Caucasian another
sample
Wu et al. Asia: mainland Cross-sectional Convenience 90; community; average age: Malignancy, Parkinson’s disease, N Oxidative stress: 8-OHdG Phenotype; outcome
(2009) China(2008) 73.1–79.9 years; or stroke, not being able to (positive)
biological sex: both; race: walk
all Chinese
Hyde et al. Asia: Australia (2001– Longitudinal (7 Population-based 3,616; community: average Prostate cancer or previous N Endocrine: free testosterone FRAIL questionnaire;
(2010) 2004, 2008–2009) years; (from the age: 76.9 years; biological orchidectomy and those (negative: incident and outcome
retention Health in Men sex: male; race: receiving GnRH analogs, prevalent frailty)
44%) study) predominantly Caucasian antiandrogen therapy, or
(proportion not testosterone
reported) supplementation
Ronning EU: Norway Cross-sectional Convenience 187; cancer patients Not undergoing elective N 1. Inflammation: CRP, IL-6, Phenotype & Balducci
et al. (unspecified) (colorectal); average age: resections of tumors in colon TNF-a (positive) CGA category;
(2010)a 80 years; biological sex: or rectum 2. Coagulation: D-dimer exposure
both; race: not reported (positive)
Ensrud et al. AM: United Longitudinal (4.6 Population-based 1,128; community; average History of hip replacement, N Endocrine: 25(OH)D (negative) Phenotype; outcome
(2011) States(2000–2002) years; (from the age: 73.8 years; biological unable to walk without
retention CHS) sex: male; race: 89.7% assistance from another
76%) Caucasian person
Leng et al. AM: United States Cross-sectional Convenience 133; community; average Parkinson’s disease, stroke with Significant 1. Inflammation: IL-6 (positive) Phenotype; outcome
(2011) (unspecified) age: 84 years; biological residual hemiparesis, cognitive 2. Immune: neopterin (positive)
sex: both; race: 95.7% symptomatic congestive deficit with
Caucasian heart failure, uncompensated MMSE < 18
endocrine disorders, active
malignancy, rheumatoid
arthritis or any other
inflammatory conditions, or
use of immune-modulating
drugs including oral
corticosteroids
Tajar et al. EU: United Kingdom Cross-sectional Population-based 1,504; community; average Prevalent pituitary, testicular, N Endocrine: testosterone Phenotype & index;
(2011) (2003–2005) (the European age: 60 years; biological or adrenal diseases or use of (negative), LH (positive), FSH outcome
Male Aging sex: male; race: medications that are likely to (positive), DHEA-S
Study) predominantly Caucasian affect HPT function (negative), SHBG (negative)
(proportion not (anabolic-androgenic
reported) steroids, DHEA, anti-
androgens, GnRH agonists,
and psycholeptic agents) or
clearance of sex steroids
(e.g., anticonvulsants)

(continued)
 Table 1. (continued)

Study Design
Article: first (Longitudinal: Sample Characteristics: Size; Frailty: Measure; As
Author, Pub- Region* (Data- Follow-Up; Setting; Age; Sex; Race/ Exclusion Based on Health Exclusion Based Biomarkers (Association With Exposure or
lication Year Collection Year[s]) Retention) Sampling Method Ethnicity Conditions on Cognition Frailty) Outcome

Coelho et al. AM: Brazil Cross-sectional Convenience 48; community; Acute inflammatory condition Cognitive Brain: BDNF (negative) Phenotype; exposure
(2012)a (unspecified) (in a quasi- average age: 70.5–72.5 or active neoplasm in the alterations
experimental years; biological sex: previous 5 years; use of detected by
study) female; race: not medication with broad-based MMSE
reported action on the immune
system; amputation or
fracture of the upper or
lower limbs in the previous 6
months; presence of any
neurological diseases
Collerton EU: United Kingdom Cross-sectional Population-based 845; institution; age range: Stroke, Parkinson’s disease MMSE < 18, or 1. Inflammation: IL-6, TNF-a, Phenotype & index;
et al. (2006-2007) (from the 85þ years (average age taking drugs CRP (positive) outcome
(2012) Newcastle not reported); biological for dementia 2. Immune: neutrophils
85þ study) sex: both; race: 99.6% (positive), total lymphocyte
Caucasian count (albumin, lymphocytes,
memory/naive CD8 T cell
ratio; all negative)
Kalyani, Tian AM: United States Longitudinal (9 Population-based 329; community: average Stroke or Parkinson’s disease, N Endocrine: HbA1c (positive) Phenotype; outcome
et al. (1994–2008) years; (from WHAS age: 73.9 years; biological HbA1c < 4.5%
(2012) retention II cohort) sex: female; race: 83.9%
90%) Caucasian
Kalyani et al. AM: United States Cross-sectional Population-based 73; community; average age: N N Endocrine: glucose and insulin Phenotype; exposure
(2012a) (2008–2009) (from WHAS 86.7 years; biological sex: levels in oral glucose
II cohort) female; race: 84.9% tolerance test (positive)
Caucasian
Kalyani et al. AM: United States Cross-sectional Population-based 73; community; average age: Known diabetes or taking N 1. Metabolic: FFa (positive) Phenotype; exposure
(2012b) (2008–2009) (from WHAS 86–87 years; biological corticosteroids, having 2. Endocrine: gut- (ghrelin
II cohort) sex: female; race: not difficulty in more than 1 of 4 [negative], GLP-1 [negative])
reported domains of physical function and adipocyte-derived
hormones (leptin [positive],
adiponectin [negative],
resistin [positive]), growth
hormone (GH [positive]),
IGF-1 [negative]
3. Inflammation: IL-6 (positive)
Yeap et al. Asia: Australia (2001– Cross-sectional Population-based 3,943; community: average History of thyroid disease, N Endocrine: TSH (NS), FT4 FRAIL questionnaire;
(2012) 2004) (from the age: 75.15–76.19 years; thyroid surgery or treatment (positive) outcome
Health in Men biological sex: male; race: with radioactive iodine,
study) predominantly Caucasian previously undiagnosed
(proportion not hyperthyroidism,
reported) undiagnosed hypothyroidism

(continued)

7
8
Table 1. (continued)

Study Design
Article: first (Longitudinal: Sample Characteristics: Size; Frailty: Measure; As
Author, Pub- Region* (Data- Follow-Up; Setting; Age; Sex; Race/ Exclusion Based on Health Exclusion Based Biomarkers (Association With Exposure or
lication Year Collection Year[s]) Retention) Sampling Method Ethnicity Conditions on Cognition Frailty) Outcome

Baylis et al. EU: United Kingdom Longitudinal (10 Population-based 254; community; average N N 1. Immune: higher baseline Phenotype; outcome
(2013) (1994–2003) years; (from the age: 66.9–67.3 years; levels of differential WBC
retention Hertfordshire biological sex: both; race: 2. Endocrine: DHEA-S
35%) Ageing Study) not reported (negative), cortisol/DHEA-S
(positive)
Dalrymple AM: United States Longitudinal Population-based 4,150; community; average Institutionalized, using a Alzheimer’s Kidney function: eGFR using Phenotype; outcome
et al. (1989–1990 & 1992– (follow-up of age: 75 years; biological wheelchair within the home, disease, serum cystatin C (negative)
(2013) 1993) 4 years, sex: both; race: 83% non- receiving chemotherapy or MMSE < 18,
retention Black radiation for cancer, or modified
unspecified) receiving hospice care, MMSE < 60
Parkinson’s disease, stroke,
prescribed medications for
Parkinson’s disease,
depression, baseline frailty
Gale et al. EU: United Kingdom Longitudinal (6 Population-based 2,146; community; average N N 1. Inflammation: CRP (positive) Phenotype; outcome
(2013) (2002–2008) years, (from the age: 70.22 years; 2. Coagulation: fibrinogen
retention English biological sex: both; race: (positive: only in women, not
46%) Longitudinal not reported in men)
Study of
Ageing)
Hart et al. AM: United States Cross-sectional Convenience (six 1,602; community; average N N Kidney function: cystatin C Phenotype; outcome
(2013) (2000–2002) clinical sites) age: 73.8 years; biological (positive), but not creatinine-
sex: male; race: 91.5% based measures
Caucasian
Tajar et al. EU: Six European Cross-sectional Stratified random 1,504; community; average N N Endocrine: 25(OH)D (negative); Phenotype & index;
(2013) countries(unspecified) (on center age: 69.5 years; biological PTH (positive) outcome
level) sex: male; race: 70–90%
Caucasian
Yeap et al. Asia: Australia (2001– Longitudinal (7 Population-based 3,447; community: average On testosterone or hormonal N Endocrine: IGF-1 (negative) and FRAIL questionnaire;
(2013) 2004, 2008–2009) years; (from the age: 75.8–78.3 years; therapies, history of prostate binding proteins (positive), outcome
retention Health In Men biological sex: male; race: cancer, metabolic syndrome total and free testosterone
48%) study) predominantly Caucasian (negative)
(proportion not
reported)
Addison AM: United States Case–control Convenience 26; community; average age: N N 1. Inflammation: IL-6 (positive), MPPT < 25
et al. (unspecified) (frail vs. 78.1–83.3 years; TNF-a (NS) (moderately frail)
(2014)a nonfrail) biological sex: both; race: 2. Metabolic (muscle): IMAT and reported little
not reported (positive) to no
planned physical
activity over the
last year; outcome

(continued)
 Table 1. (continued)

Study Design
Article: first (Longitudinal: Sample Characteristics: Size; Frailty: Measure; As
Author, Pub- Region* (Data- Follow-Up; Setting; Age; Sex; Race/ Exclusion Based on Health Exclusion Based Biomarkers (Association With Exposure or
lication Year Collection Year[s]) Retention) Sampling Method Ethnicity Conditions on Cognition Frailty) Outcome

Corona et al. EU: Italy (2009–2010) Cross-sectional Convenience 89; cancer patients (breast); N N Metabolic: amino acids CGA (Balducci);
(2014)a average age: 77 years; (positive), acylcarnitines outcome
biological sex: female; (positive), sphingo- and
race: not reported glycerol-phospholipids
(negative)
Inglés et al. EU: Spain (2006–2009 Cross-sectional Population-based 742; community; average N N Oxidative stress: MDA Phenotype; outcome
(2014)a 2013–2014) (from the age: 76.46 years; (positive), protein
Toledo Study biological sex: both; race: carbonylation (positive).
for Healthy not reported Both are circulating
Aging) oxidative-damage
biomarkers
Lai et al. China (Taiwan; (2007) Cross-sectional Convenience 386; institution (veterans Acute medical problems N Inflammation: IL-6 (positive) Phenotype; outcome
(2014) care home); average age:
81.5 years; biological sex:
male; race: all Chinese
Whitson AM: United States Cross-sectional Population-based 3,373; community; average Wheelchair bound or under N Metabolic: CML (positive) Phenotype; outcome
et al. (1996–1997) data about (from the CHS age: 78.1 years; biological active treatment for cancer
(2014) frailty in a 14- study) sex: both; race: 83.5–
year 84.5% Caucasian
longitudinal
cohort
Brouwerset EU: Belgium Cross-sectional Convenience 244; cancer patients Having new diagnosis of early or N Inflammation: IL-6 (positive) LOFS & Balducci’s
al. (2015)a (unspecified) (metastatic breast); locally advanced (i.e. CGA; exposure
average age: 76 years; nonmetastatic), primary or
biological sex: both; race: second primary breast
not reported cancer before initiation of
any chemotherapy,
radiotherapy or surgery
W. T. Chen China (Taiwan; Cross-sectional Population-based 456; community; average Major illness with limited life Dementia Brain: GMV (negative), CSF Phenotype; exposure
et al. 2011–2012) (from the I- age: 64 years; biological expectancy (less than 6 (positive)
(2015)a Lan sex: both; race: all months); having any
Longitudinal Chinese contraindication for MRI
Aging Study) such as metal implants;
having been institutionalized
for any reason; major
neuropsychiatric diseases
such as stroke, brain tumor,
or major depression
Sanchis et al. EU: Spain (2010–2012) Cross-sectional Convenience 342; hospitalized patients Prior diagnosis of heart disease N 1. Endocrine: vitamin D Phenotype; outcome
(2015) (acute coronary other than ischemic heart (negative)
syndrome survivors); disease and the indication of 2. Metabolic: hemoglobin
average age: 77–81 years; coronary surgery during (negative)
biological sex: both; race: hospitalization 3. Kidney function: cystatin-C
not reported (positive)

(continued)

9
10
Table 1. (continued)

Study Design
Article: first (Longitudinal: Sample Characteristics: Size; Frailty: Measure; As
Author, Pub- Region* (Data- Follow-Up; Setting; Age; Sex; Race/ Exclusion Based on Health Exclusion Based Biomarkers (Association With Exposure or
lication Year Collection Year[s]) Retention) Sampling Method Ethnicity Conditions on Cognition Frailty) Outcome

Urpi-Sarda EU: Italy (1998–2000) Cross-sectional Population-based 811; community; average N N Metabolic: DTP intake and its Phenotype; outcome
et al. (from the age: 74.3 years; biological biomarker (NS), UTP
(2015) InCHIANTI sex: both; race: not (negative)
study) reported
Beben et al. AM: United States Cross-sectional Population-based 2,977; community; average In hospice or receiving radiation N Endocrine: FGF-23 (positive) Phenotype; outcome
(2016) (1996–1997) (from the CHS age: 77.9 years; biological or chemotherapy for cancer
study) sex: both; race: 83%
Caucasian
Liu et al. AM: United States Cross-sectional Population-based 1,919; community; average N N 1. Inflammation: IL-6 (positive) Phenotype; outcome
(2016) (2005–2008) (from the age: 70.94 years; 2. Oxidative stress:
Framingham biological sex: both; race: isoprostanes (positive),
Offspring not reported LpPLA2 mass (positive)
Study)
Lorenzi et al. EU: Spain (2012–2013) Cross-sectional Convenience 120; community; average Estimated life expectancy less MMSE < 18 Inflammation: plasma HtrA1 Phenotype & index;
(2016)a age: 75.4 years; biological than 6 months (positive) exposure
sex: both; race: not
reported
Namioka Asia: Japan (unspecified) Cross-sectional Convenience 140; patients with Severe disability, major Moderate-to- 1. Oxidative stress: plasma Phenotype; exposure
et al. Alzheimer’s disease (mild depression, malignancies, severe diacron reactive oxygen
(2016)a to moderate); average severe cardiac or pulmonary dementia metabolite (positive),
age: 78.2–82.3 years; disease, liver cirrsis, severe with MMSE < biological
biological sex: both; race: chronic kidney disease 18 antioxidant potential
all Japanese (negative), bilirubin
(negative), endogenous
plasma antioxidants urinary
8-OHdG (positive),
epiPGF2a (8-isoprostane;
negative), plasma albumin
(NS), uric acid (NS)
2. Inflammation: IL-6 (NS), TNF-
a (NS)
Zaslavsky AM: United States Longitudinal (4.8 Population-based 1,848; community; average Baseline frailty Dementia at Endocrine: glucose and HbA1c Phenotype; outcome
et al., (1994–1996, 2000– years, (from the age: 76 years; biological baseline or (positive)
2016 2003, 2005) retention Adult Changes sex: both; race: 85.9– during
71%) in Thought 92.8% Caucasian follow-up
study)

(continued)
 Table 1. (continued)

Study Design
Article: first (Longitudinal: Sample Characteristics: Size; Frailty: Measure; As
Author, Pub- Region* (Data- Follow-Up; Setting; Age; Sex; Race/ Exclusion Based on Health Exclusion Based Biomarkers (Association With Exposure or
lication Year Collection Year[s]) Retention) Sampling Method Ethnicity Conditions on Cognition Frailty) Outcome

Zhu et al., Asia: mainland China Cross-sectional Stratified random 1,478; community; average Self-reported Parkinson’s Severe cognitive Inflammation: hsCRP (positive) Phenotype; outcome
2016 (2014) age: 75.3 years; biological disease, Alzheimer’s disease, impairment
sex: both; race: all stroke, depression, treated with revised
Chinese in emergency department Hasegawa’s
during the last 3 months or Dementia
taking anti-inflammatory Scale score <
drugs (nonsteroidal anti- 10
inflammatory drugs)
continuously for 1 month

Note. 25(OH)D ¼ 25 hydroxyvitamin D; 8-OHdG ¼ 8-hydroxy-20-deoxyguanosine; AM ¼ America; BDNF ¼ brain-derived neurotrophic factor; CGA ¼ Comprehensive Geriatric Assessment; CHS ¼ Cardiovascular
Health Study; CML ¼ carboxymethyl-lysine; CRP ¼ C-reactive protein; CSF ¼ cerebrospinal fluid; DHEA-S ¼ dehydroepiandrosterone-sulphate; DM ¼ diabetes mellitus; DTP ¼ dietary total polyphenols; eGFR ¼
estimated glomerular filtration rate; EU: Europe; F/U: follow-up; FFa ¼ free fatty acids; FGF-23 ¼ fibroblast growth factor-23; FSH ¼ follicle-stimulating hormone; FT4 ¼ free thyroxine; GlP-1 ¼ glucagon-like peptide-1;
GMV ¼ gray-matter volume; GSH ¼ glutathione; GnRH ¼ gonadotropin-releasing hormone; GSSG ¼ oxidized glutathione; HbA1c ¼ glycosylated hemoglobin; HDL ¼ high-density lipoprotein cholesterol; HNE ¼ 4-
hydroxy-2,3-nonenal; HOMA-IR ¼ homeostasis model-insulin resistance; HPT ¼ hypothalamic–pituitary–testicular; hsCRP ¼ high-sensitivity C-reactive protein; HtrA1 ¼ high-temperature requirement serine protease
A1; IGF-1 ¼ insulin-like growth factor-1; IL-6 ¼ interleukin 6; IMAT ¼ intramuscular adipose tissue; LASA ¼ Longitudinal Aging Study Amsterdam; LH ¼ luteinizing hormone; LOFS ¼ Leuven Oncogeriatric Frailty Score;
LpPLA2 ¼ lipoprotein phospholipase A2; MDA ¼ malonaldehyde; MMSE ¼ Mini-Mental State Examination; MPPT ¼ modified physical performance test score; MRI ¼ magnetic resonance imaging; NS ¼ not significant; PTH
¼ parathyroid hormones; SHBG ¼ sex hormone–binding globulin; t-PA ¼ tissue plasminogen activator; TNF-a ¼ tumor necrosis factor-alpha; TSH ¼ circulating thyrotropin (thyroid-stimulating hormone); UTP ¼ urinary
total polyphenols; WBC ¼ white blood cell; WHAS ¼ Women’s Health and Aging Study.
a
These 12 studies did not report the specific strength of identified associations between biomarkers and frailty and are, thus, not included in Table 1.

11
12 Biological Research for Nursing XX(X)

Records idenfied (n = 272)

i. database search (n = 241)

Idenficaon
ii. reference search (n = 26)
iii. -manual search (n = 5)

Duplicates excluded (n = 10)

Records aer duplicates removed

(n = 262) Records excluded (n =174)
i. topics unrelated to frailty, but
other issues in the frail
Screening

populaon (n = 114)
ii. not data driven: editorials,
Records screened for tle and leers to editors, opinions and
abstract (n = 88) discussion pieces, theorecal
papers, reviews (n = 55)
iii. no full text: conference
abstracts (n = 1)
iv. not published in English (n = 4)
Eligibility

Full-text arcles assessed for

eligibility (n =88) Records excluded (n = 36)
i. not focused on frailty or did
not measure frailty (n = 22)
ii. did not measure biomarkers (n
= 7)
iii. non-elderly sample (average
age < 60 years; n = 6)
iv. did not report the associaon
between biomarkers and frailty
Included

Studies included (N = 52) (n = 1)

Figure 1. Literature search flowchart (Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] format; Moher, Liberati,
Tetzlaff, & Altman, 2009).

Study design and data type. The majority of the studies (n ¼ 37,
71%) were cross-sectional, 12 (23%) were longitudinal, and
three (6%) were case–control. Only one study was interven-
tional (Coelho et al., 2012), and the rest were observational.
Follow-up periods in the 12 longitudinal studies ranged from 3
to 14 years. Over, half (n ¼ 33, 52%) of the studies were
secondary analyses of large-scale population cohorts, particu-
larly the Women’s Health and Aging Study (n ¼ 12, 23%) and
the Cardiovascular Health Study (n ¼ 6, 12%) in the United
States.
Population and sample. Target populations were primarily
community-dwelling older adults (n ¼ 44, 85%), followed by
nursing home residents (n ¼ 3, 6%) and older adults with
specific health conditions including cancer (n ¼ 3, 6%), acute
cardiac conditions (n ¼ 1, 2%), and Alzheimer’s disease (n ¼ 1,
2%). Most studies included older adults of both sexes (n ¼ 30,
58%), while 22 were restricted to one sex (male: n ¼ 8, 15%;
female: n ¼ 14, 27%). Among the studies (n ¼ 30, 58%) that
reported race and/or ethnicity of the sample, 44% (n ¼ 23)
comprised primarily Caucasian populations (proportion: 80–
100%). In 30 (58%) studies, the average age was 75 years.
The study populations were primarily convenience samples (n
¼ 17, 33%) or population-based cohorts (n ¼ 33, 63%), though
in two studies, researchers independently collected random
samples (6%). Sample size ranged from 26 to 4,735, with 45
(87%) studies having a sample size 100. Only two (4%)
studies reported power calculations. Retention rate in longitu-
dinal studies (n ¼ 12) ranged from 35% to 90%. Exclusion
criteria in 37 (71%) studies included various health conditions
(e.g., cardiovascular disease, cancer, stroke, and Parkinson’s
disease; see Table 1), while those in 18 (35%) included
impaired cognitive functioning identified by a diagnosis of
dementia or cognitive screening tests (e.g., Mini-Mental State
Wang et al.
Exam [MMSE] score < 18 or 24). However, one study was
conducted with patients with mild cognitive impairment in
Alzheimer’s disease (MMSE > 18; Namioka et al., 2016), and
another specifically stated that many subjects had cognitive
impairment (Hubbard, O’Mahony, Savva, Calver, & Wood-
house, 2009).
Measure of frailty, biomarkers, and analyses. The majority of stud-
ies (n ¼ 44, 85%) measured frailty using the Fried phenotype
(Fried et al., 2001) alone or with other measures, such as the
frailty index of deficits (Rockwood et al., 2005; Rockwood &
Mitnitski, 2007), the FRAIL questionnaire (Morley, Mal-
mstrom & Miller, 2012), and Balducci’s Comprehensive Ger-
iatric Assessment (CGA; Balducci & Extermann, 2000).
Among studies not using the Fried phenotype as the frailty
measure (n ¼ 8, 15%), three (6%) used the FRAIL question-
naire (Hyde et al., 2010; Yeap et al., 2012, 2013), two (4%)
used Balducci’s CGA (Brouwers et al., 2015; Corona et al.,
2014), one (2%) used the frailty index of deficits (Woo et al.,
2008), one (2%) used a modified physical performance mea-
sure (Addison et al., 2014), and one (2%) used a self-developed
tool (Puts, Visser, Twisk, Deeg, & Lips, 2005).
Biomarkers were measured as continuous variables in 28
(54%) studies, as categorical variables in 16 (31%) studies, and
as both in 8 (15%) studies. Among the 24 studies that categor-
ized the level of biomarkers, different cut points were used to
determine high-risk biomarker levels (e.g., in binary, tertile,
quartile, or quintile groups with different ranges for each).
Linear or logistic regression and Cox proportional models were
the most common analyses (n ¼ 40, 77%) to examine the
association between biomarkers and frailty, followed by mean
comparisons across groups (e.g., analysis of variance; n ¼ 9,
17%) and bivariate correlations (n ¼ 3, 6%). In analysis, 42
(81%) studies treated frailty as the outcome, the rest (n ¼ 10,
23%) treated frailty as the exposure (e.g., comparing the means
[n ¼ 9] or images [n ¼ 1] of biomarkers among frail, prefrail,
and nonfrail groups). Forty studies (77%) reported specific
strength of the association between examined biomarkers and
frailty in the forms of odds ratio, hazard ratio, correlation coef-
ficient, or regression b coefficient, while 12 (23%) studies did
not report such parameters. Confounders such as demographic
status, body mass index, and comorbidities were controlled in
87% (n ¼ 45) of the studies (Table 1).
Biological Processes Related to Frailty and Associated
Biomarkers
We identified six biological processes related to frailty in the
reviewed studies, including (1) brain changes, (2) endocrine
dysregulation, (3) enhanced inflammation, (4) immune dys-
function, (5) metabolic imbalance, and (6) oxidative stress. Out
of all the studies, 21 (40%) examined more than one process,
primarily enhanced inflammation along with immune dysfunc-
tion or endocrine dysregulation (Table 1). We categorized the
biomarkers into these six processes based on how the research-
ers had categorized them; however, it is not uncommon to see
13
that the same process was named differently in different stud-
ies. For example, some studies grouped inflammation into
immune processes while others did not.
Changes in the brain. Aging- and disease-related changes in the
brain contribute to the development of frailty, including struc-
tural, physiological, and functional brain changes and
decreased brain reserve in the stress response (Buchman
et al., 2014; Buchman, Yu, Wilson, Schneider, & Bennett,
2013; Clegg et al., 2013; D. B. Miller & O’Callaghan, 2005).
When these changes occur separately or in concert and accu-
mulate to an extent that causes cognitive decline, frailty may
ensue. For example, neuronal loss due to Alzheimer’s pathol-
ogy (amyloid plaques, neurofibrillary tangles) and infarcts
(Buchman et al., 2013, 2014) in areas of the cerebellum and
hippocampus can cause cognitive decline (i.e., in motor plan-
ning) that is related to the frailty symptom of slow gait speed
(W.T. Chen et al., 2015). As the brain changes accumulate and
cognitive decline worsens, frailty progresses through stages of
prefrailty, frailty, and eventually disability (Robertson, Savva,
& Kenny, 2013). In addition, neurons in certain brain areas,
such as the hippocampal pyramid, are key to maintaining a
balanced stress response (Clegg et al., 2013; Orlovsky,
Dosenko, Spiga, Skibo, & Lightman, 2014). Thus, losing these
neurons secondary to aging decreases the brain’s reserve in the
stress response, which may be at the core of frailty develop-
ment (El Assar et al., 2017).
Two studies identified two brain biomarkers for frailty: gray
matter volume and brain-derived neurotrophic factor (BDNF;
W.T.Chen et al., 2015; Coelho et al., 2012). Gray matter vol-
ume can be measured by magnetic resonance imaging, and
research has linked its decrease to slow gait speed, physical
inactivity, and reduced handgrip; all of which are clinical indi-
cators of frailty (W.T.Chen et al., 2015). BDNF protects adult
neurons from death during stress (Schäbitz et al., 2007) and
promotes the development of immature neurons (Lindsay,
1994). A lower level of BDNF indicates that the brain has
reduced reserves to respond to stressors. Due to the lack of
direct measures of cerebral BDNF, researchers have used
plasma BDNF concentrations, measured using centrifuged
blood samples with sandwich enzyme-linked immunosorbent
assay (ELISA) kits, as a proxy measure (Inglés et al., 2017;
Noble, Billington, Kotz, & Wang, 2011). Lower plasma BDMF
concentration is related to higher rates of frailty (Coelho et al.,
2012). Such evidence indicates the importance of the central
nervous system to the maintenance of stress adaptability and
reveals a role for the link between cognitive functioning (i.e.,
stress adaption in the central nervous system) and physical
functioning (i.e., physiological reserve) in the development
of frailty.
Endocrine dysregulation. Endocrine dysregulation entails aging-
related disturbances of homeostasis, a balance between ade-
quate protection from invading pathogens and harmful effects
of continual low-grade inflammation (Hunt, Walsh, Voegeli, &
Roberts, 2010). Through the processes of apoptosis,
14
senescence, and inflammation, hormones help maintain home-
ostasis (Fedarko, 2011). When hormones are dysregulated,
internal homeostasis is disturbed, thus reducing adaptability
to stressors and increasing the risk of frailty. Hormonal dysre-
gulation is associated with poor skeletal muscle protein synth-
esis, which leads to weakness, a frailty indicator (Cooper et al.,
2012). In the present review, 20 studies examined the relation-
ship between endocrine dysregulation and frailty (Table 1),
identifying the following biomarkers associated with one or
more indicators in the frailty phenotype:
1. Growth hormones (assessed by serum concentrations).
Researchers found that older adults with lower levels of
insulin-like growth factor-1 (IGF-1) had higher preva-
lence rates of frailty (Leng et al., 2004; Leng, Hung,
et al., 2009) and higher risk of incident frailty (Yeap
et al., 2013). In contrast, higher levels of IGF-1 binding
proteins, such as IGFBP-1, were related to higher
cerates of frailty (Yeap et al., 2013). The link may be
that reduced secretion of growth hormones is related to
decreased skeletal muscle, bone mass and strength, key
factors related to the frailty indicators of weakness and
physical inactivity.
2. Hormones related to the vitamin D axis, including 25-
hydroxyvitamin D (25[OH]D), parathyroid hormone
(PTH), and fibroblast growth factor-23 (FGF-23; in
serum concentrations). Lower levels of 25(OH)D and
higher levels of PTH were associated with higher pre-
valence rates of frailty, higher risks of incident frailty
(Ensrud et al., 2011; Puts et al., 2005; Sanchis et al.,
2015; Tajar et al., 2013), and higher rates of weakness
(frailty indicator) and sarcopenia (syndrome related to
frailty; Puts et al., 2005; Sanchis et al., 2015). Higher
levels of FGF-23, which result in reductions in
25(OH)D, are also related to higher rates of frailty
(Beben et al., 2016). These associations indicate that
the loss of muscle mass and strength, secondary to vita-
min D deficiency, may be an underlying mechanism of
frailty.
3. Thyroid hormones, that is, free thyroxine. Researchers
found higher levels of free thyroxine (even within the
euthyroid range) among frail older men than among
their nonfrail male counterparts (Yeap et al., 2012). The
link between free thyroxine and frailty is particularly
significant when the frailty indicators of fatigue and
weight loss are also present, suggesting that thyroid
function is probably contributing to weight loss and
reduced physical capability in frail older adults, though
longitudinal data are needed to verify this.
4. Adrenocorticoids of the hypothalamic–pituitary–adre-
nal axis (HPA), including cortisol, epinephrine, norepi-
nephrine, dehydroepiandrosterone (DHEA), and its
sulfated metabolite (DHEA-sulfate [DHEA-S]),
assessed by serum concentrations. Higher levels of cor-
tisol (with less diurnal variation), epinephrine and nor-
epinephrine, lower levels of DHEA-S, and a higher
Biological Research for Nursing XX(X)
cortisol/DHEA-S ratio were related to higher rates of
frailty (Baylis et al., 2013; Leng et al., 2004; Varadhan
et al., 2008). When faced with stressors, a fundamental
response of the human body is to activate the HPA axis.
Enhanced reaction of the HPA axis, such as that which
occurs during chronic, persistent stress, leading to
higher levels of cortisol, epinephrine, and norepinephr-
ine, is linked to the etiology of several age-related
health conditions that are related to frailty, such as car-
diovascular disease, diabetes, and osteoporosis (Ros-
mond & Björntorp, 2000; Tsigos & Chrousos, 2002).
This may be why hormones of the HPA axis, especially
during abnormal stress-response patterns, are related to
an overall status of frailty and higher incident rates of
health conditions such as cardiovascular disease (See-
man, Singer, Rowe, Horwitz, & McEwen, 1997). How-
ever, no associations have been reported between these
hormones and specific frailty indicators.
5. Reproductive-axis hormones, such as those related to
testosterone (assessed by plasma or urine concentra-
tions). Higher levels of circulating/free testosterone, sex
hormone–binding globulin, and DHEA-S were related
to lower rates of frailty, while lower levels of luteiniz-
ing hormone and follicle-stimulating hormone were
related to higher rates of frailty. In particular, low levels
of free testosterone were related to higher risk of inci-
dent frailty, especially to the frailty indicators of weight
loss and resistance (related to muscle strength; Hyde
et al., 2010). These associations were independent of
age (Hyde et al., 2010; Tajar et al., 2011). After adjust-
ing for circulating testosterone levels, researchers found
that increased levels of gonadotropins were still related
to frailty, suggesting that changes in pituitary–testicular
function might be a correlate, but not the cause, of
frailty (Tajar et al., 2011). Note that DHEA-S is related
to both the HPA axis and secretion of reproductive
hormones (hypothalamic–pituitary–testicular), indicat-
ing an interrelationship between these two endocrinal
pathways. DHEA, as an anabolic hormone that facili-
tates the building of muscle tissue, declines with age,
which may contribute to age-related loss of muscle
mass and strength leading to the development of weak-
ness in frailty (evidence was inconsistent; Ceci, Dur-
anti, Rossi, Savini, & Sabatini, 2011; Percheron et al.,
2003).
6. Hormones related to energy metabolism and glucose–
insulin balance, including glucose, hemoglobin A1c
[HbA1c], insulin, and ghrelin (both fasting and at 2-hr
oral glucose tolerance test [OGTT] level; Barzilay et al.,
2007; Kalyani, Tian, et al., 2012; Kalyani, Varadhan,
Weiss, Fried, & Cappola, 2012a, 2012b; Walston et al.,
2002; Zaslavsky, Walker, Crane, Gray, & Larson,
2016). Altered insulin–glucose dynamics, such as
increased fasting and 2-hr OGTT levels of glucose,
higher levels of HbA1c, and high levels of insulin and
greater degrees of insulin resistance, are related to
Wang et al.
higher rates of baseline frailty and greater odds of
frailty onset (Barzilay et al., 2007; Kalyani, Tian
et al., 2012; Kalyani et al., 2012a; Walston et al.,
2002; Zaslavsky et al., 2016). Researchers also noted
lower levels of ghrelin, a fast-acting hormone produced
by stomach endocrine cells that can stimulate appetite
and the release of growth hormone, among frail subjects
than among nonfrail subjects (Kalyani et al., 2012b).
These results suggest that abnormal glucose response,
such as higher levels of glucose and insulin resistance
and lower levels of ghrelin, can reduce food intake and
lean body mass, which may increase the odds of frailty
by affecting frailty indicators related to lower energy
intake and muscle strength, such as weight loss, hand-
grip, and slow gait speed. To date, no studies have
examined the relationship between hormones related
to energy metabolism and specific frailty indicators.
Enhanced inflammation. In cases of an enhanced inflammation
process, a prolonged immune response, caused by low-grade,
chronic inflammation secondary to aging, is abnormally sensi-
tive and persists long after the initial inflammatory stimuli have
been removed (Clegg et al., 2013; Collerton et al., 2012).
Enhanced chronic inflammation, reflected in an increased level
of pro-inflammatory cytokines, is related to muscle weakness
of the upper and lower extremities, which manifests as the
frailty indicators of reduced handgrip strength and slow gait
speed (Cesari et al., 2004; Zhu et al., 2016). Also related to
increased levels of pro-inflammatory cytokines is enhanced
coagulation activity (i.e., hypercoagulability) that leads to sus-
tained mild clotting activity. These alterations are more com-
mon in frail subjects (Cushman et al., 1996).
Researchers in 23 of the reviewed studies examined the
relationship between inflammation and frailty (Table 1). They
detected enhanced inflammation as indicated by increased
serum concentrations of pro-inflammatory cytokines, such as
C-reactive protein (CRP), tumor necrosis factor a (TNF-a), and
interleukin-6 (IL-6) as well as the secretion of related serine
protease (high-temperature requirement serine protease A1/
HtrA1). An excess of these cytokines, especially CRP, TNF-
a, and IL-6, causes muscle breakdown and increases the risk of
loss of skeletal-muscle mass and strength, or sarcopenia, a
syndrome related to frailty (Hubbard & Woodhouse, 2010).
The relationship between enhanced inflammation and frailty
persists regardless of the presence of significant clinical comor-
bidity (Walston et al., 2002), suggesting a pathophysiological
pathway of frailty that is related to, but independent from,
comorbid diseases. Furthermore, markers of hypercoagulabil-
ity are related to higher rates of frailty, such as essential pro-
teins in blood clotting (Factor I: fibrinogen [Gale, Baylis,
Cooper, & Sayer, 2013; Walston et al., 2002]; Factor VIII:
hemophilia A [Walston et al., 2002]) and an indicator of
ongoing clotting (D-dimer [Walston et al., 2002]). Although
extant research does not clearly explain the association
between hypercoagulability and frailty, it may be due to the
15
mediating effects of inflammation, as hypercoagulability both
reflects and contributes to enhanced inflammation.
Immune dysfunction. An aging immune system (i.e., immunose-
nescence) may function well in homeostasis, but it is highly
likely to fail when stressors such as acute illness, infection, and
enhanced inflammation are present. This lack of internal stress
adaptability gives rise to frailty (Clegg et al., 2013). Charac-
teristics of immunosenescence include reduced stem cell pro-
duction, slower B cell–initiated antibody response (Clegg et al.,
2013), and changes in white blood cells (Leng, Xue, Tian,
Walston, & Fried, 2007), such as lymphocytes (e.g., neutro-
phils and monocytes; Leng, Xue, et al., 2009). Immunosenes-
cence is also related to the endocrinal and inflammatory
processes associated with frailty (Clegg et al., 2013; R. A.
Miller, 1996). Better immune function, therefore, is related to
lower rates of frailty.
Of the reviewed studies, eight examined the relationship of
immune function with frailty (Table 1). Identified biomarkers
include albumin (Collerton et al., 2012; Hubbard et al., 2009;
Walston et al., 2002), differential white cells (Baylis et al.,
2013; Leng, Hung, et al., 2009; Leng et al., 2007), neutrophils
(Collerton et al., 2012; Leng, Xue, et al., 2009), monocytes
(Leng, Xue, et al., 2009), neopterin (Leng et al., 2011), total
lymphocyte counts (Collerton et al., 2012), CD8þCD28– T
cells (Semba et al., 2005), and ratio of memory/naive CD8 T
cells (Collerton et al., 2012; assessed by plasma concentrations/
counts). Increased levels of white blood cells, including neu-
trophils and monocytes, and neopterin, as well as CD8þ CD28–
T cells, were related to higher rates of frailty, while increases in
total lymphocyte count, albumin, and memory/naive CD8 T
cell ratio were related to lower rates of frailty. These associa-
tions indicate that frailty may be linked to weakened immunity,
reflected by lower counts of lymphocytes, albumin, neutro-
phils, monocytes, and lower levels of neopterin, a marker of
immune system activation. Immunosenescence, indicated by a
decrease in the number/functionality of naive T cells and an
increase in the number/functionality of memory T cells and in
CD8þ CD28 T cells, is linked to frailty, although the associ-
ation between memory/naive T cells and frailty went against
this speculation. To date, it is unclear whether biomarkers of
immunosenescence are related to specific frailty indicators.
Metabolic imbalance. Metabolic imbalances such as low serum
concentrations of micronutrients (Corona et al., 2014; Urpi-
Sarda et al., 2015) and altered enzyme activities (Corona
et al., 2014; Hubbard, O’Mahony, Calver, & Woodhouse,
2008; Matteini et al., 2008; Semba et al., 2006; Urpi-Sarda
et al., 2015) can disturb homeostasis and pharmacodynamics
(Hubbard et al., 2008), preceding the development of frailty.
Additionally, the accumulation of metabolic end products, for
example, carboxymethyl-lysine (CML), can cause tissue dam-
age and functional decline (Whitson et al., 2014), which are
also related to frailty. Furthermore, imbalanced metabolic pro-
cesses cause dysfunction in the formation and loss of muscle
cells (atrophy) and muscle fat (fat infiltration). These metabolic
16
changes in the musculoskeletal system reduce muscle mass and
strength, which are related to the slowness and weakness indi-
cators in frailty (Visser et al., 2002, 2005).
Of the reviewed studies, 12 examined the relationship
between the metabolic process and frailty (Table 1). Identified
biomarkers include (a) micronutrients (carotenoids,
a-tocopherol, 25(OH)D; Semba et al., 2006, polyphenols
[Urpi-Sarda et al., 2015]); (b) metabolites (amino acids, acyl-
carnitines, sphingo-, and glycerol-phospholipids [Corona et al.,
2014]); (c) indices of enzyme activity (plasma esterase [Hub-
bard et al., 2008], methylmalonic acid [marker of vitamin B12
deficiency; Matteini et al., 2008]); and (d) metabolic end prod-
ucts (CML [Whitson et al., 2014]).
Most micronutrients (except for polyphenols, which can be
assessed in urine samples), metabolites, enzyme-activity indi-
cators, and metabolic end products are assessed by serum con-
centrations, and decreases in these micronutrients are related to
higher rates of frailty. Markers of musculoskeletal metabolism,
for example, loss of muscle mass and strength (sarcopenia), are
measured using intramuscular adipose tissue, magnetic reso-
nance imaging, and computed tomography ultrasonography
(Addison et al., 2014; Young, Hughes, Russel, Parker, &
Nichols, 1980). These markers of muscular metabolic imbal-
ance (i.e., muscle wasting, muscle strength loss, and muscle fat
infiltration) are related to higher rates of frailty and usually
manifest in skeletal-muscle weakness, which is related to the
frailty indicators of reduced handgrip strength, slow gait speed,
and physical inactivity (Fried et al., 2001; Visser et al., 2002;
Visser et al., 2005; Xue, 2011).
Oxidative stress. Based on the free radical theory of aging (Har-
man, 1956), accumulation of oxidative damage over time leads
to physiologic dysregulation, which is related to a higher inci-
dence of frailty (Fried et al., 2001; Howard et al., 2007). Of the
reviewed studies, eight studies examined the relationship
between oxidative stress and frailty (Table 1). Identified bio-
markers include the following: (1) antioxidants—protectors
against oxidative damage, for example, vitamin E (Ble et al.,
2006) and vitamin B12 and its marker methylmalonic acid
(Matteini et al., 2008); (2) length of telomeres, the DNA “caps”
that protect the internal regions of the chromosomes, of which
shortening indicates DNA replication and reduced functional-
ity of telomerase, both reflecting oxidative damage that causes
cellular aging (Woo et al., 2008); (3) glutathione (GSH)/oxi-
dized glutathione (GSSG) ratio (Serviddio et al., 2009), a mar-
ker of redox status and oxidative stress; and (4) oxidation end
products, including diacron reactive oxygen metabolite
(Namioka et al., 2016), lipoprotein phospholipase A2 (Liu
et al., 2016), isoprostanes (Liu et al., 2016), 8-hydroxy-20-
deoxyguanosine (Wu, Shiesh, Kuo, & Lin, 2009), lipoperoxide
(i.e., malondialehyde; Inglés et al., 2014; Serviddio et al.,
2009), protein carbonylation, and 4-hydroxy-2,3-nonenal- pro-
tein plasma adducts (Inglés et al., 2014; Serviddio et al., 2009).
Researchers assessed these markers in DNA (length of telo-
mere) or serum samples (concentration of other oxidative stress
markers).
Biological Research for Nursing XX(X)
In general, markers of oxidative stress including lower
plasma levels of antioxidants, shorter telomere length, higher
GHS/GSSG ratio, and higher levels of oxidative products are
related to higher rates of frailty, though findings have been
inconsistent. In some studies, higher serum levels of oxidative
stress markers were related to both the overall frailty status (Ble
et al., 2006; Inglés et al., 2014; Matteini et al., 2008; Namioka
et al., 2016; Serviddio et al., 2009; Wu et al., 2009) and the
frailty indicator of slow gait speed (Liu et al., 2016) after
adjusting for age and sex (Inglés et al., 2014). Yet other studies
reported no association between oxidative stress (i.e., telomere
length) and frailty (Woo et al., 2008). This finding might be due
to the fact that oxidative damage on the cellular level, such as
that indicated by telomere length, is largely related to genetic
polymorphisms (Gilson & Londoño-Vallejo, 2007) that may
not extend to cause functional changes in multiple systems
(i.e., frailty). To date, no studies have reported associations
between markers of oxidative stress and frailty indicators other
than slow gait speed.
Comprehensive biomarkers. Researchers also examined biomar-
kers representing comprehensive changes in multiple systems
for their relationships with frailty. These measures include
allostatic load, a cumulative marker representing multisystem
dysregulation calculated using 13 specific biomarkers (Grue-
newald, Seeman, Karlamangla, & Sarkisian, 2009; Szanton,
Allen, Seplaki, Bandeen-Roche, & Fried, 2009); cystatin C
(Hart et al., 2013; Sanchis et al., 2015) and glomerular filtration
rate (GFR; Dalrymple et al., 2013), markers of kidney function;
and hemoglobin (Sanchis et al., 2015), a marker of nutritional
status that affects multiple body systems. Among these mar-
kers, higher alloastatic load (indicating higher stress levels),
higher cystatin C levels, and lower GFR (indicating worse
kidney function) and hemoglobin levels (poor nutritional sta-
tus) were related to higher rates of frailty, suggesting important
roles of cumulative multisystem dysregulation in the develop-
ment of frailty.
Quality Assessment of Reviewed Studies
We assessed the quality of the studies using the STROBE
Statement (von Elm et al., 2007). According to the percentage
of satisfied STROBE items, we rated the quality of five (10%)
studies “high” (>90%), of 24 (46%) studies “moderate” (75–
90%), and of 23 (44%) studies “low” (< 75%). Low STROBE
scores were caused by inadequate reporting that may or may
not reflect a lack of rigor in methodological design. Reporting
inadequacies included (1) missing components: lack of infor-
mation about research design in title or abstract (n ¼ 20, 38%),
lack of a flow diagram (n ¼ 48, 92%) or a detailed report of
study participants per stage (n ¼ 15, 29%), or missing data in
results (n ¼ 38, 73%); (2) insufficient data analysis without
accounting for missing data (n ¼ 40, 77%), subgroup or inter-
actions or sensitivity analysis (n ¼ 28, 54%); and (3) incom-
plete interpretation of results, for example, no discussion of the
generalizability of the findings (n ¼ 23, 44%).
Wang et al.
Discussion
The primary findings in this review were (1) biological changes
in the brain, endocrine, inflammatory, immune, metabolic, and
oxidative stress processes were related to frailty; however, the
causality is unclear; (2) bidirectional interrelationships exist
within and between these biological processes, particularly
those involving inflammation, immune, and endocrine
changes; and (3) because identified biomarkers and processes
are also related to nonfrailty conditions, no single process or
biomarker can detect changes unique to frailty.
Identified Biological Processes and Frailty
The reviewed studies consistently reported associations
between biomarkers of identified biological processes and
overall frailty status, but only a limited number examined how
these biomarkers were related to specific frailty indicators,
such as slow gait speed and weakness. The causality of iden-
tified associations cannot be established because the majority
of studies were observational. In addition, since most studies
were cross-sectional, it is difficult to discern whether the iden-
tified processes were risk factors, correlates, or consequences
of frailty. As frailty is not a unidimensional concept, and dif-
ferent frailty indicators may represent different underlying bio-
logical processes (Arts et al., 2015), a deeper understanding of
the unique longitudinal dynamics of each biological process
and specific frailty indicators and how they interact over time
is needed (Zaslavsky et al., 2013).
Among all identified processes related to frailty, enhanced
inflammation, reflected by increased levels of pro-
inflammatory cytokines (e.g., IL-6, CRP, and TNF-a), is the
most studied. The close relationships between inflammation
and other frailty-related processes, particularly immune and
endocrine dysregulation as well as hypercoagulation, reveal
shared markers and regulation of the reproductive axis and
vitamin D axis. In fact, some studies combined these pro-
cesses into an endocrine–immune–inflammation system
(Baylis et al., 2013), reflecting the close interrelationship
among these processes.
Many processes, especially inflammation, are related to an
array of health conditions. Therefore, the sensitivity of using
biomarkers to detect frailty is uncertain. For example, chronic
inflammation is related not only to frailty but also to other
health conditions that are common in the elderly population,
such as rheumatoid arthritis, coronary artery diseases, and dia-
betes (Espinoza, Jung, & Hazuda, 2012; Johansen et al., 2017;
Trevisan et al., 2017). Therefore, it is difficult to discern
whether changes in inflammation biomarkers are due to the
underlying process of frailty or these comorbidities. Because
of the lack of quantitative standards in using markers to identify
frailty, even when abnormal levels of biomarkers are detected
(according to traditional, disease-specific criteria), it is uncer-
tain (1) whether the changes in biomarkers are due to frailty or
other health conditions and (2) how far along the individual is
in the frailty trajectory.
17
Of note, mitochondrial dysfunction may be a universal bio-
logical model that underlies all of the processes related to
frailty (Ashar et al., 2015). As we noted in a previous publica-
tion (Maxwell & Wang, 2017), mitochondrial function reflects
cellular respiration with systemic effects across all biological
systems. Recent studies reveal that mitochondrial dysfunction
affects multiple health outcomes, such as disability (Distefano
et al., 2017), heart failure (Rosca & Hoppel, 2010), malignant
diseases (Gogvadze, Orrenius, & Zhivotovsky, 2008), and mor-
tality (Ashar et al., 2015). Mitochondrial function is also
related to the biological processes we identified in this review.
For example, mitochondria are linked to brain structure and
function through their effect on BDNF and brain plasticity
(Cheng, Hou, & Mattson, 2010; Raefsky & Mattson, 2017).
Mitochondrial function affects inflammation by regulating cel-
lular response to infection (Tschopp, 2011) and affects immu-
nity by modifying immune-cell activation and cellular
senescence (Mills, Kelly, & O’Neill, 2017). Growth and thyr-
oid hormones affect mitochondrial pathways (Clejan, Collipp,
& Maddaiah, 1980; Sterling, Milch, Brenner, & Lazarus,
1977). Finally, mitochondrial function is linked to oxidative
stress through signaling to increase endogenous antioxidants
(i.e., GSH; J. Chen et al., 2017) and to cell and organism
metabolism through influencing the stress response (Picard
et al., 2015).
Interrelationships Within and Among Biological Processes
Although each of these processes might explain a unique aspect
in frailty, there are intricate, bidirectional connections
within and between these processes, as we have summarized
in Figure 2. For example, the brain–endocrine–inflammation
interrelationship includes the connection between brain and
endocrine changes through the hypothalamic–pituitary axis and
the connection between endocrine and inflammatory changes
through cortisol, hormones of the reproductive axis, and hor-
mones of the vitamin D axis (Bishop, Lu, & Yankner, 2010;
Clegg et al., 2013). As an individual ages, the circulating level
of free cortisol increases. This prolonged exposure to cortisol
“numbs” the regulatory system in the hippocampus and miti-
gates negative feedback, leading to the release of even more
cortisol (Rohleder, Kudielka, Hellhammer, Wolf, & Kirsch-
baum, 2002). Another explanation for this connection is the
decreased secretion of sex hormones secondary to aging. Sex
hormones can dampen the inflammatory response to pathogens
and prevent overreactive responses that would otherwise harm
healthy body tissues (Hunt et al., 2010). Decreased levels of sex
hormones limit the anti-inflammatory response and lead to
enhanced inflammation. The last explanation of this connection
is the PTH–vitamin D axis. Aging-related decrease in vitamin
D upregulates the secretion of PTH, which (1) initiates more
secretion of IL-6 from osteoclasts (McCarty, 2005) and (2)
increases the level of TNF-a (Schleithoff et al., 2006).
Together, reduction in these hormones and by-products of the
endocrine system (sex hormones, cortisol, and vitamin D)
involve brain mechanisms and increase the levels of
18 Biological Research for Nursing XX(X)

hypothalamic-pituitary axis; corsol BDNF; reduced grey maer

Brain Changes

Anoxidants; telemore length; glutathione/oxidized glutathione rao;

oxidaon end products
Oxidave Stress

Metabolic imbalance
Accmulave oxidave
Metabolic end-product: Energy metabolism; micronutrients;
damage: stressor
stressor metabolites; enzyme acvity
indicators; metabolic end-product

Enhanced CRP, TNF-alpha; IL-6; high-temperature requirement

serine protease A1/HtrA1 Frailty
inflammaon
Weakness,
slowness
Factor I, factor II,
skeletal muscle
thrombin;
reproducve Growth hormones,
IL-6, TNF-alpha
axis; vitamin hormones of Factor I, Factor
D axis reproducve axis, and VIII, D-dimer
Vitamin D axis; enhanced clong
inflammatory stressor

Total WBC counts; neutrophils; monocypte counts; neopterin; lymphocyte

immune dysfuncon counts; CD8+CD28- T cell counts; memory/naïve CD8 T cell rao
*Glucose-
insulin
Endocrine balance
Dysregulaon Growth hormones; Vitamin D axis hormones; (insulin,
hormones of hypothalamic–pituitary–adrenal axis and reproducve axis glucose,
ghrelin),

Figure 2. Interrelationships within and among biological processes. BNDF ¼ brain-derived neurotrophic factor; CRP ¼ C-reactive protein;
TNF-a ¼ tumor necrosis factor-a; IL-6 ¼ interleukin-6; WBC ¼ white blood cell.

pro-inflammatory proteins (Hunt et al., 2010), which disturbs
the intrinsic capacity necessary for a balanced stress response
and increases the risk of frailty.
The inflammation–coagulation connection involves shared
biomarkers, including coagulation factors (e.g., fibrinogen/fac-
tor I) and hemostasis enzymes (e.g., thrombin, a cascading
product of prothrombin, and coagulation factor II; Cushman
et al., 1996). Coagulation factors and enzymes (e.g., thrombin)
can increase the release of pro-inflammatory cytokines (i.e.,
IL-6 and TNF-a) and promote the inflammatory response
(Davalos & Akassoglou, 2012; Robson, Shephard, & Kirsch,
1994). Inflammation, in turn, can also cause an imbalance of
normal coagulant that activates the hemostasis process (Mar-
getic, 2012). The bidirectional inflammation–coagulation con-
nection contributes to greater risk of frailty.
The core of the inflammation–immunity connection
includes an enhanced stressor (aging-related inflammation,
i.e., “inflammaging”) and a dysregulated immune response that
persists (immunosenescence; Hunt et al., 2010). Reduced
secretions of reproductive and growth hormones as well as
changes in the hormones of the vitamin D axis upregulate the
inflammatory process. Chronic inflammation, as a stressor,
also stimulates an overly reactive immune response, especially
when the immune system does not have a normal “finish line”
(such as in immunosenescence). Aging-related chronic inflam-
mation and immunosenescence thus augment each other, con-
tributing to an increased risk of frailty.
In addition, disturbances in the brain, endocrine, and
immune systems (Clegg et al., 2013), along with nutritional
deficiencies (Semba et al., 2006; Urpi-Sarda et al., 2015),
cause a multisystem metabolic imbalance that is related to
frailty. One example of such a multisystem imbalance is the
reciprocal response between glucose and insulin that is main-
tained by endocrine function (secretion and sensitivity of
insulin and ghrelin). Once the balance of this response is
disturbed, such as in diabetic and prediabetic subjects, imbal-
ances in energy and protein metabolism occur (higher levels
of circulating glucose and insulin with higher insulin resis-
tance lead to less glucose being available for energy produc-
tion), thus contributing to frailty. Such evidence supports
epidemiolgical findings of diabetes as a key risk factor for
frailty (Espinoza et al., 2012; Johansen et al., 2017), and
ongoing trials that aim to normalize the glucose–insulin
response using medications (e.g., metformin; NCT02570672).
Both stressors related to oxidative stress and advanced glyca-
tion end products in the metabolic process can cause enhanced
inflammation (Clegg et al., 2013; Hubbard & Woodhouse,
2010), forming the oxidative stress—inflammation and meta-
bolic imbalance—inflammation connections.
Given the interconnectivity of frailty-related biological pro-
cesses, biomarkers representing multiple physiological impair-
ments should be considered in frailty studies for better
prediction of adverse outcomes like disability and mortality
(Hubbard & Woodhouse, 2010; Mitnitski et al., 2015; Sanchis
et al., 2015). These markers could include changes in inflam-
matory, endocrinal, cardiovascular (e.g., heart rate variability),
or renal function (e.g., GFR) and markers of cumulative phy-
siological dysregulation (e.g., allostatic overload; Clegg et al.,
Wang et al.
2013; Dalrymple et al., 2013; Gruenewald et al., 2009; Hart
et al., 2013; Szanton et al., 2009; Varadhan et al., 2009).
The interrelationships within and among these processes
also make it challenging to unravel the causality underlying
frailty. It is difficult to discern which process might be the
trigger in the cascade of multisystem frailty development. Most
of the studies in the present review only examined one process
using a cross-sectional design without accounting for potential
interrelationship with other processes. Although inflammation
is the most studied process involved in frailty, it is unlikely the
cause of all the other processes and, consequently, is unlikely to
be the only biological mechanism of frailty.
Associations Between Frailty and Biomarkers
Although the trends of associations between frailty and biomar-
kers are mostly consistent across studies—for example, that
higher levels of pro-inflammatory cytokines are related to
higher rates of frailty, while higher levels of antioxidants are
related to lower rates of frailty—variance exists in the strengths
of reported associations (Online Supplemental Material, Table
1). This variance might be due to a few reasons. First, it could
be due to variance in the measures for frailty. The choice of
frailty measure depends on the purpose of research. When the
purpose is to examine the biological underpinnings and etiol-
ogy of frailty, researchers should use instruments with psycho-
metric validity that do not also include measures of disease,
comorbidity, or disability (Buta et al., 2016), due to the inher-
ent differences in the conceptualizations of frailty, comorbid-
ity, and disability (Fried, Ferrucci, Darer, Williamson, &
Anderson, 2004). We noted that the reviewed studies use a
variety of frailty measures, including self-developed measures
that had not been validated previously and those that also mea-
sured diseases and comorbidities (Morley et al., 2012; Rock-
wood et al., 2005).
Second, this variance in the findings regarding the associa-
tions of biomarkers with frailty might also be due to variance in
the methods for measuring and sources of biomarkers.
Researchers in these studies took a variety of approaches to
measuring the level of biomarkers, perhaps at least partially
because standards for biomarker assessment have changed over
time. For instance, investigators used traditional ELISA kits to
assess the levels of inflammatory markers, such as IL-6, TNF-
a, and CRP in some studies (Coelho et al., 2012; Hubbard et al.,
2008; Lai et al., 2014; Reiner et al., 2009), while in a more
recent study (Zhu et al., 2016), researchers used chemilumines-
cence immunoassay, a different approach with better sensitiv-
ity, to measure CRP.
The sources of biomarkers also differed. Some studies (e.g.,
Zaslavsky et al., 2016) described the collection of samples
(fasting or nonfasting blood samples and urine samples in the
morning or during the day), while in other studies, authors
provided no information as to when and how they collected
the samples. Depending on the biomarker being assessed (espe-
cially those with circadian variation in levels, such as
19
hormones), authors should report the time and procedures for
sample collection.
The researchers also used different units of measure and
different risk-group categorizations based on biomarker levels
across studies. In some studies, researchers treated levels of
biomarkers as continuous variables (i.e., used actual level, log
or natural log-transformed z scores), while in other studies, they
used ranges of measures to create categories in a variety of
ways. For example, Hubbard, O’Mahony, Savva, Calver, and
Woodhouse (2009) treated the level of CRP as a continuous
variable in inferential analysis, while Zhu et al. (2016) categor-
ized the levels of CRP into low/reference (<1 mg/dl), inter-
mediate (1.01–3 mg/dl), and high (>3 mg/dl), and Collerton
et al. (2012) categorized CRP levels into low (< 1.2 mg/dl),
intermediate/reference (1.2–6 mg/dl), and high (>6 mg/dl). It
may be that the differences in the strength of the associations
between CRP and frailty could be attributed to this variance,
with Hubbard et al. (2009) reporting a log-transformed coeffi-
cient of 0.221 for CRP’s correlation with the frailty index, Zhu
et al. (2016) reporting odds ratios of having a frailty phenotype
of 1.19 for intermediate versus low CRP and 1.43 for high
versus low CRP, and Collerton et al. (2012) reporting an odds
ratio of 1.78 for high versus intermediate. The various methods
we found that researchers used to measure biomarkers and
determine high-risk biomarker groups underscore the challenge
of interpreting findings across studies and present a threat to
external validity.
Third, the variance in sample characteristics (age, health
condition, cognitive functioning) and analytical approaches,
as reported earlier, might also explain why the strength of
reported associations varied across studies. For example, the
mean age of the samples in the reviewed studies was 75 years.
Individuals of this age might present different risk profiles
related to biomarkers (e.g., different cutoff points to determine
high risk) than would the very old (85 years and older), who
were included in some of the samples. The samples also varied
across studies in their health conditions and cognitive function-
ing. In 37 (71%) studies, researchers excluded subjects with
specific health conditions, such as acute infection, certain
chronic diseases and functional disabilities, and in 18 (35%)
studies, researchers excluded subjects with cognitive impair-
ments. Even among these studies, the specific health conditions
that were exclusionary and the criteria for determining cogni-
tive impairment differed, limiting the comparability and gen-
eralizability of findings. In particular, as cognitive functioning
is closely related to frailty (as described in “Changes in the
Brain,” above), it is possible that subjects who are cognitively
impaired may be the frailest subgroup. Thus, excluding these
subjects from frailty research might have artificially created a
sample with a decreased risk of frailty and a reduced number of
frailty indicators, which may not represent the whole spectrum
of frailty development.
It is also worth noting that the majority of participants in the
reviewed studies were Caucasian, and frailty and related bio-
logical phenomena may not manifest in the same ways across
racial and ethnic groups. For example, older people who
20
identify as part of a minority racial group have higher levels of
chronic stress and allostatic load, the “wear and tear of the
body” that accumulates in response to persistent, repeated
stressors (i.e., internal or external challenges to the body), when
compared to older people who identify as White. Thus, those
who identify as members of racial minority groups may have an
increased risk of frailty and development of health conditions
such as cardiovascular disease. Racial disparities in the devel-
opment of frailty, particularly among subgroups that contend
with persistent stressors (Seeman et al., 1997), should be fur-
ther investigated.
Besides the variation we observed in the strength of reported
associations between biomarkers and frailty across studies,
there are additional challenges for understanding the unique
role of biomarkers in the development of frailty. First,
researchers have studied a variety of biomarkers for each pro-
cess. Second, some biomarkers are related to more than one
process, such as IL-6, which plays a role in both inflammation
and immune processes; fibrinogen, which plays a role in the
inflammation and coagulation processes; and the glucose–insu-
lin balance, which plays a role in endocrine and metabolic
processes. Third, even within the same biological process,
some markers of frailty also indicate diseases that are related
to frailty but have a different etiology. For example, research-
ers used IL-6, CRP, and TNF-a as markers of enhanced inflam-
mation, but these markers are related to both frailty and chronic
disease, as previously discussed. Due to the complexity of the
roles of the biomarkers selected to represent each process,
overlap in biomarkers among different processes, and lack of
ability to determine the direction of causality between biomar-
kers and frailty, it is not possible to determine whether the
identified processes are drivers for frailty, compensatory
responses to frailty, or indicators of other pathophysiological
processes related to frailty.
Directions for Future Research
Future research is needed to determine which biological pro-
cess triggers biomarker changes that occur prior to other pro-
cesses, as well as the frailty indicators that emerge first. We
also need to understand whether this process is modifiable and,
if so, what might be the best way to intervene in this initial
process. Given the close interrelationships among the identified
biological processes related to frailty, it is possible that (1) the
causality does not reside in a single biological process but
rather is related to these interrelationships and (2) instead of
a single biomarker, a composite index of multisystem biomar-
kers with validated diagnostic thresholds might be more sensi-
tive for the early detection of frailty and specific indicators of
frailty. For example, an index including CRP, IL-6, and other
inflammatory markers might be used to identify subjects with
higher risk of slower gait speed, weaker grip strength, and
lower physical activity (Sarkisian, Gruenewald, John Boscar-
din, & Seeman, 2008), while an index with albumin, glucose,
insulin, and endocrinal markers might be used to detect people
at risk of weight loss and exhaustion. In addition, as the levels
Biological Research for Nursing XX(X)
of many biomarkers (e.g., CRP, IL-6, insulin, and albumin) are
readily available in electronic health records (EHRs), we
should also consider using data-driven analytical methods,
such as machine learning and data mining, to proactively cap-
ture data from EHR, reveal novel and nonlinear relationships
between biomarkers and frailty, and proactively identify high-
risk patients using information from routine tests (Westra et al.,
2015). Lastly, an emerging body of work has shown promise
for the identification of genetic biomarkers related to frailty
(Mekli et al., 2017). For example, specific genomes and epi-
genetic markers related to inflammatory pathways and the
stress response have been found in significantly higher levels
in frail people, highlighting the critical role of enhanced
inflammation in the development of frailty. Genomic research
should be conducted in further breadth and depth to explore the
development of specific frailty indicators among older adults
with different chronic conditions in order to improve the pre-
cision in risk prediction and design of targeted interventions for
people who present different combinations of frailty indicators
and different chronic conditions.
As changes in these biological processes might be undetect-
able in basal conditions, we need to repeatedly measure asso-
ciated biomarkers when stressors are present (Varadhan et al.,
2008), such as during acute exacerbation of chronic illnesses.
There is also a need for more diverse patient populations, as
over half the reviewed studies used data from population-based
cohorts that were conducted in a limited number of geographic
regions. Additionally, despite the racial differences in biomar-
kers and frailty (Leng, Hung, et al., 2009; Matteini et al., 2008),
the reviewed studies were conducted primarily among Cauca-
sian subjects. Since interventional studies are the best approach
for investigating causal relationship, a first step might be to
analyze existing data from multiracial samples in existing
interventional studies.
Implications for Nursing Science
Nurses are on the front lines for assessing geriatric syndromes
(e.g., frailty) and coordinating interventions. Since changes in
mechanistic biomarkers precede the development of frailty
symptomology, knowledge about frailty biomarkers provides
an opportunity to detect frailty early on, to monitor the devel-
opment of frailty, and to characterize different frailty subtypes
and trajectories in both natural and interventional conditions.
Early detection of the development of frailty is of particular
importance to older adults with multimorbidity (prevalence
25%; Mercer, Smith, Wyke, O’Dowd, & Watt, 2009), as the
processes related to frailty are also related to other conditions.
Biomarkers associated with these processes, such as insulin,
albumin, CRP and IL-6, that were commonly assessed in the
reviewed studies and are readily available in clinical nursing
practice, should be monitored closely among patients who have
already shown risk factors for frailty, such as those with dia-
betes and prediabetes. Biomarkers are also useful for identify-
ing appropriate interventions specific to related biological
mechanisms and evaluating the effectiveness of interventions
Wang et al.
(e.g., physical exercise and [pre]rehabilitation, nutritional sup-
port, and psychosocial consultation) to not only slow the prog-
ress of frailty but also proactively delay its onset and/or
decrease the risk of adverse outcomes. These interventions are
of particular importance for vulnerable (i.e., prefrail) older
adults prior to invasive or high-risk procedures, treatment
(e.g., chemotherapy), or surgery (e.g., elective hip-
replacement surgeries) that may trigger the stress response and
thus precipitate the development or worsening of frailty. As
nurses play an essential role in the coordination of these inter-
ventions (Metzelthin et al., 2012), knowledge about frailty and
related biological processes can help them identify patients
who are most likely to respond (or not) to interventions that
have the potential to improve the quality of life (Nicholson,
Meyer, Flatley, & Holman, 2013).
Strengths and Limitations
To our knowledge, this is the first review to synthesize knowl-
edge about biological processes related to frailty, identify inter-
relationships among these processes, and discuss how the
interrelationships affect the assessment of and intervention for
frailty. Readers should interpret the findings with the following
limitations in mind. First, because of the scarcity of studies that
assessed interventions for frailty and included measures of bio-
markers (n ¼ 1), we were not able to draw conclusions about
the direction of causality of the observed associations. Second,
we did not, in our literature search, specify the biological pro-
cesses associated with frailty, such as inflammation, endocrine,
and oxidative stress. Specifically, we did not use search terms
corresponding to each biomarker in the literature search, for
example, glucose or insulin, as that was beyond scope of this
review, and we might have missed studies if they did not use
the selected Medical Subject Headings (MeSH) terms (e.g.,
biological phenomena and biomarkers). Third, in 12 of the
studies, authors did not report the strength of the association
between the biomarkers and frailty, thus we could not include
specific parameters of identified associations from those stud-
ies in Supplemental Table 1. Lastly, since 51 of the 52
reviewed studies were observational, we used the STROBE
checklist to appraise quality, yet the checklist does not differ-
entiate weaknesses in methodological design from those in
reporting. Despite these limitations, our review fills a gap in
understanding about the underlying biological processes
related to frailty, and our findings are highly relevant for devel-
oping mechanism-specific interventions for frailty.
Conclusion
Frailty involves multiple biological processes, especially those
related to inflammatory, immune, and endocrinal function. To
date, the direction of causality of the relationship between these
processes and frailty remains uncertain, and no biomarkers
have been identified that can differentiate between changes
related to frailty and those related to comorbid diseases. The
lack of longitudinal and interventional studies to inform the
21
assessment of the direction of causality in the relationship
between identified biological processes and frailty and the
overlap among biomarkers used to detect changes in each pro-
cess present additional challenges for our understanding of
frailty. Frailty represents a lack of adaptive capacity of the
human body that occurs over time and leads to functional
decline and eventually death. The search for a specific biolo-
gical process to identify as the primary mechanism of frailty
may be fruitless in light of the complex and multifactorial
nature of frailty. Rather, a multisystem approach for assess-
ment and intervention is likely necessary.
Acknowledgment
The authors wanted to thank Ms. Elizabeth Connor for her assistance
with quality assessment of selected studies.
Author Contributions
JW contributed to the conceptualization, literature search, data anal-
ysis, structure, draft, and revision of the manuscript; CM contributed
to the conceptualization, data analysis, structure and revision of the
manuscript; FY contributed to the conceptualization, structure and
revision of the manuscript.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
Supplemental Material
Supplemental material for this article is available online.
References
Addison, O., Drummond, M. J., LaStayo, P. C., Dibble, L. E., Wende,
A. R., McClain, D. A., & Marcus, R. L. (2014). Intramuscular fat
and inflammation differ in older adults: The impact of frailty and
inactivity. Journal of Nutrition Health and Aging, 18, 532–538.
doi:10.1007/s12603-014-0019-1
Arts, M. H., Collard, R. M., Comijs, H. C., Naude, P. J., Risselada, R.,
Naarding, P., . . . Voshaar, R. C. (2015). Relationship between
physical frailty and low-grade inflammation in late-life depression.
Journal of American Geriatric Society, 63, 1652–1657. doi:10.
1111/jgs.13528
Ashar, F. N., Moes, A., Moore, A. Z., Grove, M. L., Chaves, P. H. M.,
Coresh, J., . . . Arking, D. E. (2015). Association of mitochondrial
DNA levels with frailty and all-cause mortality. Journal of Mole-
cular Medicine, 93, 177–186. doi:10.1007/s00109-014-1233-3
Balducci, L., & Extermann, M. (2000). Management of cancer in the
older person: A practical approach. Oncologist, 5, 224–237. doi:
10.1634/theoncologist.5-3-224
Bandeen-Roche, K., Seplaki, C. L., Huang, J., Buta, B., Kalyani, R. R.,
Varadhan, R., . . . Kasper, J. D. (2015). Frailty in older adults: A
nationally representative profile in the United States. Journals of
Gerontology Series A: Biological Sciences and Medical Sciences,
70, 1427–1434.
22
Barzilay, J. I., Blaum, C., Moore, T., Xue, Q. L., Hirsch, C. H.,
Walston, J. D., & Fried, L. P. (2007). Insulin resistance and inflam-
mation as precursors of frailty: The Cardiovascular Health Study.
Archives of Internal Medicine, 167, 635–641. doi:10.1001/
archinte.167.7.635
Baylis, D., Bartlett, D. B., Syddall, H. E., Ntani, G., Gale, C. R.,
Cooper, C., . . . Sayer, A. A. (2013). Immune-endocrine biomar-
kers as predictors of frailty and mortality: A 10-year longitudinal
study in community-dwelling older people. Age, 35, 963–971. doi:
10.1007/s11357-012-9396-8
Beben, T., Ix, J. H., Shlipak, M. G., Sarnak, M. J., Fried, L. F.,
Hoofnagle, A. N., . . . Rifkin, D. E. (2016). Fibroblast growth
factor-23 and frailty in elderly community-dwelling individuals:
The cardiovascular health study. Journal of American Geriatrics
Society, 64, 270–276. doi:10.1111/jgs.13951
Bishop, N. A., Lu, T., & Yankner, B. A. (2010). Neural mechanisms of
ageing and cognitive decline. Nature, 464, 529–535. doi:10.1038/
nature08983
Ble, A., Cherubini, A., Volpato, S., Bartali, B., Walston, J. D., Wind-
ham, B. G., . . . Ferrucci, L. (2006). Lower plasma vitamin E levels
are associated with the frailty syndrome: The InCHIANTI study.
Journals of Gerontology Series A: Biological Sciences and Medi-
cal Sciences, 61, 278–283.
Brouwers, B., Dalmasso, B., Hatse, S., Laenen, A., Kenis, C., Swerts,
E., . . . Wildiers, H. (2015). Biological ageing and frailty markers
in breast cancer patients. Aging, 7, 319–333.
Buchman, A. S., Yu, L., Wilson, R. S., Boyle, P. A., Schneider, J. A.,
& Bennett, D. A. (2014). Brain pathology contributes to simulta-
neous change in physical frailty and cognition in old age. Journals
of Gerontology Series A: Biological Sciences and Medical
Sciences, 69, 1536–1544. doi:10.1093/gerona/glu117
Buchman, A. S., Yu, L., Wilson, R. S., Schneider, J. A., & Bennett, D.
A. (2013). Association of brain pathology with the progression of
frailty in older adults. Neurology, 80, 2055–2061. doi:10.1212/
WNL.0b013e318294b462
Buta, B. J., Walston, J. D., Godino, J. G., Park, M., Kalyani, R. R.,
Xue, Q. L., . . . Varadhan, R. (2016). Frailty assessment instru-
ments: Systematic characterization of the uses and contexts of
highly-cited instruments. Ageing Research Reviews, 26, 53–61.
doi:10.1016/j.arr.2015.12.003
Calvani, R., Marini, F., Cesari, M., Tosato, M., Anker, S. D., von
Haehling, S., . . . Marzetti, E. (2015). Biomarkers for physical
frailty and sarcopenia: State of the science and future develop-
ments. Journal of Cachexia, Sarcopenia, and Muscle, 6,
278–286. doi:10.1002/jcsm.12051
Ceci, R., Duranti, G., Rossi, A., Savini, I., & Sabatini, S. (2011).
Skeletal muscle differentiation: Role of dehydroepiandrosterone
sulfate. Hormone and Metabolic Research, 43, 702–707.
Cesari, M., Penninx, B. W., Pahor, M., Lauretani, F., Corsi, A. M.,
Williams, G. R., . . . Ferrucci, L. (2004). Inflammatory markers
and physical performance in older persons: The InCHIANTI study.
Journals of Gerontology Series A: Biological Sciences and Medi-
cal Sciences, 59, M242–M248.
Chen, J., Jiang, X., Zhang, C., MacKenzie, K. R., Stossi, F., Palzkill,
T., . . . Wang, J. (2017). Reversible reaction-based fluorescent
Biological Research for Nursing XX(X)
probe for real-time imaging of glutathione dynamics in mitochon-
dria. ACS Sensors, 2, 1257–1261.
Chen, W. T., Chou, K. H., Liu, L. K., Lee, P. L., Lee, W. J., Chen, L.
K., . . . Lin, C. P. (2015). Reduced cerebellar gray matter is a
neural signature of physical frailty. Human Brain Mapping, 36,
3666–3676. doi:10.1002/hbm.22870
Cheng, A., Hou, Y., & Mattson, M. P. (2010). Mitochondria and
neuroplasticity. ASN Neuro, 2, e00045. doi:10.1042/an20100019
Choi, J., Ahn, A., Kim, S., & Won, C. W. (2015). Global prevalence of
physical frailty by Fried’s criteria in community-dwelling elderly
with national population-based surveys. Journal of the American
Medical Directors Association, 16, 548–550. doi:10.1016/j.jamda.
2015.02.004
Clegg, A., Young, J., Iliffe, S., Rikkert, M. O., & Rockwood, K.
(2013). Frailty in elderly people. Lancet, 381, 752–762. doi:10.
1016/S0140-6736(12)62167-9
Clejan, S., Collipp, P. J., & Maddaiah, V. T. (1980). Hormones
and liver mitochondria: Influence of growth hormone, thyrox-
ine, testosterone, and insulin on thermotropic effects of respira-
tion and fatty acid composition of membranes. Archives of
Biochemistry and Biophysics, 203, 744–752. doi:10.1016/
0003-9861(80)90234-9.
Coelho, F. M., Pereira, D. S., Lustosa, L. P., Silva, J. P., Dias, J. M. D.,
Dias, R. C. D., . . . Pereira, L. S. M. (2012). Physical therapy inter-
vention (PTI) increases plasma brain-derived neurotrophic factor
(BDNF) levels in non-frail and pre-frail elderly women. Archives
of Gerontology and Geriatrics, 54, 415–420. doi:10.1016/j.arch-
ger.2011.05.014
Colburn, W., DeGruttola, V., DeMets, D., Downing, G., Hoth, D., &
Oates, J., . . . Biomarkers Definitions Working Group. (2001). Bio-
markers and surrogate endpoints: Preferred definitions and con-
ceptual framework. . Clinical Pharmacology & Therapeutics, 69,
89–95.
Collard, R. M., Boter, H., Schoevers, R. A., & Oude Voshaar, R. C.
(2012). Prevalence of frailty in community-dwelling older persons:
A systematic review. Journal of the American Geriatrics Society,
60, 1487–1492. doi:10.1111/j.1532-5415.2012.04054.x
Collerton, J., Martin-Ruiz, C., Davies, K., Hilkens, C. M., Isaacs, J.,
Kolenda, C., . . . Kirkwood, T. B. L. (2012). Frailty and the role of
inflammation, immunosenescence and cellular ageing in the very
old: Cross-sectional findings from the Newcastle 85þ study.
Mechanisms of Ageing and Development, 133, 456–466. doi:10.
1016/j.mad.2012.05.005
Cooper, C., Dere, W., Evans, W., Kanis, J. A., Rizzoli, R., Sayer,
A. A., . . . Reginster, J. Y. (2012). Frailty and sarcopenia: Def-
initions and outcome parameters. Osteoporosis International,
23, 1839–1848. doi:10.1007/s00198-012-1913-1
Corona, G., Polesel, J., Fratino, L., Miolo, G., Rizzolio, F., Crivellari,
D., . . . Toffoli, G. (2014). Metabolomics biomarkers of frailty in
elderly breast cancer patients. Journal of Cellular Physiology, 229,
898–902. doi:10.1002/jcp.24520
Corwin, E. J., & Ferranti, E. (2016). Integration of biomarkers to
advance precision nursing interventions for family research across
the lifespan. Nursing Outlook, 64, 292–298. doi:10.1021/acssen-
sors.7b00425
Wang et al.
Cushman, M., Psaty, B. M., Macy, E., Bovill, E. G., Cornell, E. S.,
Kuller, L. H., & Tracy, R. P. (1996). Correlates of thrombin mar-
kers in an elderly cohort free of clinical cardiovascular disease.
Arteriosclerosis, Thrombosis, and Vascular Biology, 16,
1163–1169.
Dalrymple, L. S., Katz, R., Rifkin, D. E., Siscovick, D., Newman, A.
B., Fried, L. F., . . . Shlipak, M. G. (2013). Kidney function and
prevalent and incident frailty. Clinical Journal of the American
Society of Nephrology, 8, 2091–2099. doi:10.2215/cjn.02870313
Davalos, D., & Akassoglou, K. (2012). Fibrinogen as a key regulator
of inflammation in disease. Seminars in Immunopathology, 34,
43–62. doi:10.1007/s00281-011-0290-8
Distefano, G., Standley, R. A., Zhang, X., Carnero, E. A., Yi, F.,
Cornnell, H. H., & Coen, P. M. (2017). Physical activity unveils
the relationship between mitochondrial energetics, muscle quality
and physical function in older adults. bioRxiv, 164160. doi.org/10.
1101/164160.
Ehlenbach, W. J., Larson, E. B., Randall Curtis, J., & Hough, C. L.
(2015). Physical function and disability after acute care and critical
illness hospitalizations in a prospective cohort of older adults.
Journal of the American Geriatrics Society, 63, 2061–2069.
El Assar, M., Angulo, J., Carnicero, J. A., Walter, S., Garcia-Garcia, F.
J., Lopez-Hernandez, E., . . . Rodriguez-Manas, L. (2017). Frailty
is associated with lower expression of genes involved in cellular
response to stress: Results from the Toledo Study for Healthy
Aging. Journal of the American Medical Directors Association,
18, 734.e731–734.e737. doi:10.1016/j.jamda.2017.04.019
Ensrud, K. E., Blackwell, T. L., Cauley, J. A., Cummings, S. R.,
Barrett-Connor, E., Dam, T. T., . . . Cawthon, P. M. (2011). Cir-
culating 25-hydroxyvitamin D levels and frailty in older men: The
osteoporotic fractures in men study. Journal of the American Ger-
iatrics Society, 59, 101–106. doi:10.1111/j.1532-5415.2010.
03201.x
Ensrud, K. E., Ewing, S. K., Taylor, B. C., Fink, H. A., Stone, K. L.,
Cauley, J. A., . . . Cawthon, P. M. (2007). Frailty and risk of falls,
fracture, and mortality in older women: The study of osteoporotic
fractures. Journals of Gerontology Series A: Biological Sciences
and Medical Sciences, 62, 744–751.
Espinoza, S. E., Jung, I., & Hazuda, H. (2012). Frailty transitions in
the San Antonio longitudinal study of aging. Journal of American
Geriatric Society, 60, 652–660. doi:10.1111/j.1532-5415.2011.
03882.x
Fedarko, N. S. (2011). The biology of aging and frailty. Clinics in
Geriatric Medicine, 27, 27–37. doi:10.1016/j.cger.2010.08.006
Fougere, B., Vellas, B., Van Kan, G. A., & Cesari, M. (2015). Iden-
tification of biological markers for better characterization of older
subjects with physical frailty and sarcopenia. Translational Neu-
roscience, 6, 103–110. doi:10.1515/tnsci-2015-0009
Fried, L. P., Ferrucci, L., Darer, J., Williamson, J. D., & Anderson, G.
(2004). Untangling the concepts of disability, frailty, and comor-
bidity: Implications for improved targeting and care. Journals of
Gerontology Series A: Biological Sciences and Medical Sciences,
59, M255–M263.
Fried, L. P., Tangen, C. M., Walston, J., Newman, A. B., Hirsch, C., &
Gottdiener, J., . . . Cardiovascular Health Study Collaborative
Research Group. (2001). Frailty in older adults evidence for a
23
phenotype. Journals of Gerontology Series A: Biological Sciences
and Medical Sciences, 56, M146–M157.
Gale, C. R., Baylis, D., Cooper, C., & Sayer, A. A. (2013). Inflam-
matory markers and incident frailty in men and women: The Eng-
lish Longitudinal Study of Ageing. Age, 35, 2493–2501. doi:10.
1007/s11357-013-9528-9
Gilson, E., & Londoño-Vallejo, J. A. (2007). Telomere length profiles
in humans: All ends are not equal. Cell Cycle, 6, 2486–2494. doi:
10.4161/cc.6.20.4798
Gogvadze, V., Orrenius, S., & Zhivotovsky, B. (2008). Mitochondria
in cancer cells: What is so special about them? Trends in Cell
Biology, 18, 165–173.
Gruenewald, T. L., Seeman, T. E., Karlamangla, A. S., & Sarkisian, C.
A. (2009). Allostatic load and frailty in older adults. Journal of
American Geriatrics Society, 57, 1525–1531. doi:10.1111/j.1532-
5415.2009.02389.x
Harman, D. (1956). Aging: A theory based on free radical and radia-
tion chemistry. Journal of Gerontology, 11, 298–300.
Hart, A., Paudel, M. L., Taylor, B. C., Ishani, A., Orwoll, E. S., Caw-
thon, P. M., & Ensrud, K. E. (2013). Cystatin C and frailty in older
men. Journal of American Geriatrics Society, 61, 1530–1536. doi:
10.1111/jgs.12413
Howard, C., Ferrucci, L., Sun, K., Fried, L. P., Walston, J., Varadhan,
R., . . . Semba, R. D. (2007). Oxidative protein damage is associ-
ated with poor grip strength among older women living in the
community. Journal of Applied Physiology, 103, 17–20.
Hubbard, R. E., O’Mahony, M. S., Calver, B. L., & Woodhouse, K. W.
(2008). Plasma esterases and inflammation in ageing and frailty.
European Journal of Clinical Pharmacology, 64, 895–900. doi:10.
1007/s00228-008-0499-1
Hubbard, R. E., O’Mahony, M. S., Savva, G. M., Calver, B. L., &
Woodhouse, K. W. (2009). Inflammation and frailty measures in
older people. Journal of Cellular and Molecular Medicine, 13,
3103–3109. doi:10.1111/j.1582-4934.2009.00733.x
Hubbard, R. E., & Woodhouse, K. W. (2010). Frailty, inflammation
and the elderly. Biogerontology, 11, 635–641. doi:10.1007/
s10522-010-9292-5
Hunt, K. J., Walsh, B. M., Voegeli, D., & Roberts, H. C. (2010).
Inflammation in aging part 1: Physiology and immunological
mechanisms. Biological Research for Nursing, 11, 245–252.
Hyde, Z., Flicker, L., Almeida, O. P., Hankey, G. J., McCaul, K. A.,
Chubb, S. A., & Yeap, B. B. (2010). Low free testosterone predicts
frailty in older men: The health in men study. Journal of Clinical
Endocrinology & Metabolism, 95, 3165–3172. doi:10.1210/jc.
2009-2754
Inglés, M., Gambini, J., Carnicero, J. A., Garcı́a-Garcı́a, F. J., Rodrı́-
guez-Mañas, L., Olaso-González, G., . . . Viña, J. (2014). Oxida-
tive stress is related to frailty, not to age or sex, in a geriatric
population: Lipid and protein oxidation as biomarkers of frailty.
Journal of the American Geriatrics Society, 62, 1324–1328.
Inglés, M., Gambini, J., Mas-Bargues, C., Garcı́a-Garcı́a, F. J., Viña, J.,
& Borrás, C. (2017). Brain-derived neurotrophic factor as a
marker of cognitive frailty. Journals of Gerontology Series A:
Biological Sciences and Medical Sciences, 72, 450–451. doi:10.
1093/gerona/glw145
24
Johansen, K. L., Dalrymple, L. S., Delgado, C., Chertow, G. M.,
Segal, M. R., Chiang, J., . . . Kaysen, G. A. (2017). Factors asso-
ciated with frailty and its trajectory among patients on hemodia-
lysis. Clinical Journal of the American Society of Nephrology, 12,
1100–1108. doi:10.2215/cjn.12131116
Joseph, B., Pandit, V., Zangbar, B., Kulvatunyou, N., Hasmi, A.,
Green, D., . . . Rhee, P. (2014). Superiority of frailty over age in
predicting outcomes among geriatric trauma patients: A prospec-
tive analysis. JAMA Surgery, 149, 766–772. doi:10.1001/jamasurg.
2014.296
Kahlon, S., Pederson, J., Majumdar, S. R., Belga, S., Lau, D.,
Fradette, M., . . . Padwal, R. S. (2015). Association between
frailty and 30-day outcomes after discharge from hospital.
Canadian Medical Association Journal, 187, 799–804. doi:10.
1503/cmaj.150100
Kalyani, R. R., Tian, J., Xue, Q. L., Walston, J., Cappola, A. R.,
Fried, L. P., . . . Blaum, C. S. (2012). Hyperglycemia and inci-
dence of frailty and lower extremity mobility limitations in older
women. Journal of American Geriatrics Society, 60, 1701–1707.
doi:10.1111/j.1532-5415.2012.04099.x
Kalyani, R. R., Varadhan, R., Weiss, C. O., Fried, L. P., & Cappola, A.
R. (2012a). Frailty status and altered glucose-insulin dynamics.
Journals of Gerontology. Series A, Biological Sciences and Med-
ical Sciences, 67, 1300–1306. doi:10.1093/gerona/glr141
Kalyani, R. R., Varadhan, R., Weiss, C. O., Fried, L. P., & Cappola, A.
R. (2012b). Frailty status and altered dynamics of circulating
energy metabolism hormones after oral glucose in older women.
Journal of Nutrition Health and Aging, 16, 679–686. doi:10.1007/
s12603-012-0369-5
Lai, H. Y., Chang, H. T., Lee, Y. L., & Hwang, S. J. (2014). Associ-
ation between inflammatory markers and frailty in institutionalized
older men. Maturitas, 79, 329–333. doi:10.1016/j.maturitas.2014.
07.014
Leng, S. X., Cappola, A. R., Andersen, R. E., Blackman, M. R.,
Koenig, K., Blair, M., & Walston, J. D. (2004). 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 Clinical
and Experimental Research, 16, 153–157. doi:10.1007/
bf03324545
Leng, S. X., Hung, W., Cappola, A. R., Yu, Q., Xue, Q. L., & Fried, L.
P. (2009). White blood cell counts, insulin-like growth factor-1
levels, and frailty in community-dwelling older women. Journals
of Gerontology Series A: Biological Sciences and Medical
Sciences, 64, 499–502. doi:10.1093/gerona/gln047
Leng, S. X., Tian, X., Matteini, A., Li, H., Hughes, J., Jain, A., . . .
Fedarko, N. S. (2011). IL-6-independent association of elevated
serum neopterin levels with prevalent frailty in community-
dwelling older adults. Age and Ageing, 40, 475–481. doi:10.
1093/ageing/afr047
Leng, S. X., Xue, Q. L., Tian, J., Huang, Y., Yeh, S. H., & Fried, L. P.
(2009). Associations of neutrophil and monocyte counts with
frailty in community-dwelling disabled older women: Results from
the Women’s Health and Aging Studies I. Experimental Gerontol-
ogy, 44, 511–516. doi:10.1016/j.exger.2009.05.005
Biological Research for Nursing XX(X)
Leng, S. X., Xue, Q. L., Tian, J., Walston, J. D., & Fried, L. P. (2007).
Inflammation and frailty in older women. Journal of the American
Geriatrics Society, 55, 864–871.
Lindsay, R. M. (1994). Neurotrophic growth factors and neurodegen-
erative diseases: Therapeutic potential of the neurotrophins and
ciliary neurotrophic factor. Neurobiology of Aging, 15, 249–251.
Liu, C. K., Lyass, A., Larson, M. G., Massaro, J. M., Wang, N.,
D’Agostino, R. B. Sr., . . . Murabito, J. M. (2016). Biomarkers of
oxidative stress are associated with frailty: The Framingham Off-
spring Study. Age, 38, 1. doi:10.1007/s11357-015-9864-z
Margetic, S. (2012). Inflammation and haemostasis. Biochemia Med-
ica, 22, 49–62.
Mather, M., Jacobsen, L. A., & Pollard, K. M. (2015). Aging in the
United States. Population Bulletin, 70. Retrieved from http://www.
prb.org/pdf16/aging-us-population-bulletin.pdf
Matteini, A. M., Walston, J. D., Fallin, M. D., Bandeen-Roche, K.,
Kao, W. H., Semba, R. D., . . . Stabler, S. P. (2008). Markers of B-
vitamin deficiency and frailty in older women. Journal of Nutri-
tion, Health, & Aging, 12, 303–308.
Maxwell, C. A., & Wang, J. (2017). Understanding frailty: A nurse’s
guide. Nursing Clinics of North America, 52, 349–361. doi:10.
1016/j.cnur.2017.04.003
McCarty, M. F. (2005). Secondary hyperparathyroidism promotes the
acute phase response—a rationale for supplemental vitamin D in
prevention of vascular events in the elderly. Medical Hypotheses,
64, 1022–1026.
Mekli, K., Marshall, A., Vanhoutte, B., Tampubolon, G., Nazroo, J., &
Pendleton, N. (2017). The genetics of frailty: Summary of the
results of the genetics work in the frail project. Innovation in
Aging, 1, 137–137. doi:10.1093/geroni/igx004.552
Mercer, S. W., Smith, S. M., Wyke, S., O’Dowd, T., & Watt, G. C.
(2009). Multimorbidity in primary care: Developing the research
agenda. Family Practice, 26, 79–80. doi:10.1093/fampra/cmp020
Metzelthin, S. F., Daniëls, R., van Rossum, E., Cox, K., Habets, H., de
Witte, L. P., & Kempen, G. I. J. M. (2012). A nurse-led interdisci-
plinary primary care approach to prevent disability among
community-dwelling frail older people: A large-scale process eva-
luation. International Journal of Nursing Studies, 50, 1184–1196.
doi:10.1016/j.ijnurstu.2012.12.016
Miller, D. B., & O’Callaghan, J. P. (2005). Aging, stress and the
hippocampus. Ageing Research Reviews, 4, 123–140. doi:10.
1016/j.arr.2005.03.002***
Miller, R. A. (1996). The aging immune system: Primer and prospec-
tus. Science, 273, 70.
Mills, E. L., Kelly, B., & O’Neill, L. A. J. (2017). Mitochondria are the
powerhouses of immunity. Nature Immunology, 18, 488–498. doi:
10.1038/ni.3704
Mitnitski, A., Collerton, J., Martin-Ruiz, C., Jagger, C., von Zglinicki,
T., Rockwood, K., & Kirkwood, T. B. (2015). Age-related frailty
and its association with biological markers of ageing. BMC Med-
icine, 13, 161. doi:10.1186/s12916-015-0400-x
Moher, D., Liberati, A., Tetzlaff, J., & Altman, D. G (2009). Preferred
reporting items for systematic reviews and meta-analyses: The
PRISMA statement. Journal of Clinical Epidemiology, 62,
1606–1612. doi:10.1016/j.jclinepi.2009.06.005
Wang et al.
Mohler, M. J., Fain, M. J., Wertheimer, A. M., Najafi, B., & Nikolich-
Žugich, J. (2014). The frailty syndrome: Clinical measurements
and basic underpinnings in humans and animals. Experimental
Gerontology, 54, 6–13. doi:10.1016/j.exger.2014.01.024
Morley, J. E., Malmstrom, T., & Miller, D. (2012). A simple frailty
questionnaire (FRAIL) predicts outcomes in middle aged African
Americans. Journal of Nutrition, Health & Aging, 16, 601–608.
Namioka, N., Hanyu, H., Hirose, D., Hatanaka, H., Sato, T., & Shi-
mizu, S. (2016). Oxidative stress and inflammation are associated
with physical frailty in patients with Alzheimer’s disease. Geria-
trics & Gerontology International, 17, 913–918. doi:10.1111/ggi.
12804
Nicholson, C., Meyer, J., Flatley, M., & Holman, C. (2013). The
experience of living at home with frailty in old age: A psychosocial
qualitative study. International Journal of Nursing Studies, 50,
1172–1179. doi:10.1016/j.ijnurstu.2012.01.006
Noble, E. E., Billington, C. J., Kotz, C. M., & Wang, C. (2011). The
lighter side of BDNF. American Journal of Physiology—Regula-
tory, Integrative and Comparative Physiology, 300,
R1053–R1069.
Orlovsky, M., Dosenko, V., Spiga, F., Skibo, G., & Lightman, S.
(2014). Hippocampus remodeling by chronic stress accompanied
by GR, proteasome and caspase-3 overexpression. Brain Research,
1593, 83–94.
Percheron, G., Hogrel, J. Y., Denot-Ledunois, S., Fayet, G., Forette, F.
, Baulieu, E. E., . . . Marini, J. F. (2003). Effect of 1-year oral
administration of dehydroepiandrosterone to 60- to 80-year-old
individuals on muscle function and cross-sectional area: A
double-blind placebo-controlled trial. Archives of Internal Medi-
cine, 163, 720–727.
Picard, M., McManus, M. J., Gray, J. D., Nasca, C., Moffat, C.,
Kopinski, P. K., . . . Wallace, D. C. (2015). Mitochondrial func-
tions modulate neuroendocrine, metabolic, inflammatory, and tran-
scriptional responses to acute psychological stress. Proceedings of
the National Academy of Sciences of the United States of America,
112, E6614–6623. doi:10.1073/pnas.1515733112
Puts, M. T., Visser, M., Twisk, J. W., Deeg, D. J., & Lips, P. (2005).
Endocrine and inflammatory markers as predictors of frailty. Clin-
ical Endocrinology, 63, 403–411.
Raefsky, S. M., & Mattson, M. P. (2017). Adaptive responses of
neuronal mitochondria to bioenergetic challenges: Roles in neuro-
plasticity and disease resistance. Free Radical Biology & Medi-
cine, 102, 203–216. doi:10.1016/j.freeradbiomed.2016.11.045
Reiner, A. P., Aragaki, A. K., Gray, S. L., Wactawski-Wende, J.,
Cauley, J. A., Cochrane, B. B., . . . LaCroix, A. Z. (2009). Inflam-
mation and thrombosis biomarkers and incident frailty in postme-
nopausal women. American Journal of Medicine, 122, 947–954.
doi:10.1016/j.amjmed.2009.04.016
Robertson, D. A., Savva, G. M., & Kenny, R. A. (2013). Frailty and
cognitive impairment—A review of the evidence and causal
mechanisms. Ageing Research Reviews, 12, 840–851. doi:10.
1016/j.arr.2013.06.004
Robson, S., Shephard, E., & Kirsch, R. (1994). Fibrin degradation
product D-dimer induces the synthesis and release of biologically
active IL-1b, IL-6 and plasminogen activator inhibitors from
monocytes in vitro. British Journal of Haematology, 86, 322–326.
25
Rockwood, K., & Mitnitski, A. (2007). Frailty in relation to the accu-
mulation of deficits. Journals of Gerontology Series A: Biological
Sciences and Medical Sciences, 62, 722–727.
Rockwood, K., Song, X., MacKnight, C., Bergman, H., Hogan, D. B.,
McDowell, I., & Mitnitski, A. (2005). A global clinical measure of
fitness and frailty in elderly people. Canadian Medical Association
Journal, 173, 489–495. doi:10.1503/cmaj.050051
Rohleder, N., Kudielka, B. M., Hellhammer, D. H., Wolf, J. M., &
Kirschbaum, C. (2002). Age and sex steroid-related changes in
glucocorticoid sensitivity of pro-inflammatory cytokine produc-
tion after psychosocial stress. Journal of Neuroimmunology, 126,
69–77.
Ronning, B., Wyller, T. B., Seljeflot, I., Jordhoy, M. S., Skovlund, E.,
Nesbakken, A., & Kristjansson, S. R. (2010). Frailty measures,
inflammatory biomarkers and post-operative complications in
older surgical patients. Age and Ageing, 39, 758–761. doi:10.
1093/ageing/afq123
Rosca, M. G., & Hoppel, C. L. (2010). Mitochondria in heart failure.
Cardiovascular Research, 88, 40–50.
Rosmond, R., & Björntorp, P. (2000). The hypothalamic–pituitary–
adrenal axis activity as a predictor of cardiovascular disease, type 2
diabetes and stroke. Journal of Internal Medicine, 247, 188–197.
Saliba, D., Elliott, M., Rubenstein, L. Z., Solomon, D. H., Young, R.
T., Kamberg, C. J., . . . Sloss, E. M. (2001). The Vulnerable Elders
Survey: A tool for identifying vulnerable older people in the com-
munity. Journal of the American Geriatrics Society, 49,
1691–1699.
Sanchis, J., Nuñez, E., Ruiz, V., Bonanad, C., Fernandez, J., Cauli,
O., . . . Nuñez, J. (2015). Usefulness of clinical data and biomar-
kers for the identification of frailty after acute coronary syndromes.
Canadian Journal of Cardiology, 31, 1462–1468. doi:10.1016/j.
cjca.2015.07.737
Sarkisian, C. A., Gruenewald, T. L., John Boscardin, W., & Seeman,
T. E. (2008). Preliminary evidence for subdimensions of geriatric
frailty: The MacArthur study of successful aging. Journal of the
American Geriatrics Society, 56, 2292–2297.
Schäbitz, W. R., Steigleder, T., Cooper-Kuhn, C. M., Schwab, S.,
Sommer, C., Schneider, A., & Kuhn, H. G. (2007). Intravenous
brain-derived neurotrophic factor enhances poststroke sensorimo-
tor recovery and stimulates neurogenesis. Stroke, 38, 2165–2172.
Schleithoff, S. S., Zittermann, A., Tenderich, G., Berthold, H. K.,
Stehle, P., & Koerfer, R. (2006). Vitamin D supplementation
improves cytokine profiles in patients with congestive heart fail-
ure: A double-blind, randomized, placebo-controlled trial. Amer-
ican Journal of Clinical Nutrition, 83, 754–759.
Seeman, T. E., Singer, B. H., Rowe, J. W., Horwitz, R. I., & McEwen,
B. S. (1997). Price of adaptation—allostatic load and its health
consequences: MacArthur studies of successful aging. Archives
of Internal Medicine, 157, 2259–2268.
Semba, R. D., Bartali, B., Zhou, J., Blaum, C., Ko, C. W., & Fried, L.
P. (2006). Low serum micronutrient concentrations predict frailty
among older women living in the community. Journals of Geron-
tology Series A: Biological Sciences and Medical Sciences, 61,
594–599.
Semba, R. D., Margolick, J. B., Leng, S., Walston, J., Ricks, M. O., &
Fried, L. P. (2005). T cell subsets and mortality in older
26
community-dwelling women. Experimental Gerontology, 40,
81–87. doi:10.1016/j.exger.2004.09.006
Serviddio, G., Romano, A. D., Greco, A., Rollo, T., Bellanti, F., Alto-
mare, E., & Vendemiale, G. (2009). Frailty syndrome is associated
with altered circulating redox balance and increased markers of
oxidative stress. International Journal of Immunopathology and
Pharmacology, 22, 819–827.
Shamliyan, T., Talley, K. M., Ramakrishnan, R., & Kane, R. L.
(2013). Association of frailty with survival: A systematic literature
review. Ageing Research Reviews, 12, 719–736.
Sterling, K., Milch, P., Brenner, M., & Lazarus, J. (1977). Thyroid
hormone action: The mitochondrial pathway. Science, 197,
996–999. doi:10.1126/science.196334
Szanton, S., Allen, J., Seplaki, C., Bandeen-Roche, K., & Fried, L.
(2009). Allostatic load and frailty in the women’s health and aging
studies. Biological Research for Nursing, 10, 248–256.
Tajar, A., Lee, D. M., Pye, S. R., O’Connell, M. D., Ravindrarajah, R.,
Gielen, E., . . . O’Neill, T. W. (2013). The association of frailty
with serum 25-hydroxyvitamin D and parathyroid hormone levels
in older European men. Age and Ageing, 42, 352–359. doi:10.
1093/ageing/afs162
Tajar, A., O’Connell, M. D. L., Mitnitski, A. B., O’Neill, T. W.,
Searle, S. D., & Huhtaniemi, I. T., . . . the European Male Aging
Study, G. (2011). Frailty in relation to variations in hormone levels
of the hypothalamic–pituitary–testicular axis in older men: Results
from the European male aging study. Journal of the American
Geriatrics Society, 59, 814–821. doi:10.1111/j.1532-5415.2011.
03398.x
Trevisan, C., Veronese, N., Maggi, S., Baggio, G., Toffanello, E. D.,
Zambon, S., . . . Sergi, G. (2017). Factors influencing transitions
between frailty states in elderly adults: The Progetto Veneto
Anziani longitudinal study. Journal of American Geriatrics Soci-
ety, 65, 179–184. doi:10.1111/jgs.14515
Tschopp, J. (2011). Mitochondria: Sovereign of inflammation? Eur-
opean Journal of Immunology, 41, 1196–1202. doi:10.1002/eji.
201141436
Tsigos, C., & Chrousos, G. P. (2002). Hypothalamic–pituitary–adre-
nal axis, neuroendocrine factors and stress. Journal of Psychoso-
matic Research, 53, 865–871.
Urpi-Sarda, M., Andres-Lacueva, C., Rabassa, M., Ruggiero, C.,
Zamora-Ros, R., Bandinelli, S., . . . Cherubini, A. (2015). The
relationship between urinary total polyphenols and the frailty phe-
notype in a community-dwelling older population: The
InCHIANTI Study. Journals of Gerontology Series A: Biological
Sciences and Medical Sciences, 70, 1141–1147. doi:10.1093/ger-
ona/glv026
Varadhan, R., Chaves, P. H., Lipsitz, L. A., Stein, P. K., Tian, J.,
Windham, B. G., . . . Fried, L. P. (2009). Frailty and impaired
cardiac autonomic control: New insights from principal compo-
nents aggregation of traditional heart rate variability indices. Jour-
nals of Gerontology Series A: Biological Sciences and Medical
Sciences, 64, 682–687. doi:10.1093/gerona/glp013
Varadhan, R., Walston, J., Cappola, A. R., Carlson, M. C., Wand,
G. S., & Fried, L. P. (2008). Higher levels and blunted diurnal
variation of cortisol in frail older women. Journals of
Biological Research for Nursing XX(X)
Gerontology Series A: Biological Sciences and Medical
Sciences, 63, 190–195.
Visser, M., Goodpaster, B. H., Kritchevsky, S. B., Newman, A. B.,
Nevitt, M., Rubin, S. M., . . . Harris, T. B. (2005). Muscle mass,
muscle strength, and muscle fat infiltration as predictors of inci-
dent mobility limitations in well-functioning older persons. Jour-
nals of Gerontology Series A: Biological Sciences and Medical
Sciences, 60, 324–333.
Visser, M., Kritchevsky, S. B., Goodpaster, B. H., Newman, A. B.,
Nevitt, M., Stamm, E., & Harris, T. B. (2002). Leg muscle mass
and composition in relation to lower extremity performance in
men and women aged 70 to 79: The health, aging and body
composition study. Journal of the American Geriatrics Society,
50, 897–904.
von Elm, E., Altman, D. G., Egger, M., Pocock, S. J., Gøtzsche, P. C.,
& Vandenbroucke, J. P. (2007). The Strengthening the Reporting
of Observational Studies in Epidemiology (STROBE) Statement:
Guidelines for reporting observational studies. Preventive Medi-
cine, 45, 247–251. doi:10.1016/j.ypmed.2007.08.012
Walston, J., McBurnie, M. A., Newman, A., Tracy, R. P., Kop, W. J.,
Hirsch, C. H., . . . Fried, L. P. (2002). Frailty and activation of the
inflammation and coagulation systems with and without clinical
comorbidities: Results from the cardiovascular health study.
Archives of Internal Medicine, 162, 2333–2341.
Wang, J., Boehm, L., & Mion, L. C. (2017). Intrinsic capacity in
older hospitalized adults: Implications for nursing practice.
Geriatric Nursing, 38, 359–361. doi:10.1016/j.gerinurse.2017.
06.008
Westra, B. L., Clancy, T. R., Sensmeier, J., Warren, J. J., Weaver, C.,
& Delaney, C. W. (2015). Nursing knowledge: Big data science—
Implications for nurse leaders. Nursing Administration Quarterly,
39, 304–310. doi:10.1097/naq.0000000000000130
Whitson, H. E., Arnold, A. M., Yee, L. M., Mukamal, K. J., Kizer, J.
R., Djousse, L., . . . Zieman, S. (2014). Serum carboxymethyl-
lysine, disability, and frailty in older persons: The cardiovascular
health study. Journals of Gerontology Series A: Biological
Sciences and Medical Sciences, 69, 710–716. doi:10.1093/ger-
ona/glt155
Woo, J., Tang, N. L., Suen, E., Leung, J. C., & Leung, P. C. (2008).
Telomeres and frailty. Mechanisms of Ageing and Development,
129, 642–648. doi:10.1016/j.mad.2008.08.003
World Health Organization. (2015). World report on ageing and
health. Geneva, Switzerland: Author. Retrieved from http://
www.who.int/ageing/events/world-report-2015-launch/en/
Wu, I. C., Shiesh, S. C., Kuo, P. H., & Lin, X. Z. (2009). High
oxidative stress is correlated with frailty in elderly Chinese. Jour-
nal of American Geriatrics Society, 57, 1666–1671. doi:10.1111/j.
1532-5415.2009.02392.x
Xue, Q. L. (2011). The frailty syndrome: Definition and natural his-
tory. Clinics in Geriatric Medicine, 27, 1–15. doi:10.1016/j.cger.
2010.08.009
Yeap, B. B., Alfonso, H., Chubb, S. A., Walsh, J. P., Hankey, G. J.,
Almeida, O. P., & Flicker, L. (2012). Higher free thyroxine levels are
associated with frailty in older men: The health in men study. Clinical
Endocrinology, 76, 741–748. doi:10.1111/j.1365-2265.2011.04290.x
Wang et al.
Yeap, B. B., Paul Chubb, S. A., Lopez, D., Ho, K. K., Hankey, G.
J., & Flicker, L. (2013). Associations of insulin-like growth
factor-I and its binding proteins and testosterone with frailty
in older men. Clinical Endocrinology, 78, 752–759. doi:10.
1111/cen.12052
Young, A., Hughes, I., Russell, P., Parker, M. J., & Nichols, P. J. R.
(1980). Measurement of quadriceps muscle wasting by ultrasono-
graphy. Rheumatology, 19, 141–148. doi:10.1093/rheumatology/
19.3.141
Zaslavsky, O., Cochrane, B. B., Thompson, H. J., Woods, N. F., Hert-
ing, J. R., & LaCroix, A. (2013). Frailty: A review of the first
27
decade of research. Biological Research for Nursing, 15,
422–432. doi:10.1177/1099800412462866
Zaslavsky, O., Walker, R. L., Crane, P. K., Gray, S. L., & Larson, E. B.
(2016). Glucose levels and risk of frailty. Journals of Gerontology.
Series A: Biological Sciences and Medical Sciences, 71,
1223–1229. doi:10.1093/gerona/glw024
Zhu, Y., Liu, Z., Wang, Y., Wang, Z., Shi, J., Xie, X., . . . Wang, X.
(2016). C-reactive protein, frailty and overnight hospital admis-
sion in elderly individuals: A population-based study. Archives of
Gerontology and Geriatrics, 64, 1–5. doi:10.1016/j.archger.2015.
08.009