Ageing Research Reviews 73 (2022) 101530

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Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr

Review

Biomarkers shared by frailty and sarcopenia in older adults: A systematic

review and meta-analysis
Anna Picca a, b, Hélio José Coelho-Junior c, Riccardo Calvani a, b, *, Emanuele Marzetti a, c,
Davide Liborio Vetrano a, b
a
Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy
b
Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden
c
Università Cattolica del Sacro Cuore, Department of Geriatrics and Orthopedics, Rome, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Physical frailty and sarcopenia show extensive clinical similarities. Whether biomarkers exist that
Amino acids are shared by the two conditions is presently unclear.
Cytokines Methods: We conducted a systematic review and meta-analysis of cross-sectional and longitudinal studies that
Hematologic markers
investigated the association of frailty and/or sarcopenia with biomarkers as a primary or secondary outcome in
Inflammation
Multivariate
adults aged 60 years and older. Only studies published in English that defined frailty using a validated scale and/
Muscle or questionnaire and diagnosed sarcopenia according to the presence of muscle atrophy plus dynapenia or low
physical function were included. Studies were identified from a systematic search of MEDLINE and SCOPUS
databases from inception through August 2020. The quality of reporting of each study was assessed by using the
Quality Assessment Tool for Observational Cohort, Cross-Sectional and Case-Control studies of the National
Institute of Health. A meta-analysis was conducted when at least three studies investigated the same biomarker in
both frailty and sarcopenia. Pooled effect size was calculated based on standard mean differences and random-
effect models. Sensitivity analysis was performed based on age and the setting where the study was conducted.
Results: Eighty studies (58 on frailty and 22 on sarcopenia) met the inclusion criteria and were included in the
qualitative analysis. Studies on frailty included 33,160 community-dwellers, hospitalized, or institutionalized
older adults (60–88 years) from 21 countries. Studies on sarcopenia involved 4904 community-living and
institutionalized older adults (68–87.6 years) from 9 countries. Several metabolic, inflammatory, and hemato­
logic markers were found to be shared between the two conditions. Albumin and hemoglobin were negatively
associated with both frailty and sarcopenia. Interleukin 6 was associated with frailty and sarcopenia only in
people aged < 75. Community-dwelling older adults with frailty and sarcopenia had higher levels of tumor
necrosis factor alpha compared with their robust and non-sarcopenic counterparts.
Conclusions: A set of metabolic, hematologic, and inflammatory biomarkers was found to be shared by frailty and
sarcopenia. These findings fill a knowledge gap in the quest of biomarkers for these conditions and provide a
rationale for biomarker selection in studies on frailty and sarcopenia.

1. Introduction exists on the theoretical framework of frailty, its clinical identification is

Frailty, a decline in physiologic reserve that is commonly found in
older adults, refers to a state of increased vulnerability to stressors that
develops as a multisystemic derangement independent of chronological
aging or specific diseases and predisposes to numerous negative health-
related events (e.g., falls, morbidity, disability, hospitalization, institu­
tionalization, death) (Clegg et al., 2013). Although large agreement
hampered by the complex pathophysiology, heterogeneous phenotypic
manifestations, intra-individual fluctuations across severity states, and
the existence of multiple operational definitions (Cesari et al., 2017;
Chen et al., 2014; Looman et al., 2018; Stolz et al., 2019). Several
operational definitions of frailty have been proposed over time (Morley
et al., 2013) that are mostly inspired by two seminal models: the frailty
phenotype by Fried et al. (2001) and the frailty index by Rockwood et al.

* Correspondence to: Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L. go F. Vito 1, 00168 Rome, Italy.
E-mail addresses: riccardo.calvani@guest.policlinicogemelli.it, riccardo.calvani@policlinicogemelli.it, riccardo.calvani@ki.se (R. Calvani).

https://doi.org/10.1016/j.arr.2021.101530
Received 28 May 2021; Received in revised form 4 November 2021; Accepted 21 November 2021
Available online 25 November 2021
1568-1637/© 2021 Elsevier B.V. All rights reserved.
A. Picca et al.
(2005). The phenotypic model of frailty is based on five elements: 1)
unintentional weight loss, 2) muscle weakness, 3) exhaustion, 4) slow
walking speed, and 5) inactive lifestyle (Fried et al., 2001). The frailty
index is based on a cumulative deficit paradigm and includes health
deficits spanning multiple domains (Rockwood et al., 2005). As such, the
frailty index may be considered to serve as a proxy measure of aging
(Mitnitski et al., 2001).
However, when comparing the ability of available tools at identi­
fying frailty, only little-to-moderate overlap has been observed (Apra­
hamian et al., 2017; Theou et al., 2013). Therefore, subtle deficits that
are intrinsic to the condition may easily be missed, which impacts the
prediction of adverse outcomes associated with frailty (Coelho-Júnior
et al., 2020; Theou et al., 2013).
Loss of physical function is a cardinal manifestation of frailty (Fried
et al., 2001; Hoogendijk et al., 2019), which explains why most frailty
assessment tools are built upon the physical frailty model (Faller et al.,
2019). While being influenced by multisystemic alterations, the
conceptualization and the clinical identification of sarcopenia – a
neuromuscular disease characterized by quantitative (i.e., mass) and
qualitative (i.e., strength and/or function) muscle declines – are based
on physical deficits (Landi et al., 2018). Muscle atrophy, dynapenia, and
poor physical function are shared between the phenotypic model of
frailty and sarcopenia, with physically inactive lifestyle and fatigue
commonly being associated with the progression of both conditions
(Coelho-Junior et al., 2020; Landi et al., 2015). This scenario has led to
propose sarcopenia as the biological substratum of frailty (Landi et al.,
2015) and to merge the two conditions into a new clinical entity called
physical frailty-and-sarcopenia (Marzetti et al., 2016).
The pathophysiology of frailty and sarcopenia resembles that of
other prototypical geriatric conditions, for which a multifactorial eti­
ology is at play involving many of the biological hallmarks of aging (i.e.,
genomic and epigenetic instability, loss of proteostasis, mitochondrial
dysfunction, telomere shortening, dysregulated nutrient signaling, stem
cell exhaustion, cellular senescence, and altered intercellular signaling)
(Justice et al., 2018; López-Otín et al., 2013; Sierra, 2016). Currently
available biomarkers of biological aging might not capture the multitude
of intrinsic and extrinsic factors underlying the decline in physical
function that characterizes frailty and sarcopenia (El Assar et al., 2021;
Marzetti et al., 2014a, 2014b; Rodríguez-Mañas et al., 2021). However,
perturbations in the above-mentioned aging pillars have been proposed
as an important contributors to frailty and sarcopenia (Sierra, 2016). It
follows that multi-platform biomarker analyses are probably more
suitable strategies for characterizing the pathogenetic pathways of these
dynamic and complex conditions than single-marker approaches (Cal­
vani et al., 2015; Curcio et al., 2016; Marzetti et al., 2019; Picca et al.,
2019a). The principle underlying multimarker paradigm is rooted into
the concept of allostatic load, i.e., the cumulative biological burden to
which cells and body systems are exposed during recurrent or chronic
stresses (Seeman et al., 2001). Biomarkers are, therefore, endopheno­
types of physiological dysregulation that may support the diagnosis and
monitoring of a given condition as well as clinical decision-making and
verification of intervention efficacy. Multimarker analyses coupled with
ad hoc multivariate statistics may also identify patterns of mediators
reflecting the individual’s departure from their "normal operating con­
ditions" (Milot et al., 2014). These results may, therefore, complement
clinical appraisals and indices derived from routine clinical evaluations
(Howlett et al., 2014; Muscedere et al., 2019).
Innovative multimarker analytical strategies have already been
applied to identify candidate biomarkers of frailty and sarcopenia
(Calvani et al., 2020; Marzetti et al., 2020). However, even more
informative would be the exploitation of this information to understand
the pathways that are shared between the two conditions. This would
allow molecular targets and modifiable risk factors to be identified,
which may support the development of new tools for a more accurate
identification of frailty and sarcopenia and the design of interventions to
delay, prevent, or alleviate the associated negative outcomes.
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Ageing Research Reviews 73 (2022) 101530
We performed a systematic review and meta-analysis to provide a
state-of-the art appraisal of existing biomarkers associated with both
frailty and sarcopenia and to identify potential signaling pathways
explaining their clinical overlap. Our work may help address knowledge
gaps in the quest of biomarkers for these conditions and build a solid
rationale to guide biomarker selection for future studies on frailty and
sarcopenia.
2. Material and methods
We conducted a systematic review and meta-analysis of observa­
tional studies to investigate biomarkers shared between frailty and
sarcopenia as a phenotypic expression of common pathways. Cross-
sectional, case-control, and baseline data of longitudinal studies that
examined the association of serum, plasma, saliva, urine, feces, and
cerebrospinal fluid biomarkers with frailty and/or sarcopenia were
selected. Data from each measured molecule were retrieved and allo­
cated in spreadsheets. Then, molecules that were measured in at least
three studies on frailty and three on sarcopenia were identified as
candidate biomarkers shared between the two conditions and included
in the final qualitative and quantitative analysis. The study was fully
performed by investigators and no librarian was part of the team. The
study complies with the criteria of the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) Statement (Page
et al., 2021) and the Cochrane Handbook for Systematic Reviews and
Interventions (Higgins et al., 2019).
2.1. Selection criteria
Inclusion criteria were: (a) observational studies, including cross-
sectional, case-control, and longitudinal studies which investigated the
association of frailty and/or sarcopenia with biomarkers in older adults
as a primary or secondary outcome; (b) participant age 60 or greater; (c)
frailty defined by a validated scale and/or questionnaires; (d) sarcopenia
diagnosed according to the presence of muscle atrophy plus dynapenia
and/or low physical function (Chen et al., 2020; Cruz-Jentoft et al.,
2019); (e) studies published in the English language; and (f) availability
of means and standard deviations (SDs) for biomarker levels in cases (i.
e., frailty/sarcopenia) and non-cases (i.e., robust/non-sarcopenia). We
excluded meta-analyses, experimental, quasi-experimental, and
cross-over investigations that examined intervention strategies. Studies
that classified participants as frail according to reduced physical/or
cognitive function as well as sarcopenic according to a single parameter
(e.g., muscle atrophy) were excluded. Studies that identified genetic
markers were also excluded.
2.2. Search strategy and selection criteria
Studies published on or before 31 August 2020 were retrieved by two
investigators (AP, HJCJ) from MEDLINE (PubMed interface) and SCO­
PUS (EBSCO interface). The reference lists obtained were checked for
reviews, and Google Scholar and ResearchGate were interrogated for
additional studies and citation searches of key articles. The initial search
strategy was performed using keywords, MeSH terms, and free text
words such as frailty, sarcopenia, biomarkers. Moreover, keywords and
subject headings were exhaustively combined using Boolean operators.
The search strategy is detailed in the Supplementary File 1.
2.3. Data extraction and quality assessment
Titles and abstracts of retrieved articles were screened for eligibility
by two researchers (AP, HJCJ). The full-text was consulted if the abstract
did not provide enough information for final evaluation. Two reviewers
(AP, HJCJ) extracted coded variables (i.e., methodological quality and
the characteristics of the studies) using a standardized coding form. A
third researcher (EM) was consulted to solve disagreements. The quality
A. Picca et al.
of reporting for each study was performed by two researchers (AP,
HJCJ) using the Quality Assessment Tool for Observational Cohort and
Cross-Sectional of the National Institute of Health (NIH) and the Quality
Assessment Tool for Case-Control Studies of the NIH (NIH, 2014). These
tools contain 12–14 questions that assess several aspects associated with
risk of bias, type I and type II errors, transparency, and confounding
factors. Items 6, 7, 8, and 10 of the Quality Assessment Tool for
Observational Cohort and Cross-Sectional do not refer to cross-sectional
studies and were not considered for the quality analysis. Similarly, items
7 and 9 of the Quality Assessment Tool for Case-Control Studies of the
NIH were excluded from the analyses of case-control studies. At the end
of the evaluation, each study was assigned to one of three categories
according to the following scores: 0–4: poor, 5–6: fair, and 7–8: good.
The rate of agreement on quality assessment between reviewers was
99%.
2.4. Statistical analysis
The meta-analysis was conducted using STATA 13 (StataCorp, Col­
lege Station, TX, USA). Pooled analyses comparing frailty vs. robustness
and sarcopenia vs. non-sarcopenia were performed when at least three
studies investigated the same biomarker in both conditions. Effect sizes
(ESs) were measured using means and SDs. When data were not made
available by authors as means and SDs, they were calculated according
to the Cochrane guidelines (Higgins et al., 2019). Specifically, SDs were
calculated from confidence intervals or standard errors, and means were
converted from medians. Data from studies reporting measures of cen­
tral tendency and dispersion in graphical formats were extracted using
Fig. 1. PRISMA flow diagram.
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the Plot Digitizer 2.4.4 software (De Souza et al., 2015). A single pair­
wise comparison was created when multiple studies referred to the same
database using the formulas proposed by the Cochrane group. In
particular, data from the original database were used for the "BIO­
markers associated with Sarcopenia and PHysical frailty in EldeRly
pErsons" (BIOSPHERE) study (Calvani et al., 2020), which was available
to the assessors. Pooled ES was calculated based on standard mean
differences (SMDs), given that different techniques (e.g., ELISA, multi­
plex assays) and/or biospecimens (e.g., serum, plasma) were used for
biomarkers quantification. Due to the variability of sample character­
istics, study design, and assessment instruments for frailty and sarco­
penia, a random-effect model was used to calculate the pooled ES.
Sensitivity analysis was performed based on the stratification method
using binary data (i.e., age: <75 and ≥75 years; setting: community,
hospital, and long-term care).
3. Results
3.1. Literature search
A PRISMA flow diagram depicting the different phases of the sys­
tematic review is reported in Fig. 1. Thirty-six thousand seven-hundred
and thirteen records were identified through database searching. Eleven
thousand four-hundred and sixty-nine records were removed as dupli­
cates, and 24,933 articles were excluded by title and abstract, leaving
311 articles to be assessed for eligibility. After removing 231 studies
based on eligibility criteria, 80 were included in the qualitative analysis
and 75 investigations provided data for the pooled analysis.
A. Picca et al.
3.2. Characteristics of included studies
The general characteristics of the included studies are shown in
Table 1. Eighty investigations, 58 on frailty (Aarts et al., 2015; Al Saedi
et al., 2018; Alvarez-Ríos et al., 2015; Álvarez-Sánchez et al., 2020;
Arauna et al., 2020; Arts et al., 2015; Badrasawi et al., 2019; Brouwers
et al., 2015; Butcher et al., 2019; Darvin et al., 2014; Fried et al., 2009;
Furtado et al., 2020; Gale et al., 2017; García-García et al., 2014;
Gunawardene et al., 2016; Hou et al., 2018; Hubbard et al., 2009; Inglés
et al., 2014; Jiang et al., 2020; Kalyani et al., 2012; Kiss et al., 2019;
Kochlik et al., 2019; Komici et al., 2020; Krams et al., 2016; Leng et al.,
2002, 2011, 2009, 2007; Liang et al., 2020; Lin et al., 2017; Liu et al.,
2016; Ma et al., 2019; Mahmoudi et al., 2019; Marcos-Pérez et al., 2019,
2018; Margiotta et al., 2020; Mohamad et al., 2018; Munguia et al.,
2018; Namioka et al., 2017; Nascimento et al., 2018; Parsons et al.,
2019; Qu et al., 2009b, 2009a; Ruangsuriya et al., 2019; Rusanova et al.,
2018; Saum et al., 2015; Semmarath et al., 2019; Serviddio et al., 2009;
Su et al., 2017; Szanton et al., 2009; Tajar et al., 2013; Valdiglesias et al.,
2018; Valentini et al., 2019; Walston et al., 2002; Wu et al., 2009;
Yanagita et al., 2020; Yang et al., 2018; Yeap et al., 2013) and 22 on
sarcopenia (Ates Bulut et al., 2017; Bellanti et al., 2018; Bian et al.,
2017; Cacciatore et al., 2015; Calvani et al., 2020, 2018; Can et al.,
2017; Coto Montes et al., 2017; Kuo et al., 2019; Landi et al., 2016; Lim
et al., 2015; Lu et al., 2020; Lustosa et al., 2017; Marzetti et al., 2014a,
2014b; Mochizuki et al., 2019; Rong et al., 2018; Sánchez-Castellano
et al., 2020; Tay et al., 2018; Ter Borg et al., 2016; Vettoretti et al., 2019;
Yalcin et al., 2018; Yoo et al., 2018) were included in the qualitative
analysis. Molecules pertaining to inflammatory, metabolic, hematolog­
ic, and hormonal domains were investigated in the retrieved studies and
reported accordingly. Studies on frailty included 33,160
community-dwelling, hospitalized, and institutionalized older adults
from Australia, Belgium, Brazil, Chile, China, Egypt, France, Germany,
Hungary, Iceland, Italy, Japan, Malaysia, Mexico, Portugal, Scotland,
Spain, Taiwan, Thailand, United Kingdom, and United States of Amer­
ica. The mean age of study participants ranged from 60 to 88 years. Most
studies assessed frailty using the Frailty Phenotype (FP) (82.8%). Of
these, 51.7% used a modified FP, 24.2% did not specified cut-off values,
while 6.9% provided cut-offs and criteria information. The FRAIL scale
(3.4%), the Clinical Frailty Scale (CFS) (1.7%), the Edmonton Frailty
Scale (1.7%), the Frailty Trait Scale (1.7%), the Survey of the Health,
Ageing and Retirement in Europe (SHARE) Frailty Instrument (1.7%),
the Obu Study Health Promotion for The Elderly index (1.7%), and the
Leuven Oncogeriatric Frailty Score (1.7%) were used in the remaining
studies. Studies that investigated sarcopenia included 4904
community-living, hospitalized, and institutionalized older adults with a
mean age ranging from 68 to 87.6 years from Brazil, China, Holland,
Italy, Japan, Korea, Singapore, Spain, and Turkey. As per the study
protocol, all investigations identified sarcopenia according to
co-occurrence of muscle atrophy and dynapenia and/or low physical
function.
3.3. Methodology quality appraisal
The methodological quality of the retrieved studies ranged from 5 to
8 (Supplementary Table 1). Sixty studies were classified as fair, 17 as
good, and four as poor. All cohort and cross-sectional studies clearly
stated the research question (item 1), described the study population
(item 2), and used valid and reliable instruments to assess frailty or
sarcopenia (item 11). Participants were recruited from the same or
similar populations and were evaluated according to the same eligibility
criteria in 68 studies (item 4). Sixty-five studies used valid and reliable
instruments, and provided a clear description of biomarker assessment
(item 9), while 33 studies adjusted results according to potential con­
founding variables (item 14). Only 8 studies justified the sample size
(item 5) and reported if variables were evaluated by a blinded assessor
(item 8). Only three studies indicated if the participation rate of eligible
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Ageing Research Reviews 73 (2022) 101530
candidates was of at least 50% (item 3).
As for case-control studies, all investigations clearly stated the
research question (item 1), specified and defined the studied population
(item 2), used concurrent controls (item 8), and used valid and reliable
instruments to assess frailty or sarcopenia (item 10). Nine studies
recruited controls from the same or a similar population of cases (item
4), used the same eligibility criteria to select cases and controls (item 5),
and clearly defined and differentiated both groups (item 6). None of the
studies justified the sample size (item 3), adjusted data by potential
cofactors (item 12), or described if assessors were blinded to the case or
control status of participants (item 11).
3.4. Biomarkers shared between frailty and sarcopenia
Table 2 lists the biomarkers that were measured for both frailty and
sarcopenia in at least three studies. Metabolic, hematologic, and in­
flammatory biomarkers were identified. Albumin was negatively asso­
ciated with frailty and sarcopenia regardless of participant’s age and
setting. A similar pattern was observed for hemoglobin, although studies
on sarcopenia did not provide enough data for age-stratified analysis.
Two inflammatory molecules were significantly associated with both
frailty and sarcopenia. Interleukin (IL) 6 was associated with frailty and
sarcopenia in people aged < 75 years, whereas no associations were
observed in those older than 75. Circulating IL-6 levels were signifi­
cantly higher in frail community-dwelling and hospitalized individuals
compared with their robust counterparts. However, IL-6 was signifi­
cantly lower in frail institutionalized individuals compared with robust
peers. Community-dwelling older adults with frailty and sarcopenia had
also higher circulating levels of tumor necrosis factor alpha (TNF-α)
compared with their robust and non-sarcopenic counterparts, respec­
tively. The association of TNF-α and frailty was not affected by age, but
was significant only among community-dwelling participants. A nega­
tive association was found between TNF-α and sarcopenia in hospital­
ized patients. Glucose was positively associated with frailty only in older
participants. Triglycerides were associated negatively with sarcopenia
independently of age and clinical setting. However, no information was
available regarding the association with frailty. Plasmatic low-density
lipoprotein (LDL) levels were negatively associated only with frailty in
younger participants. Circulating C-reactive protein (CRP) was posi­
tively associated with frailty among the youngest and hospitalized in­
dividuals, but not with sarcopenia. Circulating insulin-like growth factor
1 (IGF-1) was negatively associated with frailty, regardless of age and
clinical setting, but not with sarcopenia. No significant associations were
found between total cholesterol, high-density lipoprotein (HDL),
vitamin D and either frailty or sarcopenia.
4. Discussion
The main findings of the present study indicate that selected meta­
bolic, hematologic, and inflammatory biomarkers are significantly
associated with both frailty and sarcopenia. Specifically, older adults
with frailty and/or sarcopenia had lower levels of albumin and hemo­
globin compared with their robust and non-sarcopenic counterparts,
regardless of age and setting. Inflammatory molecules showed a distinct
pattern of associations: IL-6 was higher in community-dwellers and
hospitalized frail older adults, while it was significantly associated with
sarcopenia only in people younger than 75. A negative association be­
tween IL-6 and frailty was found in older nursing-home residents.
Finally, higher TNF-α levels were identified in both frail and sarcopenic
community-dwellers, while a negative association was identified in
hospitalized older people with sarcopenia.
The existence of a core biomarker set shared by frailty and sarco­
penia is not unexpected. Indeed, most studies that explored biomarkers
of frailty were based on the phenotypic model of frailty. This oper­
ationalization of frailty is centered around the physical domain of the
condition and encompasses parameters such as muscle weakness and
A. Picca et al. Ageing Research Reviews 73 (2022) 101530

Table 1
General description of the studies included in the systematic review.
Frailty

Year Authors Country Study Sample Sample Mean age Assessment Biomarkers
design size (n) (years)

2020 Álvarez-Sánchez Spain Cohort Toledo study for 1211 65–98 Modified Fried Frailty Metabolic and
et al. healthy aging Phenotype inflammatory
2020 Arauna et al. Chile Case- Community-dwelling 58 ~73 Modified Fried Frailty Metabolic and
Control Phenotype inflammatory
2020 Furtado et al. Portugal Cross- Nursing home residents 358 88.0 Modified Fried Frailty Hormonal and
Sectional Phenotype inflammatory
2020 Jiang et al. China Cross- Senior community 230 83.9 Modified Fried Frailty Urinary RNA oxidative
Sectional Phenotype damage
2020 Komici et al. Italy Cross- Hospitalized 128 69.2 CFS Metabolic
Sectional
2020 Liang et al. China Cross- Hospitalized 508 75.0 Modified Fried Frailty Metabolic
Sectional Phenotype
2020 Margiotta et al. Italy Case- Community-dwelling 79 ~77.2 Fried Frailty Phenotype Metabolic and
Control inflammatory
2020 Yanagita et al. Japan Cross- Community-dwelling 148 76.9 CFS Metabolic
Sectional
2019 Badrasawi et al. Malaysia Cross- Community-dwelling 382 60 + Fried Frailty Phenotype Oxidative,
Sectional inflammatory,
hormonal and
metabolic
2019 Butcher et al. Spain Cohort Toledo study for 691 75.0 Modified Fried Frailty Metabolic
healthy aging Phenotype
2019 Kiss et al. Hungary Cross- Elective surgery 313 65 + Edmong Frailty Scale Inflammatory
Sectional
2019 Kochlik et al. Germany Cross- FRAILOMIC database 360 78.8 Modified Fried Frailty Metabolic
Sectional Phenotype
2019 Ma et al. China Cross- Community-dwelling 130 60 + Modified Fried Frailty Metabolic
Sectional Phenotype
2018 Mahmoudi et al. France Cohort MArkers of FRAilty in 250 84.7 Fried Frailty Phenotype Metabolic and
elderly subjects hormonal
2019 Marcos-Pérez Spain Cross- Community-dwelling 252 79.3 Fried Frailty Phenotype Oxidative and
et al. Sectional hormonal
2019 Parsons et al. UK Cohort British regional heart 1660 ~79.2 Modified Fried Frailty Inflammation
study Phenotype
2019 Ruangsuriya Thailand Cross- Community-Dwelling 56 ~71.5 Fried Frailty Phenotype Oxidative and
et al. Sectional metabolic
2019 Semmarath et al. Thailand Cross- Community-dwelling 118 68.1 Modified Fried Frailty Metabolic
Sectional Phenotype
2019 Valentini et al. Italy Cross- Hospitalized 172 79.5 Survey of Health, Ageing Hormonal and
Sectional and Retirement in Europe inflammatory
Frailty
Instrument
2018 Al Saedi et al. Australia Cross- Community-dwelling 66 74 Fried Frailty Phenotype Hormonal,
Sectional inflammatory and
metabolic
2018 Hou et al. China Cross- Hospitalized 345 ~71.3 Modified Fried Frailty Metabolic and
Sectional Phenotype inflammatory
2018 Marcos-Pérez et Spain Cross- Community-dwelling 259 65 + Modified Fried Frailty Inflammatory
al Sectional Phenotype
2018 Mohamad et al. Egypt Cross- Community-dwelling 80 65 Fried Frailty Phenotype Oxidative and
Sectional inflammatory
2018 Mungia et al Mexico Cross- Community-dwelling 170 65 + Modified Fried Frailty Oxidative and
Sectional Phenotype metabolic
2018 Nascimento et al. Brazil Cross- Community-dwelling 347 70.1 Modified Fried Frailty Metabolic and
Sectional Phenotype inflammatory
2018 Rusanova et al. Spain Case- Toledo study for 96 80.5 Modified Fried Frailty Oxidative,
Control healthy aging Phenotype inflammatory and
metabolic
2018 Valdiglesias et al. Spain Cross- Community-dwelling 180 74.9 Modified Fried Frailty Metabolic and
Sectional Phenotype inflammatory
2018 Yang et al. China Cross- Hospitalized 435 81.6 FRAIL scale Inflammatory
Sectional
2017 Gale et al. Scotland Cross- Community-dwelling 594 ~69.5 Modified Fried Frailty Inflammatory
Sectional Phenotype
2017 Lin et al. China Cross- Community-dwelling 12 77.6 Chinese-Canadian Study of Metabolic
Sectional Health and Aging Clinical
Frailty Scale
2017 Namioka et al. Japan Cross- Patients with AD 140 ~80.3 Obu study health Metabolic
Sectional promotion for the elderly
2017 Su et al. China Cross- Community-dwelling 306 70.5 Modified Fried Frailty Inflammatory
Sectional Phenotype
2016 Krams et al. France Community-dwelling 321 82.9 Hormonal
(continued on next page)

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A. Picca et al. Ageing Research Reviews 73 (2022) 101530

Table 1 (continued )
Frailty

Year Authors Country Study Sample Sample Mean age Assessment Biomarkers
design size (n) (years)

Cross- Modified Fried Frailty

Sectional Phenotype
2016 Liu et al. USA Cross- Framingham heart 1919 ~72.7 Fried Frailty Phenotype Inflammation
Sectional study original
2015 Aarts et al. Iceland Cohort AGES-Reykjavik 4.414 75.4 Modified Fried Frailty Metabolic and
Phenotype inflammatory
2015 Alvarez-Ríos Spain Cross- Toledo study for 592 74 Modified Fried Frailty Hormonal
et al. Sectional healthy aging Phenotype
2015 Arts et al. Iceland Cohort Netherlands study of 378 ~71.5 Modified Fried Frailty Inflammatory
depression in older Phenotype
persons
2015 Browers et al. Belgium Cross- Cancer patients 162 76.0 Leuven Oncogeriatric Inflammatory
Sectional Frailty Score
2015 Gunawardene Australia Cross- Community-dwelling 77 ~75.9 Fried Frailty Phenotype Hormonal,
et al. Sectional inflammatory and
metabolic
2015 Saum et al. Germany Cross- ESTHER cohort study 2.518 ~70.6 Modified Fried Frailty Oxidative and
Sectional Phenotype inflammatory
2014 Darvin et al. USA Cross- Community-dwelling 65 80.6 Fried Frailty Phenotype Metabolic and
Sectional Inflammatory
2014 García-García Spain Cohort Toledo study for 1972 75.1 Frailty Trait Scale Hormonal,
et al. healthy aging inflammatory and
metabolic
2014 Inglés et al. Spain Cohort Toledo study for 742 ~74.3 Modified Fried Frailty Oxidative and
healthy aging Phenotype metabolic
2013 Tajar et al. Europe and Cross- Community-dwelling 1504 69.5 Modified Fried Frailty Metabolic
South Sectional Phenotype
America
2013 Yeap et al. Australia Cross- The health in men study 527 70–89 FRAIL scale Hormonal
Sectional
2012 Kalyani et al. USA Cross- Women’s health and 73 84–95 Modified Fried Frailty Inflammatory and
Sectional aging studies Phenotype hormonal
2011 Leng et al. USA Cross- Community-dwelling 133 84.0 Fried Frailty Phenotype Inflammatory
Sectional
2009 Fried et al. USA Cross- Cardiovascular health 704 70–79 Fried Frailty Phenotype Inflammatory and
Sectional study metabolic
2009 Hubbard et al. England Case- Nursing home residents 110 ~82.4 Modified Fried Frailty Inflammatory
Control Phenotype
2009 Leng et al. USA Cross- Women’s health and 558 ~76.6 Fried Frailty Phenotype Inflammatory
Sectional aging studies
2009 Qu et al. USA Cross- Community-dwelling 32 83 Fried Frailty Phenotype Oxidative and
Sectional metabolic
2009 Qu et al. USA Cross- Community-dwelling 32 83 Fried Frailty Phenotype Inflammation
Sectional
2009 Serviddio et al. Italy Cross- Hospitalized 62 76.7 Modified Fried Frailty Oxidative
Sectional Phenotype
2009 Szanton et al. USA Cohort Women’s health and 728 74.2 Modified Fried Frailty Inflammatory and
aging studies Phenotype metabolic
2009 Wu et al. Taiwan Cross- Community-dwelling 90 ~76.6 Modified Fried Frailty Inflammatory and
Sectional and hospitalized Phenotype metabolic
2007 Leng et al. USA Cohort Women’s health and 548 73.9 Fried Frailty Phenotype Inflammatory
aging studies
2002 Walston et al. USA Cohort Cardiovascular health 4735 65 + Fried Frailty Phenotype Inflammatory and
study metabolic
2002 Leng et al. USA Cross- Community-dwelling 30 ~83.1 Fried Frailty Phenotype Inflammatory
Sectional and hospitalized
Sarcopenia
2020 Lu et al. Singapore Cross- Community-dwelling 189 73.2 Muscle mass plus IHG or Serum amino acids and
Sectional WS metabolic
2020 Sánchez- Spain Cross- Hospitalized 150 87.6 ASMI plus IHG Oxidative and
Castellano et al. Sectional inflammatory
2019 Kuo et al. China Cross- I-Lan longitudinal aging 731 ~74.9 Muscle mass plus IHG or Metabolic and
Sectional study WS hormonal
2019 Mochizuki et al. Japan Cross- Patients with OA 240 75.0 Muscle mass plus IHG or Hormonal, metabolic,
Sectional WS and inflammatory
2019 Vettoretti et al. Italy Cross- Patients with CKD 113 80.6 Muscle mass plus IHG or Metabolic and
Sectional WS Inflammatory
2018 Bellanti et al. Italy Cross- Community-dwelling 115 ~77.1 Muscle mass plus IHG or Metabolic, oxidative
Sectional WS and inflammatory
2018 Rong et al. China Cross- Community-dwelling 421 ~74.5 Muscle mass plus IHG or Inflammation
Sectional WS
2018 Tay et al. Singapore Cross- Community-dwelling 108 76.7 Muscle mass plus IHG or
Sectional WS
(continued on next page)

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A. Picca et al. Ageing Research Reviews 73 (2022) 101530

Table 1 (continued )
Frailty

Year Authors Country Study Sample Sample Mean age Assessment Biomarkers
design size (n) (years)

Hormonal,
inflammatory and
apolipoprotein
2018 Yalcin et al. Turkey Case- Community-dwelling 160 ~79 Muscle mass plus IHG or Hormonal and
Control WS inflammatory
2018 Yoo et al. Korea Cross- Hospitalized 327 77.6 Muscle mass plus IHG or Inflammatory and
Sectional WS metabolic
2017 Ates Bulut et al. Turkey Cross- Community-dwelling 403 ~74.0 Muscle mass plus IHG or Metabolic
Sectional WS
2017 Bian et al. China Cross- Community-dwelling 441 75.3 ASMI plus IHG Inflammatory and
Sectional metabolic
2017 Can et al. Turkey Cross- Hospitalized 72 ~78.6 Muscle mass plus IHG or Metabolic
Sectional WS
2017 Lustosa et al. Brazil Cross- Community-dwelling 63 ~77.1 Muscle mass plus IHG or Inflammatory
Sectional WS
2017 Coto Montes Spain Cross- Community-dwelling 200 ~77.1 Muscle mass plus IHG or Metabolic, oxidative
et al. Sectional WS and inflammatory
2016 Landi et al. Italy Cross- ilSIRENTE 332 ~86.3 Muscle mass plus IHG or Metabolic and
Sectional WS inflammatory
2016 Ter Borg et al. Holland Cross- MaSS 227 74.0 Muscle mass plus IHG or Metabolic and
Sectional WS hormonal
2015 Cacciatore et al. Italy Cross- Community-dwelling 337 76.8 Muscle mass plus IHG Inflammatory and
Sectional metabolic
2015 Lim et al. Singapore Cross- Community-dwelling 143 68.0 Muscle mass plus IHG or Inflammatory
Sectional WS
2014 Marzetti et al. Italy Cross- Hospitalized 42 83.7 Muscle mass plus IHG or Metabolic
Sectional WS
2018–2020 BIOSPHERE Italy Case- Community-dwelling 90 77.6 Muscle mass and SPPB Metabolic, oxidative
Control and inflammatory

Abbreviations: AD, Alzheimer’s disease; AGES-Reykjavik, Age Gene/Environment Susceptibility-Reykjavik; ASMI, appendicular skeletal muscle index; BIOSPHERE,
BIOmarkers associated with Sarcopenia and PHysical frailty in EldeRly pErsons; CFS, clinical frailty scale; CKD, chronic kidney disease; ESTHER, Epidemiological
Investigations of the Chances of Preventing, Recognizing Early and Optimally Treating Chronic Diseases in an Elderly Population; IHG, isometric handgrip; MaSS,
Maastricht Sarcopenia Study; OA, osteoarthritis; WS, walking speed

slow gait speed which are also features of sarcopenia.
A dysregulation of the cytokine network has been indicated as a
converging point of mechanistic pillars of aging and a major driver of
age-associated conditions (Cesari et al., 2004; Franceschi et al., 2018;
Michaud et al., 2013; Varadhan et al., 2014). A chronic state of
low-grade inflammation, often referred to as inflamm-aging, is sustained
by a variety of stimuli, including pathogens, end products of gut mi­
crobial activity, endogenous cellular debris, or misplaced intracellular
components (i.e., damage-associated molecular patterns) (Franceschi
et al., 2018). In response to these stimuli, local inflammatory cells (e.g.,
neutrophils and macrophages) secrete several cytokines, among which
IL-1, IL-6, and TNF-α are especially relevant (Franceschi et al., 2018).
From this perspective, the association of IL-6 and TNF-α with frailty and
sarcopenia may reflect an endophenotypic expression of inflamm-aging.
However, we found that IL-6 was associated with frailty and sarcopenia
in people aged < 75 years, whereas no associations were observed in
those older than 75. IL-6 is a "double-edged sword" mediator able to
promote muscle anabolism or catabolism depending on the tissular
milieu (Belizário et al., 2016). Following tissue infection and/or dam­
age, local immune cells release IL-6 as part of the inflammatory secre­
tome, and chronic low-grade inflammation ensues in the setting of
prolonged exposure to IL-6 signaling. IL-6 may also act as a myokine
when is produced by contractile skeletal myocytes especially during
exercise to promote glucose tolerance and insulin sensitivity (Coelho-­
Junior et al., 2019; Pedersen and Febbraio, 2006). Muscle catabolism
and atrophy have also been reported in the setting of prolonged expo­
sure to IL-6 via blunting muscle anabolism and perturbing energy ho­
meostasis (Belizário et al., 2016). However, a synergistic interaction of
IL-6 with other inflammatory mediators is needed to deploy its catabolic
effect and trigger muscle wasting (Belizário et al., 2016). The
age-related higher levels of IL-6 may not suffice to induce the catabolic
effect required for muscle wasting. Though, concomitant release and
activity of other inflammatory mediators such as TNF-α may create an
environment favoring muscle atrophy (Belizário et al., 2016; Tuttle
et al., 2020). TNF-α is a pro-inflammatory cytokine released by diseased
tissues that is able to exert endocrine effects on skeletal muscle (Powers
et al., 2016). TNF-α has also been shown to depress contractility by
acting upon skeletal muscle both in vitro and in vivo (Alloatti et al.,
2000; Wilcox et al., 1994). Hence, the higher systemic TNF-α levels
found in community-dwelling older adults with frailty and sarcopenia
supports the hypothesis that IL-6 and TNF-α may contribute to muscle
mass and strength loss during aging (Wilcox et al., 1994).
In the context of chronic inflammation, the liver responds by pro­
ducing several acute-phase reactants, while the synthesis of a number of
other proteins is depressed. Albumin is one of these "negative" acute-
phase proteins and its decrease is used as a marker of inflammation.
Decreased protein synthesis of during inflammation may serve to save
amino acids for producing "positive" acute-phase proteins more effi­
ciently. This may explain the negative association of albumin with
frailty and sarcopenia, regardless of participant’s age and setting
(Table 2).
Finally, a negative association with frailty and sarcopenia was
identified for hemoglobin, although no data were obtained in age-
stratified analysis for sarcopenia. This association, while confirming
the role of hemoglobin as a biomarker of frailty, also opens to the
implication of reduced hemopoiesis as a pathway to sarcopenia possibly
through the mediation of inflammation. Anemia is responsible for
reduced tissue oxygenation and consequent fatigue, weakness, and
increased functional impairment, and low hemoglobin concentrations
have been associated with decline of self-reported physical activity and
muscle strength in community-dwellers (Cecchi et al., 2017).
Taken as a whole, our results indicate that common pathways exist
between frailty and sarcopenia and that several mediators may be
involved in the way to the progression from one (frailty) to the other

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A. Picca et al. Ageing Research Reviews 73 (2022) 101530

Table 2
Meta-analysis stratified by age and setting.
Frailty (n = 52) Sarcopenia (n = 23)

SMD 95% CI P-value SMD 95% CI P-value

Metabolic markers
Glucose (6/4) Overall 0.205 -0.107, 0.516 0.198 -0.298 -1.404, 0.808 0.597
Age
< 75 years 0.176 -0.152, 0.503 0.293 — — —
≥ 75 years 0.700 0.472, 0.929 0.0001 — — —

Cholesterol (11/6) Overall -0.801 -1.841, 0.238 0.131 0.159 -0.793, 1.111 0.743
Age
< 75 years — — — 0.133 -2.855, 3.121 0.930
≥ 75 years — — — 0.178 -0.394, 0.751 0.542
Setting
Community-dwelling — — — 0.221 -0.897, 1.338 0.698
Hospitalized — — — -0.153 -0.607, 0.301 0.509

Triglycerides (12/6) Overall 0.407 -0.209, 1.023 0.196 -0.604 -1.022, 0.187 0.005
Age
< 75 years — — — -0.453 -0.763, − 0.143 0.004
≥ 75 years — — — -0.635 -1.155, − 0.114 0.017
Setting
Community-dwelling — — — -0.610 -1.099, − 0.121 0.014
Hospitalized — — — -0.570 -1.042, − 0.098 0.018

LDL (10/7) Overall -0.180 -0.264, − 0.097 0.0001 0.073 -0.414, 0.559 0.770
Age
< 75 years -0.180 -0.272, − 0.089 0.0001 0.443 -0.264, 1.149 0.219
≥ 75 years -0.180 -0.384, 0.024 0.084 -0.080 -0.680, 0.521 0.795
Setting
Community-dwelling — — — 0.077 -0.477, 0.631 0.785
Hospitalized — — — 0.043 -0.410, 0.497 0.851

HDL (10/4) Overall -0.130 -0.283, 0.023 0.096 0.593 -0.282, 1.469 0.184

Albumin (12/10) Overall -1.003 -1.421, − 0.586 0.0001 -0.452 -0.726, − 0.179 0.001
Age
< 75 years -0.862 -1.579, − 0.145 0.019 -0.503 -0.987, − 0.020 0.041
≥ 75 years -1.232 -1.832, − 0.633 0.0001 -0.445 -0.810, − 0.079 0.017
Setting
Community-dwelling -0.856 -1.266, − 0.447 0.0001 -0.389 -0.725, − 0.053 0.023
Hospitalized -1.281 -2.464, − 0.098 0.034 -0.620 -1.071, − 0.168 0.007

Inflammatory markers
IL-6 (23/9) Overall 0.665 0.120, 1.209 0.017 0.198 -0.192, 0.589 0.319
Age
< 75 years 1.437 0.619, 2.256 0.001 1.670 1.314, 2.026 0.0001
≥ 75 years 0.017 -0.861, 0.895 0.970 0.023 -0.245, 0.291 0.865
Setting
Community-dwelling 0.947 0.502, 1.393 0.0001 0.216 -0.234, 0.667 0.347
Hospitalized 0.836 0.279, 1.394 0.003 0.198 -0.192, 0.589 0.679
Institutionalized -5.872 -6.486, − 5.258 0.0001 — — —

CRP (21/10) Overall 0.385 -0.070, 0.839 0.097 0.141 -0.445, 0.726 0.637
Age
< 75 years 0.816 0.019, 1.614 0.045 0.500 -0.522,1.521 0.338
≥ 75 years 0.028 -0.375, 0.431 0.891 0.023 -0.445, 0.726 0.892
Setting
Community-dwelling 0.430 -0.149, 1.009 0.146 0.328 -0.022, 0.679 0.066
Hospitalized 0.652 0.283, 1.021 0.001 -0.606 -4.798, 3.585 0.777
Institutionalized -0.491 -1.482, 0.500 0.331 — — —
TNF-α (10/6)
Overall 0.438 0.222, 0.654 0.001 1.033 0.164, 1.903 0.020
Age
< 75 years 0.460 0.244, 0.675 0.0001 — — —
≥ 75 years 0.421 0.069, 0.773 0.019 — — —
Setting
Community-dwelling 0.373 0.200, 0.547 0.0001 1.344 0.268, 2.421 0.014
Hospitalized 0.953 -0.091, 1.997 0.074 -0.280 -0.550, − 0.011 0.042
Institutionalized 0.142 -1.333, 0.418 0.312 — — —

Hormonal markers
Overall -0.636 -1.296, 0.023 0.059 -0.101 -0.352, 0.149 0.427
Age
Vitamin D (9/5) < 75 years -0.551 -1.518, 0.417 0.265 — — —
≥ 75 years -0.215 -1.538, 1.108 0.750 — — —
(continued on next page)

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A. Picca et al. Ageing Research Reviews 73 (2022) 101530

Table 2 (continued )
Frailty (n = 52) Sarcopenia (n = 23)

SMD 95% CI P-value SMD 95% CI P-value

Overall -1.387 -2.639, − 0.135 0.030 -0.035 -0.606, 0.536 0.904

IGF-1 (8/3) Setting
Community-dwelling -1.513 -2.974, − 0.052 0.042 — — —
Hospitalized -0.553 -0.929, − 0.178 0.004 — — —

Hematologic markers
Hemoglobin (14/5) Overall -1.679 -2.751, − 0.607 0.002 -0.749 -1.065, − 0.433 0.0001
Age
< 75 years -1.018 -1.589, − 0.446 0.0001 — — —
≥ 75 years -2.392 -4.477, − 0.307 0.025 — — —
Setting
Community-dwelling -2.111 -4.197, − 0.025 0.047 -0.753 -1.205, − 0.301 0.014
Hospitalized -1.214 -1.692, − 0.736 0.0001 -0.784 -0.550, − 0.011 0.0001
Institutionalized -0.576 -0.856, − 0.295 0.0001 — — —

Abbreviations: (# of studies referring to frailty/sarcopenia), CI, confidence interval; CRP, C-reactive protein; HDL, high-density lipoprotein; IGF-1, Insulin-like growth
factor 1; IL-6, interleukin 6; LDL, low-density lipoprotein; SMD, standard mean difference; TNF-α, tumor necrosis factor alpha

(sarcopenia). Indeed, according to the main biomarkers identified by
our systematic review and meta-analysis in both conditions, a mecha­
nistic hypothesis may be envisioned. In particular, the age-related
reduction in hemoglobin levels and the consequent lower tissue
oxygenation may have a negative impact on several organs and, espe­
cially, on muscle which is highly reliant on oxidative metabolism. As a
response to tissue damage, the release of pro-inflammatory cytokines (i.
e., IL-6) ensues. However, in the setting of persistent inflammatory
stimuli, a synergistic expression of other inflammatory mediators that
may act also as pro-atrophy factors (e.g., TNF-α) may be triggered and
ultimately lead to muscle wasting. Reduced rates of muscle protein
synthesis paralleled by enhanced protein breakdown in the context of
overt inflammation may further sustain the decline in muscle mass, since
a metabolic shift towards amino acid saving is promoted to support
acute phase protein synthesis and inflammatory signaling. The regula­
tion of inflammatory and metabolic mediators associated with the
transition from frailty to sarcopenia is quite intricate. The negative as­
sociation found between TNF-α and sarcopenia in hospitalized people is
an example of this complexity. While acting synergistically with IL-6
during frailty, the possibility exists that clinical conditions such as
poor nutrition and severe muscle atrophy may impact the function of the
immune system (Compté et al., 2013) and be responsible for the inverse
association between TNF-α and sarcopenia in hospitalized people.
Of note, a set of molecules were also identified by our analysis as
significantly associated with only one of the two conditions, which
might indicate that different pathophysiological pathways may also be
associated with frailty and sarcopenia. Indeed, glucose, LDL, CRP and
IGF-1 were exclusively associated with frailty, whereas triglycerides
were only significantly associated with sarcopenia. However, our results
were based on measures of central tendency and dispersion instead of
adjusted measure estimations, thus limiting inferences about the effects
of important covariates on the analysis. For instance, glucose (Kim et al.,
2014; Seok et al., 2007) and IGF-1 levels (Musarò et al., 2001, 1999;
Saeki et al., 2020) have a bi-directional relationship with muscle mass
and quality. Physical activity/exercise and eating patterns may also
influence metabolic (Kelley et al., 2011, 2005; Schwingshackl et al.,
2020; Tosti et al., 2018), hormonal (Amiri et al., 2021; Tosti et al.,
2018), and inflammatory milieu (Chupel et al., 2017; Nani et al., 2021;
Schwingshackl et al., 2020). In addition, the prevalence of comorbidities
and sleep disturbance may also affect the circadian cycle and conse­
quently have an impact on biomarker levels (Montaruli et al., 2021).
The stratified analysis of the present study also provided relevant
insights. In particular, IL-6 was positively associated with frailty in
community-living and hospitalized older adults, whereas a negative
association was found in those living in long-term institutions. These
findings are in line with previous investigations reporting lower
lymphocyte counts according to frailty severity in institutionalized older
adults (Fernandez-Garrido et al., 2018). Although the exact mechanism
underlying this association is unknown (Fernandez-Garrido et al.,
2018), frailty progression has been associated with a lower cellular
response to stress (El Assar et al., 2017). In addition, long-term treat­
ment with glucocorticoid medications, which are frequently prescribed
to institutionalized older adults (Tjia et al., 2010), may also induce
immunosuppression by inhibiting leukocyte trafficking, modifying im­
mune cell’s function, and suppressing the production and actions of
humoral factors involved in the inflammatory process (Strehl et al.,
2019). However, the possibility that only less impaired nursing-home
residents were assessed in this study cannot be ruled out. Though, the
generalizability of this finding is limited as only one study investigated
the association between IL-6 levels and frailty in older adults who lived
in long-term institutions. Hence, further studies reporting results
adjusted for confounding factors are required. Moreover, studies
investigating specific populations (e.g., institutionalized older adults)
and genders with both sarcopenia and frailty are lacking, thus
hampering the conduction of stratified analysis. Other important limi­
tations were identified by the quality analysis, including the lack of a
clear description of the source of biomarkers (e.g., plasma, serum),
sample size calculations, and whether assessors were blinded. The in­
formation on biomarker source is particularly relevant as it has been
reported to influence the association between levels of several molecules
and frailty (Furtado et al., 2020). The above-listed limitations might
provide a possible explanation to the counterintuitive negative associ­
ation between circulating levels of TNF-α and sarcopenia in hospitalized
older people.
As previously mentioned, substantial agreement exists on the theo­
retical construct of frailty and sarcopenia. Yet, their operationalization
is still a matter of debate. This is reflected by the fact that the two
conditions were operationalized according to different criteria across
the studies included in our investigation. This might have an impact on
the identification of associated biomarkers. The present study included a
large array of biomarkers and indicated a clear set of candidate mole­
cules and pathways shared between frailty and sarcopenia. However,
numerous other molecules that may explain the pathophysiology of both
conditions have been investigated, but were not included in our report
due to the small number of studies (<3 in frailty and sarcopenia). Among
these, gut microbial derivatives and mediators carried within extracel­
lular vesicles warrant investigation. Indeed, gut dysbiosis is a pillar of
the gut-muscle axis that has been included among the mechanisms
contributing to physical frailty and sarcopenia (Picca et al., 2019b).
Along with this, altered intracellular trafficking is among the main
mechanisms underlying the bioenergetic deficit and overall decline in
cellular quality control mechanisms observed in old age (Picca et al.,

9
A. Picca et al.
2020). The small number of studies eligible for inclusion, the hetero­
geneity of assayed biomolecules, and the limited access to raw data
impeded conducting deeper statistical analysis. For instance, principal
components analysis (PCA), a promising approach to identify bio­
markers for frailty and sarcopenia in older adults (Calvani et al., 2015),
was not applicable to our study because of the limited availability of raw
data. To gather preliminary information, a PCA was run using available
data (Supplementary File 2). PCA returned six biomarkers: albumin,
cholesterol, CRP, glucose, IL-6, and vitamin D, and with factorial
weights ranging from 0.638 to 0.966 and explaining 94.5% of the
variance (Supplementary Table 2). These findings corroborate, at least
partially, our results and deserve further investigation.
5. Conclusion
A major goal in the process of biomarker discovery is the identifi­
cation of a small number of mediators that can reliably be used as
endophenotypes of physiological dysregulation to support the diagnosis
and monitoring of a specific condition as well as clinical decision-
making and verification of intervention efficacy. Changes over time in
specific sets of molecules may also support the definition of patterns of
biomarkers reflecting the individual’s departure from their "normal
operating conditions". The inclusion of biomarkers of frailty and sarco­
penia in daily practice and clinical research is yet to come. However, the
identification of a set of metabolic, hematologic, and inflammatory
biomarkers shared by frailty and sarcopenia through our systematic
review and meta-analysis is a pivotal step towards the achievement of a
solid rationale for biomarker selection in studies investigating these
conditions. Following validation, these mediators may eventually assist
in the diagnostic makeup and prognostication of frailty and sarcopenia
in clinical practice.
Declaration of Competing Interest
E.M., and R.C. are partners of the SPRINTT Consortium, which was
partly funded by the European Federation of Pharmaceutical Industries
and Associations (EFPIA). The other authors have no conflict interest to
disclose.
Funding
This work was supported by an Intramural Research Grant from the
Università Cattolica del Sacro Cuore [D1 2020], the nonprofit research
foundation “Centro Studi Achille e Linda Lorenzon”, and the Swedish
Research Council [Ref.: 2017-06088]. Hélio José Coelho-Junior is fun­
ded by a scholarship from the Brazilian federal government [Coor­
denação de Aperfeiçoamento de Pessoal de Nivel Superior; 001]. The
funders had no role in study design, data collection and analysis, deci­
sion to publish, or preparation of the manuscript.
Authors’ contributions
AP and HJCJ designed the study question, completed the literature
search, selected articles, extracted data, prepared tables and figures, and
wrote the article. EM was consulted to solve disagreements on data
extraction and quality assessment and, together with RC and DLV,
revised the article and provided critical recommendations on structure
and presentation. All authors approved the final version of the
manuscript.
Ethic approval
Institutional review board approval for data related to the
BIOSPHERE study was obtained by the Ethics Committee of the Uni­
versità Cattolica del Sacro Cuore (Rome, Italy; protocol number: 8498/
15). No approval was needed for all other studied of the systematic
10
Ageing Research Reviews 73 (2022) 101530
review because data were obtained from secondary sources.
Appendix A. Supporting information
Supplementary data associated with this article can be found in the
online version at doi:10.1016/j.arr.2021.101530.
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