Gene 844 (2022) 146775

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Gene
journal homepage: www.elsevier.com/locate/gene

The Japan Frailty Scale is a promising screening test for frailty and
pre-frailty in Japanese elderly people
Ryuichiro Egashira a, Tomoharu Sato b, Akimitsu Miyake c, d, Mariko Takeuchi a, Mai Nakano a,
Hitomi Saito a, Misaki Moriguchi a, Satoko Tonari a, Keisuke Hagihara a, *
a
Department of Advanced Hybrid Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
b
Department of Biostatistics and Data Science, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
c
Department of Medical Innovation, Osaka University Hospital, Suita, Osaka 565-0871, Japan
d
Tohoku University School of Medicine, Sendai 980-8575, Japan

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

Edited by X. Carette Frailty is one of the most important problems in a super-aged society. It is necessary to identify frailty quickly
and easily at the bedside. We developed a simple patient-reported frailty screening scale, the Japan Frailty Scale
Keywords: (JFS), based on the aging concept of Kampo medicine. Eight candidate questions were prepared by Kampo
Frailty medicine experts, and a simple prediction model was created in the development cohort (n = 434) and externally
Kihon checklist
validated in an independent validation cohort (n = 276). The physical indicators and questionnaires associated
Japan Frailty Scale
with frailty were also comprehensively evaluated. The reference standard for frailty or pre-frailty was deter­
Sarcopenia
Locomotive syndrome mined based on the Kihon checklist. In the development cohort, four questions, nocturia (0–2), lumbago (0–2),
cold sensitivity (0–2), exhaustion (0–4), and age (0–1) were selected by multivariable logistic regression analysis.
The total JFS score is 0–11. Receiver-operating characteristic curve analysis of the JFS for identifying frailty
status showed moderately good discrimination (area under the curve (AUC) = 0.78, 95 % confidence interval
(CI): 0.73–0.82). At the JFS cutoff value of 3/4 for frailty or pre-frailty, the sensitivity, specificity, positive
predictive value (PPV), and negative predictive value (NPV) were 86.9 %, 53.3 %, 62.8 %, and 81.7 %,
respectively. External validation of the JFS showed moderately good discrimination (AUC = 0.76, 95 % CI:
0.70–0.81). The sensitivity, specificity, PPV, and NPV were 79.9 %, 61.4 %, 69.3 %, and 73.7 %, respectively.
These results indicate that the JFS is a promising patient-reported clinical scale for early identification of pre-
frail/frail patients at the bedside in primary care.

1. Introduction
Frailty is one of the most important medical issues because the
population of elderly people is increasing globally (Gale et al., 2015;
Hoogendijk et al., 2019; Ma et al., 2018). Japan has seen the most rapid
emergence of a super-aged society in the world, and the high prevalence
of frailty in the elderly has been reported in various studies (Satake
et al., 2017a). Frailty is characterized as a decline in reserve capacity
associated with various physiological systems with aging, and adverse
health outcomes such as disability and death can be caused by relatively
mild stress (Clegg et al., 2013; Fried et al., 2004; Xue, 2011). It is said
that the progression of frailty may be reversible if diagnosed and treated
early. Therefore, it is important to diagnose frailty with a simple
screening tool in clinical settings (Morley et al., 2013).
Currently, the frailty phenotype has been discussed from a multidi­
mensional point of view containing physical and psychosocial factors
(Fried et al., 2004). The Cardiovascular Health Study (CHS) frailty
index, proposed and validated by Fried et al., consists of simple defini­
tions based on exhaustion, inactivity, slowness, weakness, and weight
loss (Fried et al., 2001). The CHS is simple, but walking speed and grip

Abbreviations: BMI, body mass index; CQ, candidate question; CF, cognitive function; DM, depressive mood; ECW/TBW, extracellular water/total body water;
GDS-15, 15-item Geriatric Depression Scale; IADL, instrumental activities of daily living; IQR, interquartile range; JFS, Japan Frailty Scale; J-CHS, Japanese version
of the Cardiovascular Health Study criteria; KCL, Kihon checklist; Locomo 5, 5-question Geriatric Locomotive Function Scale; NS, nutritional status; OF, oral function;
PF, physical function; SA, social activities; SMI, skeletal muscle mass index.
* Corresponding author.
E-mail address: k.hagihara@kanpou.med.osaka-u.ac.jp (K. Hagihara).

https://doi.org/10.1016/j.gene.2022.146775
Received 24 March 2022; Received in revised form 13 July 2022; Accepted 25 July 2022
Available online 22 August 2022
0378-1119/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
R. Egashira et al.
strength need to be measured using equipment. Rockwood and col­
leagues proposed the Frailty Index of Accumulative Deficits (FI-CD),
which stratified elderly persons based on the accumulation of 92 defi­
cits, consisting of mental states, physical functions, and various diseases,
e.g. cancer or diabetes mellitus and so on (Mitnitski et al., 2001).
Although the FI-CD is well validated and has predictive ability, it is very
complex and unpopular at the bedside. In Japan, the Japanese-CHS
criteria (J-CHS) (Satake and Arai, 2020), locomotive syndrome (Naka­
mura and Ogata, 2016), sarcopenia (Chen et al., 2020), and the Kihon
checklist (KCL) (Arai and Satake, 2015; Sampaio et al., 2016) are widely
used to identify older adults with frailty. Locomotive syndrome, pro­
posed by the Japanese Orthopaedic Association, has focused attention
on motor function. The J-CHS, proposed by the Japanese Geriatrics
Society in 2015, is a modified form of the CHS criteria. The KCL was
developed by Japan’s Ministry of Health, Labour and Welfare to identify
patients who need a high level of care or are likely to need it in the
future. It consists of a 25-item, self-reported, Yes/No questionnaire on
instrumental and social activities of daily living, physical functioning,
nutritional status, oral functioning, cognitive functioning, and depressed
mood. This questionnaire allows us to assess elderly people
comprehensively.
Clinical guidelines for frailty management recommend using vali­
dated measures to identify frailty, but many of these frailty scales are
time-consuming, require objective measurement with devices, and are
difficult to perform in routine clinical settings (Dent et al., 2017). Simple
self-reported screening scales are needed to identify subjects quickly and
easily who would benefit from more complex assessments.
Traditional Japanese herbal medicine (Kampo medicine) is widely
used at the bedside for the treatment of functional dyspepsia, manage­
ment of behavioral and psychological symptoms of dementia (BPSD),
and so on (Takayama et al., 2018). Compared to modern medicine,
Kampo medicine uses a five viscera theory that clusters the various
symptoms of the living body. In particular, Kidney (TM), called “Jin” in
Japanese, is considered to control the genitourinary system and vital
energy (Hagihara et al., 2017). In the aging concept of Kampo medicine,
the vital energy of Kidney (TM) is thought to decrease with age, which is
called “Jin-kyo” (Nakae et al., 2018). In “The Yellow Emperor’s Classic
of Internal Medicine” (Veith, 2015) which is one of the most important
texts in Kampo medicine, the phenomenon of human aging is mentioned
primarily in Chapter 1. This chapter describes the changes in hair, teeth,
and skin that occur as Kidney (TM) energy declines with age, as well as
the decline in the body’s ability to metabolize water and in physical
performance. In other Chapters, it is mentioned that the Kidney (TM) is
associated with the lower back, ears, and body temperature control. The
mechanism of manifestation of “Jin-kyo” is also described in Chapter 1,
but the description is not in line with modern physiology and
biochemistry, and the presence or absence of “Jin-kyo” is evaluated
based on the medical history and physical findings according to Kampo
concepts. The scientific elucidation of the pathophysiology of “Jin-kyo”
is a subject for the future, and we have worked on this theme through the
exploration of the effect on animal models of Go-sha-jinki-Gan (GJG),
which is one of the typical anti-aging herbal medicines. We believe that
quantifying the patients’ symptoms is one important step in this
direction.
In this study, a new simple frailty screening scale (Japan Frailty
Scale: JFS), consisting of age and four simple questions about the clinical
manifestations associated with the aging concept of Kampo medicine,
was developed. The JFS created in the development cohort was vali­
dated for accuracy and calibration in different validation cohorts. In
addition, the relationships among KCL, J-CHS, sarcopenia, locomotive
syndrome, several physical measurements, and JFS were also
investigated.
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Gene 844 (2022) 146775
2. Materials and methods
2.1. Study design and patient population
In order to establish a simple prediction scale for the early detection
of frailty, the following steps were taken. First, candidate questions for
the JFS were prepared through discussions between experts in geriatrics
and Kampo medicine. Next, a simple prediction model was created in the
development cohort. Finally, the model was externally validated in an
independent validation cohort. This study followed the TRIPOD
(Transparent Reporting of a Multivariable Prediction Model for Indi­
vidual Prognosis or Diagnosis) reporting guidelines (Collins et al.,
2015).
2.1.1. Development cohort
To develop the JFS, participants were recruited in cultural circles
organized by the town of Sango, Nara prefecture, during May to June
and October to December 2019. The inclusion criteria were age 65 years
or older and able to participate in circle activities on their own. The
exclusion criterion was certified as needing long-term care. The elderly
people who met the criteria and gave their consent were evaluated
through a frailty check-up on the same day they were recruited.
2.1.2. Validation cohort
To validate the JFS created in the development cohort, participants
were recruited by flyer in an outpatient clinic in Suita city, Osaka pre­
fecture from January to February 2020. The inclusion criteria were age
65 years or older and able to go to the clinic without being helped by
others. The exclusion criterion was the same as for the development
cohort. The elderly people who met the criteria and gave their consent
were evaluated through a frailty check-up on other days during the in­
clusion period.
2.2. KCL criterion for frailty status
The Comprehensive Geriatric Assessment (CGA) is a standard
method to comprehensively assess the daily life function of the elderly,
and the frailty index of the CGA (FI-CGA), which is calculated by
accumulating the number of deficits, has been shown to predict future
adverse outcomes (Jones et al., 2004). In Japan, the Ministry of Health,
Labour and Welfare has developed the KCL as part of its national policy.
The KCL, like the FI-CGA, is intended to be a comprehensive evaluation
of elderly persons (Dent et al., 2016), and it is used to screen frail elderly
persons and intended to identify not only the people who need long-term
care, but also identify those whose progression to needing long-term
care could be prevented through intervention.
The KCL consists of 7 domains of a total of 25 self-reporting items
assessing instrumental activities of daily living (IADL, 5 items), physical
function (PF, 5 items), nutritional status (NS, 2 items), oral function (OF,
3 items), social activities (SA, 2 items), cognitive function (CF, 3 items),
and depressive mood (DM, 5 items), including all physical, psycholog­
ical, and social domains of frailty. In addition, the sum of questions 1
through 20 represents general life functions (Kamegaya et al., 2017;
Sampaio et al., 2016). Each question is answered with a yes/no
response, and one point is given for each item, with a maximum score of
25 points. Based on the total score, the patients were classified as robust
(0–3 points), pre-frail (4–7 points), and frail (8 points or more) (Satake
et al., 2017b). Its reliability and validity as a frailly assessment scale
have already been established (Dent et al., 2019), and it has been vali­
dated in other cultures (Esenkaya et al., 2019; Sampaio et al., 2014).
Since the JFS is intended to screen for general life function, the KCL
was used as the reference standard for determining frailty. The main
purpose was to discriminate between robust and pre-frail patients and
identify patients who would benefit from more complex assessments.
R. Egashira et al.
2.3. Questions used for the development of the JFS
In Kampo medicine, there is a certain accepted pattern, like a syn­
drome, of symptoms that manifest due to aging, and some of them can be
reversed with therapy. Therefore, to develop a statistical model to es­
timate the probability of frailty, an expert committee composed of three
experts in Kampo medicine and geriatrics examined the concepts of
Kampo medicine, frailty, and geriatric syndromes together. In this study,
the aim was to quantify the symptoms of “Jin-kyo”, and the symptoms
were extracted from the “Yellow Emperor’s Classic of Internal Medicine”
(Veith, 2015). Factors already included in many frailty indices estab­
lished in modern medicine and evidence suggesting factors associated
with frailty were also taken into account, and subjective findings that
were considered most reflective of frailty were selected.
Finally, it was agreed to adopt the following eight questions: amount
of gray hair (Candidate Question 1: CQ1), number of teeth (Candidate
Question 2: CQ2), hearing loss (Candidate Question 3: CQ3), skin dry­
ness (Candidate Question 4: CQ4), nocturia (Candidate Question 5:
CQ5), lower back pain (Candidate Question 6: CQ6), cold hypersensi­
tivity (Candidate Question 7: CQ7), and exhaustion (Candidate Question
8: CQ8). Each item is scored with a baseline of 0 and a higher score given
to conditions closer to frailty (Table 1). For hearing loss, the answer for
the worse side was adopted.
2.4. Health check-up for frailty and related conditions
Sarcopenia (Chen et al., 2020) and locomotive syndrome (Nakamura
and Ogata, 2016), which are concepts similar to frailty and focus more
on the musculoskeletal system, and the J-CHS (Satake and Arai, 2020)
which is a frailty scale, are widely used in Japan. Therefore, various
physical measurements were taken, and these data were used to deter­
mine sarcopenia and frailty based on the J-CHS. Locomotive syndrome
was measured with a questionnaire, the 5-question Geriatric Locomotive
Function Scale (Seichi et al., 2012). Although depression is included as a
domain of the KCL, the 15-item Geriatric Depression Scale (GDS-15)
Table 1
Candidate questions for JFS components Abbreviations: CQ, candidate question; JFS, Japan Frailty Scale.
CQ1 Amount of gray hair
“How much gray hair do you have?”
CQ2 Number of teeth
“Has your number of teeth decreased?”
CQ3 Hearing loss
“Do you have any difficulty with your hearing (without hearing aids)? “
CQ4 Skin dryness
“Do you feel flakiness of your skin?”
CQ5 Nocturia
“How many times do you typically get up at night to urinate?”
CQ6 Lower back pain
“Do you have lower back pain?”
CQ7 Cold hypersensitivity (Coldness in the feet)
“Do you have cold hypersensitivity (coldness) in the feet?”　 0→
CQ8 Exhaustion
“Do you feel tired?”
Gene 844 (2022) 146775
(Yesavage, 1988) was also administered to determine depression in a
more validated method. On the day of the check-up, age and sex were
collected as demographic indicators, and height, weight, grip strength,
gait speed, two-step values, and body composition were measured as
physical measurements.
Isometric grip strength is mainly measured as an indicator of muscle
strength, but it has been found to be associated with a variety of factors
(Lauretani et al., 2003). It is included in the J-CHS and sarcopenia. The
measurement was carried out twice in the self-reported dominant hand
in a standing position, using a Smedley dynamometer (TKK5401, Takei
Scientific Instruments Co., ltd., Niigata, Japan), and the higher of the
two values was used for analysis.
Gait speed is an indicator of physical performance and a strong
predictor of adverse outcomes (Kuys et al., 2014), and it is included in
the J-CHS and a clinical criterion of sarcopenia. An 11-m section was
divided into a 5-m section to be measured, with 3-m sections before and
after, and subjects were asked to walk at a normal speed measured by a
stopwatch.
The two-step test is also a measure of physical function, and it is
primarily used to diagnosis locomotive syndrome. It can detect disorders
in both feet, can be performed in a small space, and the movement
pattern evaluated is like the subject’s actual gait (Demura and Yamada,
2011). Subjects were asked to stand at the starting point with both feet
together, take two steps with as large a stride as possible, and end with
both feet together. The distance between the two steps was measured,
and the value was corrected by dividing it by the height to get the two-
step value.
In addition to muscle strength, muscle mass and composition are
considered to be important factors related to frailty and associated
conditions, and measurement of body composition is included in the
criteria of sarcopenia. Subjects were measured for the body mass index
(BMI), ratio of total body water (TBW) to extracellular water (ECW)
(ECW/TBW), skeletal muscle mass index (SMI), and the phase angle
with bioelectrical impedance analysis (InBody770; InBody, Seoul,
Korea).
0→ “I have no or very little gray hair.”
1→ “It’s not noticeable, but I have gray hair.”
2→ “I have enough gray hair to be noticeable.”
0→ “I haven’t lost any of my teeth.”
1→ “I’ve lost some of my teeth.”
0→ “My hearing is normal.”
1→ “I have some difficulty with my hearing.”
2→ “I have major hearing loss.”
0→ “I don’t feel any flaky skin, or if I have flaky skin, it doesn’t bother me.”
1→ “I have enough flaky skin to worry about, or I have flaky skin to the point where I feel itchy.”
0→ “I don’t usually get up once to urinate at night.”
1→ “I usually get up once to urinate at night.”
2→ “I usually get up twice to urinate at night.”
3→ “I usually get up more than 3 times to urinate at night.”
0→ “I don’t have any lower back pain.”
1→ “I have occasional lower back pain.”
2→ “I have lower back pain, always or often.”
“I don’t have cold hypersensitivity, or I rarely have cold hypersensitivity in my feet.”
1→ “I have occasional cold hypersensitivity in my feet.”
2→ “I always have cold hypersensitivity in my feet, or I often have cold hypersensitivity in my feet.”
0→ “I never or rarely feel tired.”
1→ “I am feeling tired sometimes.”
2→ “I am feeling tired all the time or often.”
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R. Egashira et al.
Data collection was conducted by laboratory staff including physi­
cians who shared a manual and standardized data collection protocol.
The survey with questionnaire was conducted by having the participants
fill out an electronic questionnaire using a tablet device. For the elderly
who had difficulty entering their answers on the device, the staff of the
health check-up listened to and entered the answers. Therefore, both
KCL and JFS did not require the intervention of an evaluator, but the
same staff sometimes responded to cases that needed help to answer
both scales.
2.5. Statistical analysis
Continuous variables are reported as means and standard deviation.
Categorical variables are reported as n (%) or median and interquartile
range values.
The data from the development cohort was used to develop the JFS to
discriminate between frail or pre-frail subjects and robust subjects.
Multivariable logistic regression analysis was conducted to narrow
down the candidate items with frailty and pre-frailty judged by the KCL
as the objective variable and the score of all eight questions, age, and sex
as explanatory variables. The p-value cutoff for inclusion of the candi­
date factors in the restricted model was set to 0.05. For nocturia, “2
times” and “3 times or more” were combined into “2 times or more”, as
the number of cases in these items was small, and it was complicated to
use in the clinical setting. Age was discretized to a binary variable with a
cutoff of 75 years, which is the age of late-stage elderly persons in Japan.
As a result of the analysis, a restricted logistic regression model with
variables that independently contributed to the determination was
created. The factors determined in the multivariable analysis were
weighted by the integer closest to the value obtained by doubling the β
regression coefficient.
The predictive performance of the JFS was assessed in the develop­
ment cohort by examining measures of discrimination and calibration.
To evaluate discriminatory performance, receiver-operating character­
istic (ROC) curves (Metz, 1978) were plotted to verify the accuracy of
the JFS based on KCL judgments, and the accuracy was quantified by the
area under the curve (AUC). A clinically relevant cutoff point was
determined to be the point at which the sensitivity was greater than 80
%, and sensitivity, specificity, positive predictive value (PPV), and
negative predictive value (NPV) were calculated. Subsequently, cali­
bration was assessed graphically using nonparametric calibration curves
with pointwise 95 % confidence intervals (CIs), and their graphical
summaries (calibration-in-the-large and calibration slope) (Calster et al.,
2016). Flexible calibration curves can be estimated with the locally
weighted scatter plot smoother (LOESS) function. If the calibration-in-
the-large is 0 and calibration slope is 1, the predictive model for JFS is
perfectly calibrated. The external validity of the JFS was examined using
the data of the validation cohort. The ROC curves were plotted in the
same way, and AUC was calculated to quantify discriminatory perfor­
mance. The sensitivity, specificity, PPV, and NPV were calculated using
the cutoff determined in the development cohort. Then, calibration plots
were plotted to compare the predicted probabilities with the actual
outcomes.
The relationships between each question of the JFS and Kihon
checklist domains, physical indicators, and clinical indicators that di­
agnose frailty and related conditions were examined using Cramer’s
coefficient of association. Clinically relevant cutoffs were set for Locomo
5, GDS-15, gait speed, two-step value, grip strength, and body compo­
sition (BMI, ECW/TBW, SMI) to make them categorical variables. The
phase angle, which is included in InBody, was not converted to cate­
gorical data because clinically relevant cutoffs could not be established.
In addition, associations between clinical indices, including the JFS
score, were tested using Spearman’s rank correlation coefficient.
In each analysis, only cases with no missing values were included in
the analysis. R version 4.1.2 (R Foundation for Statistical Computing,
Vienna, Austria) was used for the analyses. ROC curves were plotted
4
Gene 844 (2022) 146775
with the R package pROC, and calibrations were assessed with the R
package rms. A p value of < 0.05 was considered significant. All sta­
tistical analyses were performed by independent statisticians.
2.6. Ethical considerations
This study was approved by the Institutional Review Board (IRB) of
the Osaka University School of Medicine. A group briefing session was
held for the subjects to explain the outline of the study using materials,
and written, informed consent was obtained using a consent form.
3. Results
3.1. Subjects’ characteristics
The development cohort included 434 eligible participants, and the
validation cohort included 276 eligible participants. The development
cohort had one case with missing data for the KCL and JFS; thus, 433
participants were included in the primary analysis (Fig. 1A). The vali­
dation cohorts had no missing values for the JFS and KCL (Fig. 1B). In
the development cohort, the mean age was 76.0 ± 5.5 years, and 305
(70.3 %) were female. According to the KCL, 227 (52.4 %) cases were
robust, 160 (37.0 %) cases were pre-frail, and 46 (10.6 %) cases were
frail. In the validation cohort, the mean age was 76.5 ± 6.1 years, and
187 (67.8 %) were female. Overall, 132 (47.8 %) were robust, 102 (40.0
%) were pre-frail, and 42 (15.2 %) were frail. The KCL contains three
items to assess cognitive function (Arai and Satake, 2015) (Table S1),
which are simply summed to give a score of 0–3 (Table S2). When the
two groups were combined, the distribution of scores among the subjects
was as follows: 56.1 % scored 0; 32.6 % scored 1; 10.6 % scored 2; and
0.7 % scored 3 (Table S2). In particular, in question 19, 95.3 % of the
participants had the ability to look up a phone number and make a call
on their own. Participants in the validation cohort tended to have lower
physical measurements, such as walking speed, two-step value, and grip
strength, but their background characteristics were generally the same.
This may be because the locations where participants were recruited
were different, cultural centers and clinics. The characteristics of the
subjects are shown in Table 2.
3.2. Development of the JFS
Eight CQs were selected to develop a clinical scale that predicted the
onset of frailty based on the concept of Kampo medicine (Table 1). The
KCL was used as the standard reference for frailty determination. To
refine the 8 questions to create a simplified clinical scale, the relation­
ships between frailty and the eight questions were examined by multiple
logistic regression analysis. Multivariable logistic regression analysis
was performed with frailty or pre-frailty based on the KCL as the
dependent variable and eight question items, age, and sex as indepen­
dent variables. Nocturia (CQ5), back pain (CQ6), cold hypersensitivity
(CQ7), exhaustion (CQ8), and age 75 years or older were significantly
associated with pre-frailty or frailty status as determined by the KCL
(Table 3A). Multivariable logistic analysis using a restricted model with
these five items as explanatory variables showed that the significance of
each item was maintained. A backward stepwise selection method was
also performed to reduce the variables, and the same five variables were
selected for the final model. Therefore, the above five items were
selected as the components of the JFS. Based on the β regression co­
efficients of the final model, each factor was given an integer weighting:
2 points for CQ8, and 1 point each for the other items (Table 3A). The
JFS was calculated by a simple sum of these five scores with a minimum
of zero and a maximum of 11 points (Table 3B). The JFS tended to be
higher in participants who were pre-frail and frail, and the distribution
of scores is shown in Fig. 2A.
The ROC curve of the JFS for estimation of frailty status based on the
KCL criteria is shown in Fig. 2B (AUC = 0.78, 95 % CI: 0.73–0.82). The
R. Egashira et al.
Fig. 1. The flowchart of patient enrolment for the development and validation cohorts.(A) Development cohort. (B) Validation cohort. Abbreviations: KCL, Kihon
checklist; JFS, Japan Frailty Scale.
JFS showed moderately good discrimination. In the calibration plot
(Calster et al., 2016), the predicted risk showed good agreement with
the actual risks of frailty with calibration-in-large of − 0.15 and cali­
bration slope of 0.90 (Fig. 3A). The clinically relevant cutoff point was
determined to be the point at which the sensitivity was greater than 80
%. The cutoff value of the JFS was 3/4, and its sensitivity, specificity,
PPV, and NPV were 86.9 %, 53.3 %, 62.8 %, and 81.7 %, respectively
(Fig. 2C). If the cutoff for discriminating between pre-frailty and frailty
was determined with the same clinical relevance, the cutoff was 5/6,
and its sensitivity, specificity, PPV, and NPV were 80.4 %, 71.3 %, 25.0
%, and 96.8 %, respectively.
5
Gene 844 (2022) 146775
3.3. External validation of the JFS
As an external validation of the five-item JFS created in the devel­
opment cohort, discriminant performance and calibration were assessed
in the validation cohort. The distribution of scores in the validation
cohort is shown in Fig. 2A, and the ROC curve is shown in Fig. 2B (AUC
= 0.76, 95 % CI: 0.70–0.81). In the calibration plot, the predicted risk
showed moderate agreement with the actual risks of frailty with the
calibration-in-large of − 0.26 and calibration slope of 0.79 (Fig. 3B). The
sensitivity, specificity, PPV, and NPV at the cutoff 3/4 were calculated to
be 79.9 %, 61.4 %, 69.3 %, and 73.7 %, respectively (Fig. 2C).
R. Egashira et al. Gene 844 (2022) 146775

Table 2 3.4. Correlation between the JFS and other clinical indices
Subject characteristics in the development cohort and validation cohort Ab­
breviations: BMI, Body Mass Index; ECW/TBW, Extracellular Water/Total Body The relationships were examined using Cramer’s coefficient of as­
Water; IQR, interquartile range; J-CHS, Japanese version of Cardiovascular sociation between the four questions of the JFS and KCL subdomains,
Health Study criteria; SMI, Skeletal Muscle mass Index. physical indicators, J-CHS, Locomo 5, Sarcopenia, and GDS-15 (Table 4)
Characteristics Sango-cho (n = Suita-shi (n = (Cohen, 1988). The analyses were performed on all cases in both cohorts
434) 276) that were not missing in the respective correlation analyses. The highest
(Development (Validation
number of missing cases was 9 for the J-CHS. Question 1 of the final
cohort) cohort)
version of JFS about nocturia was moderately correlated (0.21 ≤ r ≤
Age (y) 76.0 ± 5.5 76.5 ± 6.1
0.35) with questions 1–20 of the KCL (r = 0.22) and the phase angle (r =
Sex, Female, n (%) 305 (70.3) 187 (67.8)
Prevalence of frailty status, n (%) total 433 total 276 0.23). Question 2 of the JFS about low back pain was moderately
Robust 227 (52.4) 132 (47.8) correlated with questions 1–20 of the KCL (r = 0.27), PF (r = 0.22), and
Pre-frailty 160 (37.0) 102 (40.0) Locomo 5 (r = 0.24). Question 3 of the JFS about cold hypersensitivity
Frailty 46 (10.6) 42 (15.2) was moderately correlated with questions 1–20 of the KCL (r = 0.26),
Gait speed (m/s) 1.33 ± 0.25 1.16 ± 0.27
phase angle (r = 0.27), and Locomo 5 (r = 0.22). Question 4 of the JFS
Two-step value 1.27 ± 0.16 1.16 ± 0.19
Grip strength (kg) 25.8 ± 7.13 24.2 ± 7.07 about exhaustion was moderately correlated with the J-CHS (r = 0.22),
BMI (kg/m2) 22.9 ± 2.94 23.0 ± 3.13 questions 1–20 of the KCL (r = 0.32), PF (r = 0.28), OF (r = 0.22), CF (r
SMI (kg/m2) 6.30 ± 0.92 6.24 ± 0.95 = 0.21), DM (r = 0.30), phase angle (r = 0.22), Locomo 5 (r = 0.22), and
ECW/TBW 0.393 ± 0.007 0.393 ± 0.007
GDS-15 (r = 0.21). In particular, Question 4 was mildly or moderately
Phase angle (◦ ) 4.49 ± 0.59 4.32 ± 0.56
Geriatric depression scale-15 score 2 [1–3] 2 [1–4] associated with all factors.
median [IQR] The associations between clinical indices, including the JFS score,
J-CHS, n (%) total 427 total 276 were tested using Spearman’s rank correlation coefficient (Table 5). The
Robust 263 (61.6) 100 (36.5) JFS showed moderate positive correlations with the KCL total score (r =
Pre-frailty 155 (36.3) 142 (51.8)
0.55), Locomo 5 (r = 0.51), and GDS-15 (r = 0.44), but only mild cor­
Frailty 9 (2.1) 32 (11.6)
Sarcopenia, n (%) total 427 total 272 relation with J-CHS (r = 0.27). The KCL total score showed moderate
Robust 382 (89.5) 218 (80.1) positive correlations with the J-CHS (r = 0.44), Locomo 5 (r = 0.51), and
Sarcopenia 39 (9.1) 35 (12.9) GDS-15 (r = 0.60). Grip strength showed a strong positive correlation
Sever sarcopenia 6 (1.4) 19 (7.0)
with SMI (r = 0.72), and ECW/TBW showed a strong negative correla­
Locomo 5, median [IQR] 1 [0–4] 1 [0–4]
tion with the phase angle (r = -0.86).

Table 3
Results of the multivariate logistic regression analysis and final version of the JFS. (A) Multivariable logistic regression analysis of predictive factors for pre-frailty or
frailty based on the KCL in the development cohort. Points were weighted by the integer closest to the final model regression coefficient times two. (B) Final version of
the JFS and score calculation method.Abbreviations: CQ, Candidate of Question; JFS, Japan Frailty Scale; KCL, Kihon checklist; Q, Question.
(A)
Full model Final model

Adjusted OR 95 % CI p-value Adjusted OR 95 % CI p-value β regression coefficient Points

CQ1. Amount of gray hair 1.15 0.75–1.74 0.53 – – – – –

CQ2. Number of teeth 0.75 0.47–1.20 0.23 – – – – –
CQ3. Hearing loss 0.87 0.60–1.26 0.46 – – – – –
CQ4. Skin dryness 1.18 0.70–1.99 0.54 – – – – –
CQ5. Nocturia 1.80 1.31–2.47 < 0.01 1.81 1.34–2.45 < 0.01 0.59 1
CQ6. Lower back pain 1.68 1.21–2.34 < 0.01 1.71 1.24–2.36 < 0.01 0.54 1
CQ7. Cold hypersensitivity 1.71 1.20–2.42 < 0.01 1.71 1.23–2.38 < 0.01 0.54 1
CQ8. Exhaustion 2.72 1.80–4.11 < 0.01 2.67 1.79–3.97 < 0.01 0.98 2
Age ≥ 75 y 1.92 1.21–3.04 < 0.01 1.84 1.17–2.87 < 0.01 0.61 1
Sex 1.08 0.64–1.81 0.78 – – – – –

(B)
Q1 Nocturia
“How many times do you typically get up at night to urinate?” 0→ “I don’t usually get up once to urinate at night.”
1→ “I usually get up once to urinate at night.”
2→ “I usually get up twice or more to urinate at night.”
Q2 Lower back pain
“Do you have lower back pain?” 0→ “I don’t have any lower back pain.”
1→ “I have occasional lower back pain.”
2→ “I have lower back pain, always or often.”
Q3 Cold hypersensitivity (Coldness in the feet)
“Do you have cold hypersensitivity (coldness) in the feet?” 0→ “I don’t have cold hypersensitivity, or I rarely have cold hypersensitivity in my feet.”
1→ “I have occasional cold hypersensitivity in my feet.”
2→ “I always have cold hypersensitivity in my feet, or I often have cold hypersensitivity in my feet.”
Q4 Exhaustion
“Do you feel tired?” 0→ “I never or rarely feel tired.”
2→ “I am feeling tired sometimes.”
4→ “I am feeling tired all the time or often.”
Q5 Age
Patient’s age (y) 0→ <75
1→ ≥ 75

JFS = Q1 + Q2 + Q3 + Q4 + Q5 ≥ 4 ⇒ Pre-Frailty or Frailty.

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R. Egashira et al. Gene 844 (2022) 146775

Fig. 2. Score distribution, discrimination capability, and diagnostic accuracy of the JFS in the development cohort and validation cohort. (A) Score distribution of
the JFS in the development cohort and validation cohort. (B) Discrimination capacity of the JFS for the identification of frailty status based on the KCL was examined
by ROC curves. (C) Sensitivity, specificity, positive predictive value, and negative predictive value for a score of 4 or more as pre-frailty or frailty.Abbreviations: AUC,
area under the curve; KCL, Kihon checklist; JFS, Japan Frailty Scale; ROC, receiver-operating characteristic.

7
R. Egashira et al.
Fig. 3. Calibration plot in the development cohort and validation cohort.
Calibration is assessed graphically using the nonparametric calibration curves
with pointwise 95% confidence intervals, and their graphical summaries
(calibration-in-the-large and calibration slope) (A) Development cohort. (B)
Validation cohort.Abbreviations: JFS, Japan Frailty Scale.
4. Discussion
In this study, a simple self-reported screening scale for frailty was
developed based on the aging concept of Kampo medicine. The JFS can
be used to screen for frailty using five questions: nocturia, low back pain,
cold hypersensitivity, exhaustion, and age greater than 75 years. This
scale is suitable for use in primary care settings where time is limited,
because it does not require measurements using devices or specialized
consultation and has a small number of items.
The concept of frailty is still not well-established, and it is unclear at
what level of severity intervention should be initiated (Dent et al.,
8
Gene 844 (2022) 146775
2019). Considering the nature of frailty scales to assist physicians in
making decisions, the JFS has shown a certain ability to evaluate frailty
based on the diagnosis by KCL, and the novelty of its components is also
one of its strengths. Clinicians can use the results of the JFS to identify
patients who need further comprehensive geriatric assessment, and they
can gain insight into their own patient assessment.
Since elderly patients should be screened for frailty in primary care
in a short period of time, several simple tools have been developed (Dent
et al., 2019; Morley et al., 2013). The Study of Osteoporotic Fractures
(SOF) index predicts falls, fracture, disability, and death as accurately as
the CHF frailty index with three items, but it requires weight and
physical measurements (Ensrud et al., 2008). The Gerontopole Frailty
Screening Tool (GFST) is a simple questionnaire composed of six items,
but medical professionals need to answer the items by themselves when
they see a patient (Vellas et al., 2013). The FRAIL scale consists of five
patient-reported outcomes, but four of the components are conceptually
the same as the CHS index and are not novel (van Kan et al., 2008).
Compared to previous scales of modern medicine, the JFS is based on
the aging concept of Kampo medicine, “Jin-kyo”. The JFS includes age
and four other items: exhaustion, nocturia, low back pain, and cold
hypersensitivity. To the best of our knowledge, nocturia, low back pain,
and cold hypersensitivity are not included as common indicators of
frailty. It is almost certain that frailty increases with age (Gale et al.,
2015; Song et al., 2010). In this study, a question item of exhaustion was
strongly correlated with the Geriatric Depression Scale and moderately
correlated with several domains of the KCL. Depression and frailty have
been shown to be related bidirectionally (Hubbard and Lang, 2015),
suggesting that exhaustion, depression, and frailty have complex re­
lationships. Exhaustion is also included in the CHS frailty index and
other frailty criteria (Fried et al., 2001; Theou et al., 2015). One report
suggested that exhaustion appears the earliest of the CHS frailty index
items (Stenholm et al., 2018), whereas others suggest that it appears
after other CHS indicators (Xue et al., 2008). At least subjective
exhaustion predicts disability (Hardy and Studenski, 2008a) and mor­
tality (Avlund et al., 1998; Hardy and Studenski, 2008b; Moreh et al.,
2009) therefore, it is reasonable that exhaustion is weighted twofold.
Nocturia is already seen from middle age and associated with the
onset of frailty (Coyne et al., 2009; Irwin et al., 2006; Soma et al., 2020).
Nocturia predicts falls, fractures, depression, decreased quality of life,
and death (Nakagawa et al., 2010; Parsons et al., 2009; Stanley, 2005).
In this study, nocturia was moderately correlated with gait speed and
two-step values. Therefore, nocturia is a useful indicator of the decline in
life function of elderly persons and an important part of the frailty.
Low back pain also increases with age (Hartvigsen et al., 2018).
Dysfunction of muscles is a risk for low back pain, especially through
weakness of the trunk muscles (Cho et al., 2014). This time, low back
pain was moderately correlated with locomotive syndrome and the
motor function domains of the KCL. It has been reported that interver­
tebral disc degeneration (IDD) is considered to be one of the important
causes (Adams and Roughley, 2006). IDD involves an inflammatory
response process mediated by TNF-α and IL-6 (Wang et al., 2020). It has
been shown that various inflammatory markers increase with the pro­
gression of frailty (Soysal et al., 2016), and low back pain may be a
phenotype reflecting such inflammation.
Cold hypersensitivity is considered to be important in Kampo med­
icine, but cold sensation in the lower extremities is difficult to measure
quantitatively because of the subjective nature of the evaluation item
(Bae et al., 2018). Body temperature decreases and oscillates at lower
amplitudes with age (Weinert, 2010), and sensitivity to cold sensation
increases with age in men, but not women (Yasui et al., 2007). Low BMI
is associated with increased susceptibility to cold in women (Mozaffar­
ieh et al., 2010), and in the present study, there was a moderate or
greater correlation between cold hypersensitivity and BMI or SMI.
Recently, the TRP channel has been the focus of attention as a channel of
temperature sensitivity, and some of the mammalian TRP channels are
recognized as thermal TRPs activated at specific temperatures (Vay
R. Egashira et al. Gene 844 (2022) 146775

Table 4
Cramer’s coefficient of association between each question of the JFS and other indicators. (A) Kihon checklist domains. (B) Physical indicators. (C) Clinical indicators.
(D) Interpretation of associated values. Abbreviations: BMI, body mass Index; CF, cognitive function; DM, depressive mood; ECW/TBW, extracellular water/total body
water; GDS-15, 15-item Geriatric Depression Scale; IADL, instrumental activities of daily living; JFS, Japan Frailty Scale; J-CHS, Japanese version of the Cardiovascular
Health Study criteria; KCL, Kihon checklist; Locomo 5, 5-question Geriatric Locomotive Function Scale; NS, nutritional status; OF, oral function; PF, physical function;
Q, question; SA, social activities; SMI, skeletal muscle mass index.

et al., 2012; Yue and Xu, 2021). However, further investigation is
needed to evaluate cold sensitivity.
The ability to maintain circadian rhythms decreases with age (Brown
et al., 2011), and this may disrupt the circadian rhythm of urinary
function and cause nocturia (Negoro et al., 2013). Sleep deprivation
caused by nocturia can lead to impaired immune function and chronic
inflammation (Prinz, 2004). Especially regarding falls, it has been
assumed that central nervous system dysfunction is common to nocturia
and gait instability, rather than increased risk of falling due to nocturnal
activity (Gibson et al., 2018). Exhaustion is also thought to be related to
autonomic nervous system dysfunction and circadian rhythm disorders
(Tanaka et al., 2015). The spine and intervertebral discs are adapted to a
circadian rhythm resulting in an increase in osmotic pressure during the
day and are released from the pressure at night (Dudek et al., 2017). It
has been suggested that this disruption of circadian rhythms adversely
affects disc degeneration (Dudek et al., 2017). Low back pain may be
associated with nocturia and exhaustion via disruption of circadian
rhythms. It is interesting to note that the concept of frailty is thought to
be related to the disruption of circadian rhythms.
In the present study, the amount of gray hair, number of teeth,
hearing loss, and dry skin were not significantly related to frailty. The
lack of associations of gray hair and dry skin with frailty may be due to
the development of cosmetology technologies that have reduced their
usefulness as findings. Oral function is one domain of the KCL, and self-
reported number of teeth is associated with locomotive syndrome
(Akahane et al., 2017), and the dentist-confirmed tooth count is asso­
ciated with physical and cognitive functional decline (Tsakos et al.,
2015). Hearing loss increases with age, may interfere with daily life, and
has been suggested to be related to dementia (Livingston et al., 2017). If
we change the way we ask about the number of teeth and hearing, we

9
R. Egashira et al. Gene 844 (2022) 146775

Table 5
Spearman’s rank correlation coefficients between clinical indices including the JFS score. Abbreviations: BMI, body mass index; ECW/TBW, extracellular water/total
body water; GDS-15, 15-item Geriatric Depression Scale; JFS, Japan Frailty Scale; J-CHS, Japanese version of the Cardiovascular Health Study criteria; KCL, Kihon
checklist; Locomo 5, 5-question Geriatric Locomotive Function Scale; SMI, skeletal muscle mass index.
JFS KCL Gait speed Two-step value Grip strength BMI SMI ECW/TBW Phase angle J-CHS Locomo 5 GDS-15

JFS –
KCL 0.55 –
Gait speed − 0.28 − 0.35 –
Two-step value − 0.23 − 0.31 0.58 –
Grip strength − 0.17 − 0.17 0.20 0.30 –
BMI 0.02 0.01 − 0.15 − 0.19 0.18 –
SMI − 0.09 − 0.10 0.02 0.09 0.72 0.53 –
ECW/TBW 0.25 0.29 − 0.31 − 0.42 − 0.46 0.04 0.26 –
Phase angle − 0.22 − 0.27 0.27 0.39 0.63 0.15 0.60 − 0.86 –
J-CHS 0.27 0.44 − 0.50 − 0.37 − 0.31 0.06 − 0.10 0.32 − 0.31 –
Locomo 5 0.51 0.51 − 0.43 − 0.40 − 0.23 0.19 − 0.06 0.44 − 0.34 0.37 –
GDS-15 0.44 0.60 − 0.24 − 0.20 − 0.19 0.06 − 0.18 0.18 − 0.21 0.33 0.36 –

might obtain a significant association with frailty.
Aging and frailty are thought to be different processes. The patho­
genesis of frailty has been suggested to be associated with inflammation
(Fielding, 2015), altered nutrient-sensitive pathways, and hormonal
balance (Evans et al., 2010). Aging alone does not induce a chronic in­
flammatory response (Furman et al., 2019), and the inflammatory
response process mediated by TNF-α and IL-6 has been considered a
hallmark in frailty research (Mañas, 2015; Soysal et al., 2016). We have
demonstrated that GJG had effects on muscle and the peripheral and
central nervous systems and improved sarcopenia, allodynia, and pa­
ralysis in senescence-accelerated mice, chronic constriction injury mice,
and experimental autoimmune encephalomyelitis model mice by sup­
pressing the production of TNF-α from activated microglial cells
(Hagihara et al., 2022; Jiang et al., 2021; Kishida et al., 2015; Nakanishi
et al., 2016; Takemoto et al., 2017). Thus, the fact that GJG has an effect
on the inflammatory response and has been clinically shown to improve
symptoms included in the JFS (Takayama et al., 2018; Yagi et al., 2015)
suggests that TNF-α and IL-6-mediated networks are possibly among the
treatable frailty conditions. There are also reports that genetic poly­
morphisms contribute to the onset of frailty (Ho et al., 2011; Viña et al.,
2016), and that intron retention, an important regulatory mechanism
affecting gene expression and protein function, can be restored by
Kampo medicine (Okada et al., 2021). In recent years, the development
of geroprotectors that suppress age-related diseases has attracted
attention (Bellantuono, 2018; Trendelenburg et al., 2019), suggesting
that GJG will have significant implications for frailty. There is an
attempt to quantify the pre-symptomatic state from omics data, and its
relevance to the concept of the pre-symptomatic state in Kampo medi­
cine has been discussed (Aihara et al., 2022). Clinical scoring based on
Kampo concepts has been reported in the past (Terasawa, 1989), but to
the best of our knowledge, there is nothing specific to diagnose frailty.
The JFS, which is a quantification of clinical findings in Kampo medi­
cine, can provide additional insight into the expression of age-related
genes.
This study has some limitations. First, this study used the KCL as the
standard, but the KCL itself is not an absolute criterion for frailty. Lon­
gitudinal studies are needed to better validate the accuracy of the JFS in
the future. Second, one must take into account that the population
sample included elderly people who were able to come to health
checkups or clinics on their own and participate actively. Caution is
needed when applying it in different countries and clinical situations.
Third, although more detailed weighting may have improved the ac­
curacy, only a simple weighting was used to prioritize clinical simplicity.
Forth, whereas the well-known Kampo diagnostic concept of “sho” is
often used to determine the Kampo formula for an individual patient,
“Jin-kyo” is a broader concept than the individual patient’s “sho”, and
JFS is intended to screen patients for frailty or pre-frailty on that basis.
An individual consultation with a clinician is necessary to determine the
Kampo formula. Fifth, it is possible that the association between KCL
and JFS would have changed if objective cognitive function assessment
had been performed and the results had been taken into account. To the
best of our knowledge, the only report that examined the KCL and
objective cognitive function assessment cross-sectionally was published
in Japanese, and it involved elderly people living in the community
(Goda et al., 2019). In this report, 64.9 % scored 0, 27.7 % scored 1, and
7.4 % scored 2, slightly lower than the present subjects, but no patient
with apparent dementia with a Mini-Mental State Examination score less
than 23 was found. In Japan, evaluation of cognitive function by an
attending physician is mandatory for long-term care certification, and
persons who were certified as requiring long-term care were excluded.
Based on these results, the lack of objective cognitive function assess­
ment is unlikely to undermine the validity of the present results.
5. Conclusion
A simple, self-reported, screening scale for frailty was developed
based on the aging concept of Kampo medicine. It is composed of five
questions: nocturia, low back pain, cold hypersensitivity, exhaustion,
and age. The combination of these symptoms is novel, and it is possibly
an important phenotype of the vicious cycle of frailty. The JFS is a
promising screening tool for pre-frailty or frailty at the bedside in pri­
mary care.
CRediT authorship contribution statement
Ryuichiro Egashira: Writing – original draft, Methodology, Visu­
alization, Data curation. Tomoharu Sato: Methodology, Software,
Validation, Formal analysis. Akimitsu Miyake: Methodology, Software,
Validation, Formal analysis. Mariko Takeuchi: Investigation. Mai
Nakano: Investigation. Hitomi Saito: Investigation. Misaki Mor­
iguchi: Investigation. Satoko Tonari: Investigation. Keisuke Hagi­
hara: Conceptualization, Methodology, Writing – review & editing,
Visualization, Supervision, Project administration, Funding acquisition.
Declaration of Competing Interest
The authors declare the following financial interests/personal re­
lationships which may be considered as potential competing interests:
Dr. Hagihara holds the position of Joint Research Chair in collaboration
with Tsumura Co. who produced GJG. Dr. Egashira is a member of the
Joint Research group. The other authors have no competing interests.
This research was supported by AMED under Grant Number
19lk0310057h0001.
Data availability
No data was used for the research described in the article.

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R. Egashira et al. Gene 844 (2022) 146775

Acknowledgements Ensrud, K.E., Ewing, S.K., Taylor, B.C., Fink, H.A., Cawthon, P.M., Stone, K.L., Hillier, T.
A., Cauley, J.A., Hochberg, M.C., Rodondi, N., Tracy, J.K., Cummings, S.R., 2008.
Comparison of 2 Frailty Indexes for Prediction of Falls, Disability, Fractures, and
The authors would like to thank Ms. Yuko Hirakawa and Ms. Takako Death in Older Women. Arch. Intern. Med. 168, 382–389. https://doi.org/10.1001/
Takeda for their excellent technical assistance. archinternmed.2007.113.
Esenkaya, M.E., Dokuzlar, O., Soysal, P., Smith, L., Jackson, S.E., Isik, A.T., 2019.
Validity of the Kihon Checklist for evaluating frailty status in Turkish older adults.
Appendix A. Supplementary material Geriatr. Gerontol. Int. 19, 616–621. https://doi.org/10.1111/ggi.13678.
Evans, W.J., Paolisso, G., Abbatecola, A.M., Corsonello, A., Bustacchini, S., Strollo, F.,
Supplementary data to this article can be found online at https://doi. Lattanzio, F., 2010. Frailty and muscle metabolism dysregulation in the elderly.
Biogerontology 11, 527–536. https://doi.org/10.1007/s10522-010-9297-0.
org/10.1016/j.gene.2022.146775. Fielding, R.A., 2015. A Summary of the Biological Basis of Frailty. Nestlé Nutrition Inst.
Work Ser. 83, 41–44. https://doi.org/10.1159/000430966.
References Fried, L.P., Ferrucci, L., Darer, J., Williamson, J.D., Anderson, G., 2004. Untangling the
Concepts of Disability, Frailty, and Comorbidity: Implications for Improved
Targeting and Care. J. Gerontol. Ser. 59, M255–M263. https://doi.org/10.1093/
Adams, M.A., Roughley, P.J., 2006. What is Intervertebral Disc Degeneration, and What
gerona/59.3.m255.
Causes It? Spine 31, 2151–2161. https://doi.org/10.1097/01.
Fried, L.P., Tangen, C.M., Walston, J., Newman, A.B., Hirsch, C., Gottdiener, J., Seeman,
brs.0000231761.73859.2c.
T., Tracy, R., Kop, W.J., Burke, G., McBurnie, M.A., Group, C.H.S.C.R., 2001. Frailty
Aihara, K., Liu, R., Koizumi, K., Liu, X., Chen, L., 2022. Dynamical network biomarkers:
in Older AdultsEvidence for a Phenotype. J. Gerontol. Ser. 56, M146–M157.
Theory and applications. Gene 808, 145997. https://doi.org/10.1016/j.
10.1093/gerona/56.3.m146.
gene.2021.145997.
Furman, D., Campisi, J., Verdin, E., Carrera-Bastos, P., Targ, S., Franceschi, C.,
Akahane, M., Yoshihara, S., Maeyashiki, A., Tanaka, Y., Imamura, T., 2017. Lifestyle
Ferrucci, L., Gilroy, D.W., Fasano, A., Miller, G.W., Miller, A.H., Mantovani, A.,
factors are significantly associated with the locomotive syndrome: a cross-sectional
Weyand, C.M., Barzilai, N., Goronzy, J.J., Rando, T.A., Effros, R.B., Lucia, A.,
study. Bmc Geriatr. 17, 241. https://doi.org/10.1186/s12877-017-0630-1.
Kleinstreuer, N., Slavich, G.M., 2019. Chronic inflammation in the etiology of
Arai, H., Satake, S., 2015. English translation of the Kihon Checklist. Geriatr. Gerontol.
disease across the life span. Nat. Med. 25, 1822–1832. https://doi.org/10.1038/
Int. 15, 518–519. https://doi.org/10.1111/ggi.12397.
s41591-019-0675-0.
Avlund, K., Schultz-Larsen, K., Davidsen, M., 1998. Tiredness in Daily Activities at Age
Gale, C.R., Cooper, C., Sayer, A.A., 2015. Prevalence of frailty and disability: findings
70 as a Predictor of Mortality During the Next 10 Years. J. Clin. Epidemiol. 51,
from the English Longitudinal Study of Ageing. Age Ageing 44, 162–165. https://
323–333. https://doi.org/10.1016/s0895-4356(97)00296-5.
doi.org/10.1093/ageing/afu148.
Bae, K.-H., Jeong, Y.-S., Go, H.-Y., Sun, S.-H., Kim, T.-H., Jung, K.-Y., Song, Y.-K., Ko, S.-
Gibson, W., Hunter, K.F., Camicioli, R., Booth, J., Skelton, D.A., Dumoulin, C., Paul, L.,
G., Choi, Y.-K., Park, J.-H., Lee, S., Lee, Y., Jeon, C.-Y., 2018. The definition and
Wagg, A., 2018. The association between lower urinary tract symptoms and falls:
diagnosis of cold hypersensitivity in the hands and feet: Finding from the experts
Forming a theoretical model for a research agenda. Neurourol. Urodynam. 37,
survey. Integr. Med. Res. 7, 61–67. https://doi.org/10.1016/j.imr.2017.11.001.
501–509. https://doi.org/10.1002/nau.23295.
Bellantuono, I., 2018. Find drugs that delay many diseases of old age. Nature 554,
Goda, A., Murata, S., Shiraiwa, K., Nonaka, K., Nakano, H., Abiko, T., Horie, J., 2019.
293–295. https://doi.org/10.1038/d41586-018-01668-0.
Relationship between subjective cognitive decline and objective cognitive decline
Brown, S.A., Pagani, L., Cajochen, C., Eckert, A., 2011. Systemic and Cellular Reflections
among the community-dwelling elderly persons. J. Japan Soc. Early Stage Dementia
on Ageing and the Circadian Oscillator – A Mini-Review. Gerontology 57, 427–434.
12(1), 44–51. https://cir.nii.ac.jp/crid/1520290884840577536.
https://doi.org/10.1159/000320673.
Hagihara, K., Nunomura, K., Lin, B., Fumimoto, M., Watanabe, J., Mizuhara, Y., 2022.
Calster, B.V., Nieboer, D., Vergouwe, Y., Cock, B.D., Pencina, M.J., Steyerberg, E.W.,
Gosha-jinki-Gan (GJG) shows anti-aging effects through suppression of TNF-α
2016. A calibration hierarchy for risk models was defined: from utopia to empirical
production by Chikusetsusaponin V. Gene 815, 146178. https://doi.org/10.1016/j.
data. J. Clin. Epidemiol. 74, 167–176. https://doi.org/10.1016/j.
gene.2021.146178.
jclinepi.2015.12.005.
Hagihara, K., Group, A. of K.F., Yakubo, S., Medicine, C. for V. in the J.S. for O., Namiki,
Chen, L.-K., Woo, J., Assantachai, P., Auyeung, T.-W., Chou, M.-Y., Iijima, K., Jang, H.C.,
T., Makino, T., Nakata, H., Matsuoka, H., Arimitsu, J., Ogawa, K., Itakura, H.,
Kang, L., Kim, M., Kim, S., Kojima, T., Kuzuya, M., Lee, J.S.W., Lee, S.Y., Lee, W.-J.,
Amano, Y., Ito, M., Kobayashi, K., Shinohara, S., Sumino, M., Togasaki, M., Togo, T.,
Lee, Y., Liang, C.-K., Lim, J.-Y., Lim, W.S., Peng, L.-N., Sugimoto, K., Tanaka, T.,
Ueda, Y., Watanabe, K., 2017. Abbreviation of kampo formulations and basic
Won, C.W., Yamada, M., Zhang, T., Akishita, M., Arai, H., 2020. Asian Working
terminology in kampo medicine. Traditional Kampo Med. 4, 65–88. 10.1002/
Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and
tkm2.1078.
Treatment. J. Am. Med. Dir. Assoc. 21, 300–307.e2. https://doi.org/10.1016/j.
Hardy, S.E., Studenski, S.A., 2008a. Fatigue and Function Over 3 Years Among Older
jamda.2019.12.012.
Adults. J. Gerontol. Ser. 63, 1389–1392. https://doi.org/10.1093/gerona/
Cho, K.H., Beom, J.W., Lee, T.S., Lim, J.H., Lee, T.H., Yuk, J.H., 2014. Trunk Muscles
63.12.1389.
Strength as a Risk Factor for Nonspecific Low Back Pain: A Pilot Study. Ann.
Hardy, S.E., Studenski, S.A., 2008b. Fatigue Predicts Mortality in Older Adults. J. Am.
Rehabilit. Med. 38, 234–240. https://doi.org/10.5535/arm.2014.38.2.234.
Geriatr. Soc. 56, 1910–1914. https://doi.org/10.1111/j.1532-5415.2008.01957.x.
Clegg, A., Young, J., Iliffe, S., Rikkert, M.O., Rockwood, K., 2013. Frailty in elderly
Hartvigsen, J., Hancock, M.J., Kongsted, A., Louw, Q., Ferreira, M.L., Genevay, S., Hoy,
people. Lancet 381, 752–762. https://doi.org/10.1016/s0140-6736(12)62167-9.
D., Karppinen, J., Pransky, G., Sieper, J., Smeets, R.J., Underwood, M., Group, L.L.B.
Cohen, J., 1988. Statistical Power Analysis for the Behavioral Sciences. 10.4324/
P.S.W., Buchbinder, R., Hartvigsen, J., Cherkin, D., Foster, N.E., Maher, C.G.,
9780203771587.
Underwood, M., Tulder, M. van, Anema, J.R., Chou, R., Cohen, S.P., Costa, L.M.,
Collins, G.S., Reitsma, J.B., Altman, D.G., Moons, K.G.M., Group, T., 2015. Transparent
Croft, P., Ferreira, M., Ferreira, P.H., Fritz, J.M., Genevay, S., Gross, D.P., Hancock,
Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis
M.J., Hoy, D., Karppinen, J., Koes, B.W., Kongsted, A., Louw, Q., Öberg, B., Peul, W.
(TRIPOD). Circulation 131, 211–219. 10.1161/circulationaha.114.014508.
C., Pransky, G., Schoene, M., Sieper, J., Smeets, R.J., Turner, J.A., Woolf, A., 2018.
Coyne, K.S., Sexton, C.C., Thompson, C.L., Milsom, I., Irwin, D., Kopp, Z.S., Chapple, C.
What low back pain is and why we need to pay attention. Lancet 391, 2356–2367.
R., Kaplan, S., Tubaro, A., Aiyer, L.P., Wein, A.J., 2009. The prevalence of lower
10.1016/s0140-6736(18)30480-x.
urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the
Ho, Y.-Y., Matteini, A.M., Beamer, B., Fried, L., Xue, Q., Arking, D.E., Chakravarti, A.,
Epidemiology of LUTS (EpiLUTS) study. Bju Int. 104, 352–360. https://doi.org/
Fallin, M.D., Walston, J., 2011. Exploring Biologically Relevant Pathways in Frailty.
10.1111/j.1464-410x.2009.08427.x.
J. Gerontol. Ser. 66A, 975–979. https://doi.org/10.1093/gerona/glr061.
Demura, S., Yamada, T., 2011. The maximal double step length test can evaluate more
Hoogendijk, E.O., Afilalo, J., Ensrud, K.E., Kowal, P., Onder, G., Fried, L.P., 2019. Frailty:
adequately the decrease of physical function with age, than the maximal single step
implications for clinical practice and public health. Lancet 394, 1365–1375. https://
length test. Arch. Gerontol. Geriat. 53, e21–e24. https://doi.org/10.1016/j.
doi.org/10.1016/s0140-6736(19)31786-6.
archger.2010.09.009.
Hubbard, R.E., Lang, I., 2015. Avoiding Depression, Dementia, and Frailty: Do You Feel
Dent, E., Kowal, P., Hoogendijk, E.O., 2016. Frailty measurement in research and clinical
Lucky? J. Am. Med. Dir. Assoc. 16, 270–271. https://doi.org/10.1016/j.
practice: A review. Eur. J. Int. Med. 31, 3–10. https://doi.org/10.1016/j.
jamda.2015.01.085.
ejim.2016.03.007.
Irwin, D.E., Milsom, I., Hunskaar, S., Reilly, K., Kopp, Z., Herschorn, S., Coyne, K.,
Dent, E., Lien, C., Lim, W.S., Wong, W.C., Wong, C.H., Ng, T.P., Woo, J., Dong, B., de la
Kelleher, C., Hampel, C., Artibani, W., Abrams, P., Giannantoni, A., 2006.
Vega, S., Poi, P.J.H., Kamaruzzaman, S.B.B., Won, C., Chen, L.-K., Rockwood, K.,
Population-Based Survey of Urinary Incontinence, Overactive Bladder, and Other
Arai, H., Rodriguez-Mañas, L., Cao, L., Cesari, M., Chan, P., Leung, E., Landi, F.,
Lower Urinary Tract Symptoms in Five Countries: Results of the EPIC Study. Eur.
Fried, L.P., Morley, J.E., Vellas, B., Flicker, L., 2017. The Asia-Pacific Clinical
Urol. 50, 1306–1315. https://doi.org/10.1016/j.eururo.2006.09.019.
Practice Guidelines for the Management of Frailty. J. Am. Med. Dir. Assoc. 18,
Jiang, S., Baba, K., Okuno, T., Kinoshita, M., Choong, C.-J., Hayakawa, H., Sakiyama, H.,
564–575. https://doi.org/10.1016/j.jamda.2017.04.018.
Ikenaka, K., Nagano, S., Sasaki, T., Shimamura, M., Nagai, Y., Hagihara, K.,
Dent, E., Martin, F.C., Bergman, H., Woo, J., Romero-Ortuno, R., Walston, J.D., 2019.
Mochizuki, H., 2021. Go-sha-jinki-Gan Alleviates Inflammation in Neurological
Management of frailty: opportunities, challenges, and future directions. Lancet 394,
Disorders via p38-TNF Signaling in the Central Nervous System. Neurotherapeutics
1376–1386. https://doi.org/10.1016/s0140-6736(19)31785-4.
18, 460–473. https://doi.org/10.1007/s13311-020-00948-w.
Dudek, M., Yang, N., Ruckshanthi, J.P., Williams, J., Borysiewicz, E., Wang, P.,
Jones, D.M., Song, X., Rockwood, K., 2004. Operationalizing a Frailty Index from a
Adamson, A., Li, J., Bateman, J.F., White, M.R., Boot-Handford, R.P., Hoyland, J.A.,
Standardized Comprehensive Geriatric Assessment. J. Am. Geriatr. Soc. 52,
Meng, Q.-J., 2017. The intervertebral disc contains intrinsic circadian clocks that are
1929–1933. https://doi.org/10.1111/j.1532-5415.2004.52521.x.
regulated by age and cytokines and linked to degeneration. Ann. Rheum. Dis. 76,
576–584. https://doi.org/10.1136/annrheumdis-2016-209428.

11
R. Egashira et al.
Kamegaya, T., Yamaguchi, H., Hayashi, K., 2017. Evaluation by the Basic Checklist and
the risk of 3 years incident long-term care insurance certification. J. Gen Fam Med.
18, 230–236. https://doi.org/10.1002/jgf2.52.
Kishida, Y., Kagawa, S., Arimitsu, J., Nakanishi, M., Sakashita, N., Otsuka, S.,
Yoshikawa, H., Hagihara, K., 2015. Go-sha-jinki-Gan (GJG), a traditional Japanese
herbal medicine, protects against sarcopenia in senescence-accelerated mice.
Phytomedicine 22, 16–22. https://doi.org/10.1016/j.phymed.2014.11.005.
Kuys, S.S., Peel, N.M., Klein, K., Slater, A., Hubbard, R.E., 2014. Gait Speed in Ambulant
Older People in Long Term Care: A Systematic Review and Meta-Analysis. J. Am.
Med. Dir. Assoc. 15, 194–200. https://doi.org/10.1016/j.jamda.2013.10.015.
Lauretani, F., Russo, C.R., Bandinelli, S., Bartali, B., Cavazzini, C., Iorio, A.D., Corsi, A.
M., Rantanen, T., Guralnik, J.M., Ferrucci, L., 2003. Age-associated changes in
skeletal muscles and their effect on mobility: an operational diagnosis of sarcopenia.
J. Appl. Physiol. 95, 1851–1860. https://doi.org/10.1152/japplphysiol.00246.2003.
Livingston, G., Sommerlad, A., Orgeta, V., Costafreda, S.G., Huntley, J., Ames, D.,
Ballard, C., Banerjee, S., Burns, A., Cohen-Mansfield, J., Cooper, C., Fox, N., Gitlin, L.
N., Howard, R., Kales, H.C., Larson, E.B., Ritchie, K., Rockwood, K., Sampson, E.L.,
Samus, Q., Schneider, L.S., Selbæk, G., Teri, L., Mukadam, N., 2017. Dementia
prevention, intervention, and care. Lancet 390, 2673–2734. https://doi.org/
10.1016/s0140-6736(17)31363-6.
Ma, L., Tang, Z., Zhang, L., Sun, F., Li, Y., Chan, P., 2018. Prevalence of Frailty and
Associated Factors in the Community-Dwelling Population of China. J. Am. Geriatr.
Soc. 66, 559–564. https://doi.org/10.1111/jgs.15214.
Mañas, L.R., 2015. Determinants of Frailty and Longevity: Are They the Same Ones?
Nestlé Nutrition Inst Work Ser 83, 29–40. https://doi.org/10.1159/000382057.
Metz, C.E., 1978. Basic principles of ROC analysis. Semin. Nucl. Med. 8, 283–298.
https://doi.org/10.1016/s0001-2998(78)80014-2.
Mitnitski, A.B., Mogilner, A.J., Rockwood, K., 2001. Accumulation of Deficits as a Proxy
Measure of Aging. Sci. World J. 1, 323–336. https://doi.org/10.1100/tsw.2001.58.
Moreh, E., Jacobs, J.M., Stessman, J., 2009. Feeling tired predicts functional status,
physical activity, and mortality in elderly people. J. Am. Geriatr. Soc. 57, 742–743.
https://doi.org/10.1111/j.1532-5415.2009.02214.x.
Morley, J.E., Vellas, B., van Kan, G.A., Anker, S.D., Bauer, J.M., Bernabei, R., Cesari, M.,
Chumlea, W.C., Doehner, W., Evans, J., Fried, L.P., Guralnik, J.M., Katz, P.R.,
Malmstrom, T.K., McCarter, R.J., Robledo, L.M.G., Rockwood, K., von Haehling, S.,
Vandewoude, M.F., Walston, J., 2013. Frailty Consensus: A Call to Action. J. Am.
Med. Dir. Assoc. 14, 392–397. https://doi.org/10.1016/j.jamda.2013.03.022.
Mozaffarieh, M., Gasio, P.F., Schötzau, A., Orgül, S., Flammer, J., Kräuchi, K., 2010.
Thermal discomfort with cold extremities in relation to age, gender, and body mass
index in a random sample of a Swiss urban population. Popul. Health Metr. 8
https://doi.org/10.1186/1478-7954-8-17.
Nakae, H., Hiroshima, Y., Hebiguchi, M., 2018. Kampo Medicines for Frailty in
Locomotor Disease. Front. Nutrition 5, 31. https://doi.org/10.3389/
fnut.2018.00031.
Nakagawa, H., Niu, K., Hozawa, A., Ikeda, Y., Kaiho, Y., Ohmori-Matsuda, K.,
Nakaya, N., Kuriyama, S., Ebihara, S., Nagatomi, R., Tsuji, I., Arai, Y., 2010. Impact
of Nocturia on Bone Fracture and Mortality in Older Individuals: A Japanese
Longitudinal Cohort Study. J. Urol. 184, 1413–1418. https://doi.org/10.1016/j.
juro.2010.05.093.
Nakamura, K., Ogata, T., 2016. Locomotive Syndrome: Definition and Management. Clin.
Rev. Bone Mineral Metabolism 14, 56–67. https://doi.org/10.1007/s12018-016-
9208-2.
Nakanishi, M., Nakae, A., Kishida, Y., Baba, K., Sakashita, N., Shibata, M., Yoshikawa, H.,
Hagihara, K., 2016. Go-sha-jinki-Gan (GJG) ameliorates allodynia in chronic
constriction injury model mice via suppression of TNF-α expression in the spinal
cord. Mol. Pain 12, 1744806916656382. 10.1177/1744806916656382.
Negoro, H., Kanematsu, A., Yoshimura, K., Ogawa, O., 2013. Chronobiology of
Micturition: Putative Role of the Circadian Clock. J. Urol. 190, 843–849. https://doi.
org/10.1016/j.juro.2013.02.024.
Okada, N., Oshima, K., Iwasaki, Y., Maruko, A., Matsumura, K., Iioka, E., Vu, T.-D.,
Fujitsuka, N., Nishi, A., Sugiyama, A., Nishiyama, M., Kaneko, A., Mizoguchi, K.,
Yamamoto, M., Nishimura, S., 2021. Intron retention as a new pre-symptomatic
marker of aging and its recovery to the normal state by a traditional Japanese multi-
herbal medicine. Gene 794, 145752. https://doi.org/10.1016/j.gene.2021.145752.
Parsons, J.K., Mougey, J., Lambert, L., Wilt, T.J., Fink, H.A., Garzotto, M., Barrett-
Connor, E., Marshall, L.M., 2009. Lower urinary tract symptoms increase the risk of
falls in older men. Bju Int. 104, 63–68. https://doi.org/10.1111/j.1464-
410x.2008.08317.x.
Prinz, P.N., 2004. Age impairments in sleep, metabolic and immune functions. Exp.
Gerontol. 39, 1739–1743. https://doi.org/10.1016/j.exger.2004.06.023.
Sampaio, P.Y.S., Sampaio, R.A.C., Yamada, M., Ogita, M., Arai, H., 2014. Validation and
translation of the Kihon Checklist (frailty index) into Brazilian Portuguese. Geriatr.
Gerontol. Int. 14, 561–569. https://doi.org/10.1111/ggi.12134.
Sampaio, P.Y.S., Sampaio, R.A.C., Yamada, M., Arai, H., 2016. Systematic review of the
Kihon Checklist: Is it a reliable assessment of frailty? Geriatr. Gerontol. Int. 16,
893–902. https://doi.org/10.1111/ggi.12833.
Satake, S., Arai, H., 2020. The revised Japanese version of the Cardiovascular Health
Study criteria (revised J-CHS criteria). Geriatr. Gerontol. Int. 20, 992–993. https://
doi.org/10.1111/ggi.14005.
Satake, S., Shimada, H., Yamada, M., Kim, H., Yoshida, H., Gondo, Y., Matsubayashi, K.,
Matsushita, E., Kuzuya, M., Kozaki, K., Sugimoto, K., Senda, K., Sakuma, M.,
Endo, N., Arai, H., 2017a. Prevalence of frailty among community-dwellers and
outpatients in Japan as defined by the Japanese version of the Cardiovascular Health
12
Gene 844 (2022) 146775
Study criteria. Geriatr. Gerontol. Int. 17, 2629–2634. https://doi.org/10.1111/
ggi.13129.
Satake, S., Shimokata, H., Senda, K., Kondo, I., Toba, K., 2017b. Validity of Total Kihon
Checklist Score for Predicting the Incidence of 3-Year Dependency and Mortality in a
Community-Dwelling Older Population. J. Am. Med. Dir. Assoc. 18, 552.e1–552.e6.
https://doi.org/10.1016/j.jamda.2017.03.013.
Seichi, A., Hoshino, Y., Doi, T., Akai, M., Tobimatsu, Y., Iwaya, T., 2012. Development of
a screening tool for risk of locomotive syndrome in the elderly: the 25-question
Geriatric Locomotive Function Scale. J. Orthop. Sci. 17, 163–172. https://doi.org/
10.1007/s00776-011-0193-5.
Soma, O., Hatakeyama, S., Imai, A., Matsumoto, T., Hamano, I., Fujita, N., Iwamura, H.,
Okamoto, T., Yamamoto, H., Tobisawa, Y., Yoneyama, T., Yoneyama, T.,
Hashimoto, Y., Nakaji, S., Ohyama, C., 2020. Relationship between frailty and lower
urinary tract symptoms among community-dwelling adults. Luts Low Urin Tract
Symptoms 12, 128–136. https://doi.org/10.1111/luts.12292.
Song, X., Mitnitski, A., Rockwood, K., 2010. Prevalence and 10-Year Outcomes of Frailty
in Older Adults in Relation to Deficit Accumulation. J. Am. Geriatr. Soc. 58,
681–687. https://doi.org/10.1111/j.1532-5415.2010.02764.x.
Soysal, P., Stubbs, B., Lucato, P., Luchini, C., Solmi, M., Peluso, R., Sergi, G., Isik, A.T.,
Manzato, E., Maggi, S., Maggio, M., Prina, A.M., Cosco, T.D., Wu, Y.-T., Veronese, N.,
2016. Inflammation and frailty in the elderly: A systematic review and meta-
analysis. Ageing Res. Rev. 31, 1–8. https://doi.org/10.1016/j.arr.2016.08.006.
Stanley, N., 2005. The Underestimated Impact of Nocturia on Quality of Life. Eur. Urol.
Suppl. 4, 17–19. https://doi.org/10.1016/j.eursup.2005.07.002.
Stenholm, S., Ferrucci, L., Vahtera, J., Hoogendijk, E.O., Huisman, M., Pentti, J.,
Lindbohm, J.V., Bandinelli, S., Guralnik, J.M., Kivimäki, M., 2018. Natural Course of
Frailty Components in People Who Develop Frailty Syndrome: Evidence From Two
Cohort Studies. J. Gerontol. Ser. 74, 667–674. https://doi.org/10.1093/gerona/
gly132.
Takayama, S., Arita, R., Kikuchi, A., Ohsawa, M., Kaneko, S., Ishii, T., 2018. Clinical
Practice Guidelines and Evidence for the Efficacy of Traditional Japanese Herbal
Medicine (Kampo) in Treating Geriatric Patients. Front. Nutrition 5, 66. https://doi.
org/10.3389/fnut.2018.00066.
Takemoto, Y., Inaba, S., Zhang, L., Baba, K., Hagihara, K., Fukada, S., 2017. An herbal
medicine, Go-sha-jinki-gan (GJG), increases muscle weight in severe muscle
dystrophy model mice. Clin. Nutrition Exp. 16, 13–23. https://doi.org/10.1016/j.
yclnex.2017.08.003.
Tanaka, M., Tajima, S., Mizuno, K., Ishii, A., Konishi, Y., Miike, T., Watanabe, Y., 2015.
Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder.
J. Physiol. Sci. 65, 483–498. https://doi.org/10.1007/s12576-015-0399-y.
Terasawa, K., 1989. The presentation of diagnostic criteria for “Yu-xie” (stagnated blood)
conformation. Int. J. Oriental Med. 14, 194–213. https://cir.nii.ac.jp/crid/
1573668924905085952?lang=en.
Theou, O., Cann, L., Blodgett, J., Wallace, L.M.K., Brothers, T.D., Rockwood, K., 2015.
Modifications to the frailty phenotype criteria: Systematic review of the current
literature and investigation of 262 frailty phenotypes in the Survey of Health,
Ageing, and Retirement in Europe. Ageing Res. Rev. 21, 78–94. https://doi.org/
10.1016/j.arr.2015.04.001.
Trendelenburg, A.U., Scheuren, A.C., Potter, P., Müller, R., Bellantuono, I., 2019.
Geroprotectors: A role in the treatment of frailty. Mech. Ageing Dev. 180, 11–20.
https://doi.org/10.1016/j.mad.2019.03.002.
Tsakos, G., Watt, R.G., Rouxel, P.L., Oliveira, C., Demakakos, P., 2015. Tooth Loss
Associated with Physical and Cognitive Decline in Older Adults. J. Am. Geriatr. Soc.
63, 91–99. https://doi.org/10.1111/jgs.13190.
van Kan, G.A., Rolland, Y.M., Morley, J.E., Vellas, B., 2008. Frailty: Toward a Clinical
Definition. J. Am. Med. Dir. Assoc. 9, 71–72. https://doi.org/10.1016/j.
jamda.2007.11.005.
Vay, L., Gu, C., McNaughton, P.A., 2012. The thermo-TRP ion channel family: properties
and therapeutic implications. Brit. J. Pharmacol. 165, 787–801. https://doi.org/
10.1111/j.1476-5381.2011.01601.x.
Veith, I., 2015. The Yellow Emperor’s Classic of Internal Medicine. 10.1525/
9780520963245.
Vellas, B., Balardy, L., Gillette-Guyonnet, S., Kan, G.A.V., Ghisolfi-Marque, A., Subra, J.,
Bismuth, S., Oustric, S., Cesari, M., 2013. Looking for frailty in community-dwelling
older persons: The Gerontopole Frailty Screening Tool (GFST). J. Nutrition Heal.
Aging 17, 629–631. https://doi.org/10.1007/s12603-013-0363-6.
Viña, J., Tarazona-Santabalbina, F.J., Pérez-Ros, P., Martínez-Arnau, F.M., Borras, C.,
Olaso-Gonzalez, G., Salvador-Pascual, A., Gomez-Cabrera, M.C., 2016. Biology of
frailty: Modulation of ageing genes and its importance to prevent age-associated loss
of function. Mol. Aspects Med. 50, 88–108. https://doi.org/10.1016/j.
mam.2016.04.005.
Wang, Y., Che, M., Xin, J., Zheng, Z., Li, J., Zhang, S., 2020. The role of IL-1β and TNF-α
in intervertebral disc degeneration. Biomed. Pharmacother. 131, 110660 https://
doi.org/10.1016/j.biopha.2020.110660.
Weinert, D., 2010. Circadian temperature variation and ageing. Ageing Res. Rev. 9,
51–60. https://doi.org/10.1016/j.arr.2009.07.003.
Xue, Q.-L., 2011. The Frailty Syndrome: Definition and Natural History. Clin. Geriatr.
Med. 27, 1–15. https://doi.org/10.1016/j.cger.2010.08.009.
Xue, Q.-L., Bandeen-Roche, K., Varadhan, R., Zhou, J., Fried, L.P., 2008. Initial
Manifestations of Frailty Criteria and the Development of Frailty Phenotype in the
Women’s Health and Aging Study II. J. Gerontol. Ser. 63, 984–990. https://doi.org/
10.1093/gerona/63.9.984.
R. Egashira et al.
Yagi, H., Sato, R., Nishio, K., Arai, G., Soh, S., Okada, H., 2015. Clinical efficacy and
tolerability of two Japanese traditional herbal medicines, Hachimi-jio-gan and
Gosha-jinki-gan, for lower urinary tract symptoms with cold sensitivity.
J. Traditional Complement. Med. 5, 258–261. https://doi.org/10.1016/j.
jtcme.2015.03.010.
Yasui, T., Uemura, H., Irahara, M., Arai, M., Kojimahara, N., Okabe, R., Yasutomo, I.,
Tashiro, S., Sato, H., 2007. Differences in Sensitivity to Cold in Japanese Men and
13
Gene 844 (2022) 146775
Postmenopausal Women Aged ≥50 Years. Gender Med. 4, 359–366. https://doi.org/
10.1016/s1550-8579(07)80065-9.
Yesavage, J.A., 1988. Geriatric depression scale. Psychopharmacol. Bull. 24, 709–711.
Yue, L., Xu, H., 2021. TRP channels in health and disease at a glance. J. Cell Sci. 134
https://doi.org/10.1242/jcs.258372.