Circulating levels of IGF1 are associated with muscle strength in middle-aged- and oldest-old women
Abstract
In aging populations, poor handgrip strength has been associated with physical disability and mortality. IGF1 is an important mediator of muscle growth and regeneration affecting muscle function. We studied the relationship between circulating levels of IGF1, its binding protein 3 (IGFBP3), and handgrip strength and physical performance in middle-aged- and oldest-old subjects.
Cross-sectional analysis in two different cohorts composed of middle-aged- (n = 672, mean 63.9 ± 6.7 years) and oldest-old subjects (n = 272, all 89 years).
Handgrip strength, functional performance and ability, and serum levels of IGF1 and IGFBP3 were measured in all subjects and analyzed by linear regression for men and women separately.
IGF1 and IGFBP3 levels declined with chronological age and were positively associated with handgrip strength in middle-aged- and oldest-old women (both, P < 0.05), but not in men of either age group. Furthermore, higher serum levels of IGF1 were associated with slower walking speed in oldest-old men (P = 0.012), and serum levels of IGFBP3 were positively associated with activities of daily living in the oldest-old women (P = 0.002).
The significant relationship between IGF1 levels and muscle strength found in women but not in men suggests a gender-specific influence of IGF1 on muscle strength. Further studies are necessary to test the relationship with physical performance.
CLINICAL STUDY
Circulating levels of IGF1 are associated with muscle strength in
middle-aged- and oldest-old women
Diana G Taekema
1,2
, Carolina H Y Ling
1
, Gerard Jan Blauw
1
, Carel G Meskers
3
, Rudi G J Westendorp
1,4
,
Anton J M de Craen
1,4
and Andrea B Maier
1,4
1
Department of Gerontology and Geriatrics, C2-R-133, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands,
2
Department
of Geriatrics, Rijnstate Hospital, PO Box 9555, 6800 TA, Arnhem, The Netherlands and
3
Department of Rehabilitation Medicine and
4
Netherlands
Consortium for Healthy Aging, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands
(Correspondence should be addressed to D G Taekema at Department of Gerontology and Geriatrics, C2-R-133, Leiden University Medical Center;
Email: d.g.taekema@lumc.nl)
Abstract
Objective: In aging populations, poor handgrip strength has been associated with physical disability and
mortality. IGF1 is an important mediator of muscle growth and regeneration affecting muscle function.
We studied the relationship between circulating levels of IGF1, its binding protein 3 (IGFBP3), and
handgrip strength and physical performance in middle-aged- and oldest-old subjects.
Design: Cross-sectional analysis in two different cohorts composed of middle-aged- (nZ672, mean
63.9G6.7 years) and oldest-old subjects (nZ272, all 89 years).
Methods: Handgrip strength, functional performance and ability, and serum levels of IGF1 and IGFBP3
were measured in all subjects and analyzed by linear regression for men and women separately.
Results: IGF1 and IGFBP3 levels declined with chronological age and were positively associated with
handgrip strength in middle-aged- and oldest-old women (both, P!0.05), but not in men of either age
group. Furthermore, higher serum levels of IGF1 were associated with slower walking speed in oldest-
old men (PZ0.012), and serum levels of IGFBP3 were positively associated with activities of daily
living in the oldest-old women (PZ0.002).
Conclusion: The significant relationship between IGF1 levels and muscle strength found in women but
not in men suggests a gender-specific influence of IGF1 on muscle strength. Further studies are
necessary to test the relationship with physical performance.
European Journal of Endocrinology 164 189–196
Introduction
Aging is associated with a decline in muscle mass,
commonly referred to as sarcopenia. Sarcopenia is a
major determinant of muscle strength loss in the elderly.
Poor muscular strength is in turn associated with
adverse outcomes, such as physical disability and
mortality (1–3). Depending on the definition used, the
prevalence of sarcopenia is reported to be as high as
60% in the general oldest-old population over 85 years
of age (4). By 2050, oldest-old subjects will account for
one-fifth of all older persons globally (5). In view of the
detrimental functional effects, sarcopenia may have on
the quality of life and survival of our aging societies;
research into its etiology is important for optimization of
preventive and therapeutic strategies.
The pathophysiology of sarcopenia is complex and
involves interplay of multiple factors including chronic
diseases, inflammatory, metabolic, nutritional, and
hormonal factors (4). With regard to hormonal factors,
evidence increasingly suggests an association between
age-dependent decline in levels of growth hormone (GH)
and insulin-like growth factor 1 (IGF1), the major
mediator of GH action, with unfavorable changes in
body composition with age (6, 7).Moreover,the
reduction in physical activity also contributes to the
decline in GH secretion and alteration in body
composition during aging (6). Both GH and IGF1 have
important anabolic effects on skeletal muscle tissue.
IGF1 has been shown to stimulate muscle cell
proliferation and differentiation, facilitate muscle
protein synthesis, and inhibit its degradation (8).
Previous studies have assessed the association
between IGF1 and IGF-binding protein 3 (IGFBP3) and
functional outcome in older people. Low serum levels of
IGF1 and IGFBP3 were reported to be associated with
poorer muscular strength, walking speed, mobility
tasks, various physical performance, and all-cause
mortality in the elderly (9–12). GH therapy has been
associated with increased lean body mass and decreased
fat mass (13–15), but evidence is still lacking on its
effectiveness in improving muscle function and overall
European Journal of Endocrinology (2011) 164 189–196 ISSN 0804-4643
q2011 European Society of Endocrinology DOI: 10.1530/EJE-10-0703
Online version via www.eje-online.org
physical performance in the old. However, aforemen-
tioned studies were not consistent in their findings and
did not include the group of the oldest-old subjects.
More research is needed to assess the association
between these hormonal factors and muscle function,
overall physical performance and disability. We assessed
this relationship in two different age groups composed of
middle-aged- and oldest-old subjects. We hypothesized
that lower levels of IGF1 are associated with lower muscle
strength in middle-aged- and oldest-old subjects, and that
lower levels of IGF1 are associated with impaired physical
performance and disability in the oldest-old subjects.
Method
Subjects
Data for the middle-aged- and oldest-old subjects were
obtained from the Leiden Longevity Study and Leiden
85-plus Study respectively. In the Leiden Longevity
Study, 420 families consisting of long-living Caucasian
siblings together with their middle-aged-old offspring
and the partners thereof were recruited (16). This study
included 672 of the middle-aged-old offspring and their
partners. All subjects visited the study center where
measurements were performed. The Leiden 85-plus
Study is a community-based prospective follow-up study
of inhabitants of the city of Leiden, The Netherlands
(17). Enrollment took place between 1997 and 1999.
All inhabitants who reached the age of 85 years were
eligible to participate (nZ599). Subjects were visited
annually at their place of residence where various tests
were performed. Follow-up continued until death or 90
years of age. The current study included 272 oldest-old
subjects who were alive at the age of 89 years. There
were no selection criteria on health or demographic
characteristics in both studies (16, 17). The medical
ethical committee of the Leiden University Medical
Centre approved both studies. Informed consent was
obtained from all subjects. In case of severe cognitive
impairment, a guardian gave informed consent.
Subject characteristics and possible
confounders
Anthropometric data was collected from all subjects. At
baseline, information on common chronic diseases and
medication use was obtained from the general prac-
titioner, pharmacist’s records and blood sample
analysis. Information on menopausal state and past
and current use of hormone replacement therapy in the
middle-aged-old women was assessed by a question-
naire at baseline. The chronic diseases recorded were
diabetes mellitus, chronic obstructive pulmonary
disease, malignancy, myocardial infarction, stroke, and
hypertension. For each subject, a sum score of chronic
diseases (defined as comorbidity) was assigned.
Serum parameters
Since systemic inflammation is negatively associated
with serum levels of IGF1 (18), serum C-reactive protein
(CRP) levels were measured as a proxy for systemic
inflammation. Serum levels of IGF1, IGFBP3, and CRP
were determined in the middle-aged-old subjects and at
the age of 89 years in the oldest-old subjects. In both
studies, IGF1 and IGFBP3 were determined using
the automated Immulite 2500 from DPC (Los Angeles,
CA, USA). CRP was measured with a standard, fully
automated P800 Modular system (Roche) with a
sensitivity ranging from 1 mg/l in the oldest-old
subjects to 0.6 mg/l in the middle-aged-old subjects.
The increased sensitivity in the middle-aged-old subjects
is explained by improvements to the CRP assay in later
models of the analyzer.
Handgrip strength
Handgrip strength was used as a proxy for global
muscle strength (19, 20) and was measured using a
Jamar hand dynamometer (Sammons Preston, Inc.,
Bolingbrook, IL, USA) to the nearest kilograms.
Measurement of handgrip strength is a reliable
instrument and has been tested in different age groups,
including oldest-old subjects (21–23). All subjects were
instructed to maintain an upright standing position,
arms down by the side, and holding the dynamometer
in the dominant hand without squeezing the arm
against the body. The width of the dynamometer’s
handle was adjusted to the hand size of the subjects
such that the middle phalanx rested on the inner
handle. Subjects were allowed to perform one test trial,
followed by three trials, and the best measure was taken
for analysis. Handgrip strength was measured at one
time point in the middle-aged-old subjects and at the
age of 89 years in the oldest-old subjects.
Measurements of functional ability in
oldest-old subjects
Functional ability was measured only in the group of
oldest-old subjects. Competence in the activities of daily
living (ADL) was measured in the oldest-old subjects with
the Groningen Activity Restriction Scale (GARS) that
assesses nine areas of basic ADL and instrumental ADL
(IADL) respectively (24). The sum scores for the ADL and
IADL range from 9 (competent in all activities) to 36
(unable to perform any activity without help) respectively,
and their sum scores together give the total GARS score.
Walking speed was assessed in the oldest-old subjects by a
standardized 6 m walking test, which was validated in
previous longitudinal aging studies (25). Subjects were
instructed to walk two laps of 3 m each as quickly as
possible. The time it took for the subjects to walk the total
6 m was recorded in seconds, using a stopwatch. The use
of a walking aid was allowed during the test.
190 D G Taekema and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2011) 164
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Statistical analysis
Data were analyzed separately for men and women. The
association between IGF1, IGFBP3 and handgrip
strength was analyzed by linear regression using three
different models. In model 1, the analysis was adjusted
for height, weight, and age for the middle-aged-old
subjects and height and weight for the oldest-old
subjects. Models 2 and 3 were adjusted for the same
covariates as for model 1 with further adjustments for
CRP and comorbidity respectively. In addition, the
population of middle-aged-old women was stratified by
menopausal state, and all linear regression analyses
were repeated. SPSS 17.0 (SPSS Inc., Chicago, IL, USA)
for Windows was used for all analyses. Pvalues !0.05
were considered statistically significant.
Results
Subjects’ characteristics
Baseline characteristics of the study subjects are
presented in Table 1. Mean age of the middle-aged-old
subjects was 64.3 years, and the age of the oldest-old
subjects was 89 years. Height, weight, and handgrip
strength were significantly higher in men and overall
lower in the oldest-old subjects. As expected, the oldest-
old subjects had a higher number of chronic diseases.
IGF1 and IGFBP3 levels were lower in the oldest-old
subjects than in the middle-aged-old subjects (P!0.001).
For both the middle-aged- and oldest-old subjects, there
were no significant gender differences in the serum IGF1
levels, but women had significantly higher IGFBP3 levels
than men in both studies (P!0.001).
Information on menopausal status was available for
325 out of 339 middle-aged-old women. Postmenopau-
sal state, defined as cessation of menstrual period for
at least 1 year, was present in 288 (88.6%) women.
Of these, only five (1.5%) women were current users
of hormone replacement therapy. Of the 22 (6.8%)
perimenopausal middle-aged-old women, there were
three (0.9%) current users of hormone replacement
therapy.
Serum levels of IGF1, IGFBP3, and handgrip
strength
The multiple regression models for the association
between IGF1, IGFBP3 levels and handgrip strength in
the middle-aged- and oldest-old subjects are presented
in Tables 2 and 3respectively. Serum levels of IGF1 were
significantly associated with higher handgrip strength
in the middle-aged-old women after adjusting for age,
height, and weight (0.11 kg higher handgrip strength
per 1 mmol/l increase in IGF1 level, PZ0.049).
However, significance was lost after adjustment for
CRP and comorbidity. No significant association was
observed between handgrip strength and IGF1 in men
and IGFBP3 in both genders. In addition, we stratified
the group of middle-aged-old women by menopausal
status and repeated all linear regression analyses.
IGF1 was positively associated with handgrip
strength in the postmenopausal middle-aged-old
women (0.13 kg higher handgrip strength per
1 mmol/l increase in IGF1, PZ0.037) but not in
premenopausal and perimenopausal women. The
association did not change with adjustment for CRP
(0.12 kg higher handgrip strength per 1 mmol/l
increase in IGF1, PZ0.040). In postmenopausal
middle-aged-old women, IGF1 was positively associated
with handgrip strength in the fully adjusted model
(0.15 kg higher handgrip strength per 1 mmol/l
increase in IGF1, PZ0.013), but not in premenopausal
and perimenopausal women. After exclusion of women
receiving hormone replacement therapy, these
Table 1 Baseline characteristics of study subjects.
Middle-aged-old (nZ672) Oldest-old (nZ272)
Men
(nZ333)
Women
(nZ339) Pvalue
Men
(nZ74)
Women
(nZ198) Pvalue
Age (years; mean, S.D.) 64.3 (6.5) 61.6 (6.6) !0.001 89.0 89.0 –
Height (m; mean, S.D.) 1.78 (0.1) 1.66 (0.1) !0.001 1.68 (0.1) 1.56 (0.1) !0.001
Weight (kg; mean, S.D.) 85.5 (11.3) 72.6 (12.7) !0.001 71.7 (12.1) 65.8 (12.8) !0.001
Handgrip strength (kg; mean, S.D.) 46.8 (8.1) 29.7 (5.7) !0.001 26.5 (8.1) 16.6 (5.2) !0.001
Chronic diseases (n,%)
Diabetes mellitus 27 (8.1) 14 (4.1) 0.080 7 (9.5) 27 (13.6) 0.356
COPD 15 (4.5) 9 (2.7) 0.247 8 (10.8) 16 (8.1) 0.482
Malignancy 21 (6.3) 23 (6.8) 0.015 13 (17.6) 24 (12.1) 0.245
Hypertension 80 (24.0) 86 (25.4) !0.001 27 (36.5) 79 (39.9) 0.609
Myocardial infarction 12 (3.6) 2 (0.6) 0.021 21 (28.4) 29 (14.6) 0.009
Stroke 11 (3.3) 5 (1.5) 0.021 6 (8.1) 11 (5.6) 0.477
Serum parameters
IGF1 (mmol/l; mean, S.D.) 17.2 (4.7) 17.2 (5.1) 0.968 10.4 (4.8) 11.0 (4.0) 0.346
IGFBP3 (mg/l; mean, S.D.) 4.3 (0.9) 4.5 (0.9) !0.001 2.6 (1.0) 3.3 (0.9) !0.001
CRP (mg/l; median, IQR) 1.2 (0.7–2.4) 1.3 (0.7–3.1) 0.017 3.0 (1.0–6.0) 3.0 (1.0–7.0) 0.903
COPD, chronic obstructive pulmonary disease; IQR, interquartile range. Comparison between groups by ANOVA.
IGF1 serum levels and handgrip strength 191EUROPEAN JOURNAL OF ENDOCRINOLOGY (2011) 164
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associations remained significant in the postmenopau-
sal middle-aged-old women (0.13 kg higher handgrip
strength per 1 mmol/l increase in IGF1, PZ0.037). No
significant associations were found between IGFBP3
and handgrip strength according to menopausal status
(all, PO0.05).
Serum IGF1 levels were significantly associated with
higher handgrip strength in the oldest-old women
(0.19 kg higher handgrip strength per 1 mmol/l
increase in IGF1 level, PZ0.027) but not in men. After
adjustment for CRP and comorbidity, the association
remained significant (PZ0.023 and PZ0.029, respect-
ively). Moreover, serum levels of IGFBP3 were also
significantly associated with higher handgrip strength in
women only (1.56 kg higher handgrip strength per
1 mg/l increase in IGFBP3 level, P!0.001). Further
adjustments did not change this association.
Serum levels of IGF1, IGFBP3, and functional
performance and ability
Table 4 shows the multiple regression models for the
association between serum levels of IGF1 and IGFBP3
and ADL and walking speed in the oldest-old subjects.
No association was observed between serum levels of
IGF1 and ADL in both genders. Serum levels of IGFBP3
were positively associated with the GARS scores in the
oldest-old women (3.17 points better GARS score per
1 mg/l increase in IGFBP3 level, PZ0.002), but
statistical significance was not reached in men. An
inverse association was observed between serum IGF1
levels and walking speed in the oldest-old men (1.28 s
slower walking speed per 1 mmol/l increase in IGF1
level, PZ0.012). There was no significant association
between walking speed and serum levels of IGFBP3 in
both genders.
Discussion
We hypothesized that lower levels of anabolic factor
IGF1 are associated with lower muscle strength in the
middle-aged- and oldest-old subjects. Moreover, we
hypothesized that lower serum levels of IGF1 are
associated with impaired physical performance and
disability in the oldest-old men and women. Our results
Table 2 Serum IGF1 and IGFBP3 levels as determinants of handgrip strength in middle-aged-old men and women.
Handgrip strength (kg)
Men (nZ333) Women (nZ339)
bS.E.M.Pvalue bS.E.M.Pvalue
IGF1 (mmol/l)
Adjusted for age, height, and weight K0.01 0.09 0.929 0.11 0.06 0.049
Additional adjustment for CRP K0.01 0.09 0.921 0.11 0.06 0.051
Additional adjustment for comorbidity
a
K0.08 0.10 0.406 0.11 0.06 0.054
IGFBP3 (mg/l)
Adjusted for age, height, and weight 0.07 0.45 0.870 0.38 0.33 0.243
Additional adjustment for CRP 0.06 0.46 0.902 0.36 0.33 0.272
Additional adjustment for comorbidity
a
K0.07 0.49 0.889 0.24 0.34 0.477
b, estimate.
a
For each subject, a sum score of chronic diseases (defined as comorbidity) was assigned. Chronic diseases included diabetes mellitus, chronic obstructive
pulmonary disease, malignancy, myocardial infarction, stroke, and hypertension.
Table 3 Serum IGF1 and IGFBP3 levels as determinants of handgrip strength in oldest-old men and women.
Handgrip strength (kg)
Men (nZ74) Women (nZ198)
bS.E.M.Pvalue bS.E.M.Pvalue
IGF1 (mmol/l)
Adjusted for height and weight 0.10 0.19 0.690 0.19 0.08 0.027
Additional adjustment for CRP K0.10 0.21 0.661 0.21 0.09 0.023
Additional adjustment for comorbidity
a
0.07 0.20 0.734 0.19 0.09 0.029
IGFBP3 (mg/l)
Adjusted for height and weight K0.50 1.00 0.094 1.56 0.37 !0.001
Additional adjustment for CRP 0.45 1.01 0.651 1.46 0.40 !0.001
Additional adjustment for comorbidity
a
0.61 0.99 0.536 1.56 0.37 !0.001
b, estimate.
a
For each subject, a sum score of chronic diseases (defined as comorbidity) was computed. Chronic diseases included diabetes mellitus, chronic obstructive
pulmonary disease, malignancy, myocardial infarction, stroke, and hypertension.
192 D G Taekema and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2011) 164
www.eje-online.org
show that levels of IGF1 and IGFBP3, both decrease
with age, and that they are positively associated with
muscle strength in postmenopausal middle-aged- and
oldest-old women, but not in men. Furthermore, we
found that serum levels of IGF1 were negatively
associated with walking speed in oldest-old men, and
IGFBP3 serum levels were positively associated with
ADL in oldest-old women.
IGF1 is one of the most important mediators of
muscle growth and subsequent regeneration (26)
affecting muscle performance due to its anabolic,
hypertrophying signaling effect. IGF1 is produced
mainly in the liver, where its synthesis is GH dependent
(27) but is also produced in multiple extrahepatic
tissues acting in an autocrine and a paracrine fashion
(28). Besides the age-dependent decline in IGF1 serum
levels, tissue responsiveness to IGF1 (29, 30) as well as
intracellular signaling is less efficient with age (31).
Previous studies have shown an association of IGF1
serum levels in the elderly and functional outcome
parameters such as muscle strength (10, 32, 33).
In agreement with other studies, we found a decrease
in IGF1 and IGFBP3 levels with age, probably as a
consequence of the decline in GH synthesis, in both
male and female subjects (34–36). However, in contrast
to recently published studies, we found no significant
gender differences in IGF1 levels in the middle-aged- and
oldest-old subjects (37, 38). Gender differences were
present for IGFBP3 levels consistent with the findings of
previous studies (39). The relationship between serum
IGF1 levels and handgrip strength was present only in
women. Two other studies concluded that handgrip
strength and lower values for maximal muscle power
and optimal shortening velocity were associated with
lower circulating levels of IGF1 in women only (32, 40).
More recently, IGF1 levels were associated with exercise
capacity in healthy female volunteers (41). The missing
positive relation in elderly men in our study might be
partly explained by the lower IGF1 levels in men than in
women. A recent study reported gender-specific
reference ranges for different age groups (39). The
serum levels of the oldest-old male subjects in our study
were much lower than expected from the reference
values (below 25th percentile). A possible explanation
could be that lower levels of IGF1 are reflective of
increased frailty in oldest-old men aged 89 years in our
study cohort. Another reason for the absence of an
association in elderly men could be that in men the
decline in total hormonal burden is associated with
detrimental outcome, rather than deficiency in a single
hormone (42). Also sex hormones are strongly
associated with muscle mass in men but not in
women (40). Finally, the missing relationship between
IGF1 levels and handgrip strength in oldest-old men
could be explained by lack of power due to the limited
number of oldest-old subjects; however, this does not
explain why in the larger sample of middle-aged-old
men the relation is also missing. More research is needed
to point out possible underlying mechanisms of gender
differences in IGF1 signaling and muscle strength.
The age-related decline in GH and IGF1 serum levels
may promote frailty by contributing to the loss of
muscle mass and strength. A significant positive
relationship has been shown between low plasma
IGF1 and functional outcome, such as impaired physical
performance and self-reported difficulties with mobility
tasks (10, 32, 33). However, physical performance has
also been found to be negatively associated with IGF1
serum levels (13, 35, 43–45). Our findings regarding
functional performance and ADL disability are also
conflicting with higher IGF1 serum levels being
associated with slower walking speed in oldest-old
men and a positive association between serum levels
of IGFBP3 and ADL in oldest-old women. This last
Table 4 Serum IGF1 and IGFBP3 levels as determinants of functional performance and ability in oldest-old men and women.
Activities of daily living
a
(points) Walking speed (s)
b
Men (nZ74) Women (nZ198) Men (nZ74) Women (nZ198)
bS.E.M.Pvalue bS.E.M.Pvalue bS.E.M.Pvalue bS.E.M.Pvalue
IGF1 (mmol/l)
Adjusted for height and weight K0.33 0.3 0.324 K0.27 0.2 0.240 1.28 0.5 0.012 0.08 0.2 0.688
Additional adjustment for CRP K0.21 0.4 0.568 K0.31 0.3 0.238 1.51 0.6 0.011 0.14 0.3 0.578
Additional adjustment for
comorbidity
c
K0.35 0.3 0.292 K0.27 0.2 0.234 1.28 0.5 0.013 0.09 0.2 0.644
IGFBP3 (mg/l)
Adjusted for height and weight K2.73 1.6 0.099 K3.17 1.0 0.002 1.84 2.6 0.475 0.32 0.9 0.729
Additional adjustment for CRP K2.66 1.9 0.158 K3.00 1.1 0.009 2.78 3.0 0.367 0.60 1.1 0.601
Additional adjustment for
comorbidity
c
K2.88 1.6 0.083 K3.17 1.0 0.002 1.79 2.6 0.484 0.34 0.9 0.706
b, estimate.
a
Competence in activities of daily living was measured with the Groningen Activity Restriction Scale (GARS), scores ranging from 9 (competent in all activities)
to 36 (unable to perform any activity without help).
b
Walking speed was assessed by a standardized 6 m walking test.
c
For each subject, a sum score of chronic diseases (defined as comorbidity) was computed. Chronic diseases included diabetes mellitus, chronic obstructive
pulmonary disease, malignancy, myocardial infarction, stroke, and hypertension.
IGF1 serum levels and handgrip strength 193EUROPEAN JOURNAL OF ENDOCRINOLOGY (2011) 164
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finding is consistent with an earlier study that found a
potential positive influence of IGFI and IGFBP3 in
women with regard to walking speed and disability (10).
Others have reported on the association between
walking speed and IGF1 serum levels in 349 oldest-old
subjects and found an association between IGF1 levels
and walking speed only in 54 subjects with a body mass
index above 30 (9). The finding that IGF1 levels are
negatively associated with walking speed in oldest-old
men is counterintuitive and is not supported by a limited
number of earlier studies (9, 10). A chance finding in
spite of the limited size of oldest-old men in this study
cannot be excluded.
Despite these conflicting results, which could be
explained by study population homogeneity with
subsequent smaller ranges of IGF1 levels, the potential
influence of GH/IGF1 on muscle function can best be
illustrated by administration of these hormones. Acute
administration of GH regulates muscle mitochondrial
function by increasing the levels of several key
mitochondrial proteins switching fuel utilization toward
fat oxidation (46). In addition, exogenous systemic
administration of IGF1 increases the rate of skeletal
muscle functional recovery after injury (47), improves
contractile function (48, 49) and fatigue resistance, and
induces an increase in muscle oxidative enzymes (47).
Our study has several strong points, particularly the
large size of the study population, the large age range
and its external validity, i.e. the included subjects
representing the general population. The number of
oldest-old subjects included in our study is significantly
higher than other studies. Therefore, we conclude that
our study is very comprehensive with a large number of
subjects (nZ944, age range 38–89 years) and the
largest number of oldest-old subjects (nZ272, all aged
89 years). Furthermore, handgrip strength is a reliable
tool to measure overall muscle strength (21–23).
However, this study was set up in a cross-sectional
way, and IGF1 and IGFBP3 were only measured at one
time point in both study cohorts. Future longitudinal
analysis in our middle-aged-old cohort will allow for
further insight into the association of GH and muscle
strength as well as functional performance and ability.
We were unable to measure body composition, because
the oldest-old subjects were visited at their home.
Furthermore, we did not control for additional factors
that could potentially influence the associations between
the somatotropic axis and muscle strength, such as sex
hormones, which were not available due to sample
limitations. Finally, the relationship between serum and
muscle IGF1 is not necessarily strong, because of
different isoforms in muscle and liver (50, 51) and we
were not able to assess muscle IGF1 directly. Also, we
have not measured IGF1 bioactivity (52) as a possibly
more accurate measure of IGF1 biological activity.
In summary, we found an association between serum
IGF1 levels and handgrip strength in middle-aged-old
postmenopausal and oldest-old women, but not in men.
Maintenance of higher IGF1 levels could therefore
contribute to preservation of muscle function and
subsequent muscle performance in an elderly female
population. Further research is needed to address
gender differences in IGF1 signaling in muscle in
oldest-old subjects.
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the research reported.
Funding
This study was supported by an unrestricted grant from The
Netherlands Organization of Scientific Research (ZonMw), the
Ministry of Health, Welfare and Sports, The Netherlands Genomics
Initiative/Netherlands Organization for scientific research (NGI/NWO;
05040202 and 050-060-810 Netherlands Consortium for Healthy
Aging (NCHA)) and the seventh framework program MYOAGE
(HEALTH-2007-2.4.5-10).
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Received 25 November 2010
Accepted 1 December 2010
196 D G Taekema and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2011) 164
www.eje-online.org
- CitationsCitations21
- ReferencesReferences58
- A higher level of S-IGF-1 has been associated with better physical fitness among both younger [26] and Table 3Values obtained at high-intensity exercise performance in women with fibromyalgia (FM) (n = 22) and the healthy reference group (n = 27). Mean value and SD of differences (Δ), p-value for within-group differences as well as for between-group differences are presented High-intensity exercise Women with FM, n = 22 Healthy reference group, n = 27 Between-group differences 0 min 15 min–0 min 0 min 15 min–0 min 0 min older individuals [27]. In healthy women, IGF-1 and ratio of IGF-1/IGFBP-3 were associated with maximum power output [28].
[Show abstract] [Hide abstract] ABSTRACT: Background Increased Serum insulin-like growth factor-1 (S-IGF-1) has been noted after physical activity in healthy subjects, while the acute release of S-IGF-1 in relation to exercise has not previously been studied in women with fibromyalgia (FM). S-IGF-1 and its binding protein (S-IGFBP-3) are mediated by growth hormone and have anabolic effects on the skeletal muscle. Aim of the study was to investigate acute release of IGF-1 after aerobic exercise in women with FM. Methods The acute effect of physical exercise on S-IGF-1 and S-IGFBP-3 were studied in 22 women with FM and in 27 healthy controls during moderate and high-intensity cycling (i.e. ratings 12–13 and 15–17, on Borg’s perceived exertion scale (RPE), respectively). Self-reported pain and fatigue were recorded. Differences within and between the two groups were analyzed. ResultsAfter 15 min of bicycling, S-IGF-1 and S-IGFBP-3 increased both within the group with FM and in the healthy controls (p < 0.01). The increases in S-IGF-1 did not significantly differ between the women with FM and the healthy control group (mean increase 11 ± 10 vs. 11 ± 15 ng/ml and 13 ± 10 vs. 19 ± 22 ng/ml) when bicycling at moderate or high intensity, respectively. Self-reported pain and fatigue during exercise, irrespective of intensity, were higher in women with FM compared with healthy controls (p < 0.001). Conclusions Fifteen minutes bicycling at moderate intensity was sufficient to acutely mobilise S-IGF-1 in women with FM similarly to healthy controls in spite of higher score of fatigue and pain in women with FM. Hence, patients with FM were able to activate their skeletal muscle metabolism during a short, moderate bout of exercise and were not resistant to training effects. The result is important for encouraging clinical rehabilitation of patients with FM who commonly exercise at a moderate, rather than at a high-intensity level. Trial registrationClinicalTrials.govNCT01592916, May 4, 2012.- The data further suggested that the initial level of grip strength was more predictive of mortality than the rate of change, and the predictive effects were similar in men and women. Our results suggest that older women are more sensitive to muscle strength alterations throughout ageing, probably as a result of sex differences in muscle mass as well as hormonal factors [25, 26] . It seems to be particularly important for the weakest to enhance their levels of muscular strength and build up muscle mass early in life, where targeted preventative efforts may be launched, to reduce their risk of premature death.
[Show abstract] [Hide abstract] ABSTRACT: Background Reduced muscular strength in the old age is strongly related to activity impairment and mortality. However, studies evaluating the gender-specific association between muscularity and mortality among older adults are lacking. Thus, the objective of the present study was to examine gender differences in the association between muscular strength and mortality in a prospective population-based cohort study. Methods Data used in this study derived from the Cooperative Health Research in the Region of Augsburg (KORA)-Age Study. The present analysis includes 1,066 individuals (mean age 76 ± 11 SD years) followed up over 3 years. Handgrip strength was measured using the Jamar Dynamometer. A Cox proportional hazard model was used to determine adjusted hazard ratios of mortality with 95% confidence intervals (95% CI) for handgrip strength. Potential confounders (i.e. age, nutritional status, number of prescribed drugs, diseases and level of physical activity) were pre-selected according to evidence-based information. ResultsDuring the follow-up period, 56 men (11%) and 39 women (7%) died. Age-adjusted mortality rates per 1,000 person years (95% CI) were 77 (59–106), 24 (13–41) and 14 (7–30) for men and 57 (39–81), 14 (7–27) and 1 (0–19) for women for the first, second and third sex-specific tertile of muscular strength, respectively. Low handgrip strength was significantly associated with all-cause mortality among older men and women from the general population after controlling for significant confounders. Hazard ratios (95% CI) comparing the first and second tertile to the third tertle were 3.33 (1.53–7.22) and 1.42 (0.61-3.28), respectively. Respective hazard ratios (95% CI) for mortality were higher in women than in men ((5.23 (0.67–40.91) and 2.17 (0.27–17.68) versus 2.36 (0.97–5.75) and 0.97 (0.36–2.57)). Conclusions Grip strength is inversely associated with mortality risk in older adults, and this association is independent of age, nutritional status, number of prescribed drugs, number of chronic diseases and level of physical activity. The association between muscular strength and all-cause mortality tended to be stronger in women. It seems to be particularly important for the weakest to enhance their levels of muscular strength in order to reduce the risk of dying early.- Sarcopenia has been associated with a chronic low-grade pro-inflammatory milieu, increased oxidative stress and endothelial dys- function [9]. Inflammatory mediators such as interleukin-6, tumour necrosis factor-a and C-reactive protein can directly affect muscle catabolism and may also act indirectly by reducing insulin sensitivity or lowering growth hormones [10]. These pathways are shared in vascular calcification suggesting a link between low muscle mass and calcification [11].
[Show abstract] [Hide abstract] ABSTRACT: Background: Age-related loss of skeletal muscle is associated with increased risk of functional limitation and cardiovascular (CV) mortality. In the elderly abdominal aortic calcification (AAC) can increase CV risk by altering aortic properties which may raise blood pressure and increase cardiac workload. This study investigated the association between low muscle mass and AAC in community-dwelling older Australians. Design: Cross-sectional from 2010 sub-study of the Melbourne Collaborative Cohort Study Setting: Community-dwelling older adults Participants and Measurements: Three hundred and twenty-seven participants [mean age =71±6years; mean BMI =28±5kg/m2; Females n= 199 (62%)] had body composition determined by dual-energy x-ray absorptiometry (DXA) and AAC determined by radiography. Participants were stratified into tertiles of sex-specific BMI-normalised appendicular lean mass (ALM). Those in the lowest tertile were considered to have low relative muscle mass. Aortic calcification score (ACS) was determined visually as the extent of calcification on the aortic walls between L1-L4 vertebrae (range: 0-24). Severe AAC was defined as ACS ≥6. Results: Prevalence of any AAC was highest in participants with low relative muscle mass (74%) compared to the middle (65%) and upper (53%) tertiles (p trend=0.006). The lower ALM/BMI tertile had increased odds (Odds ratio=2.3; 95% confidence interval: 1.1-4.6; p=0.021) of having any AAC; and having more severe AAC (2.2; 1.2-4.0; p=0.009) independent of CV risk factors, serum calcium and physical activity. Conclusion: AAC is more prevalent and severe in community-dwelling older adults with low relative muscle mass. Maintaining muscle mass could form part of a broader primary prevention strategy in reducing AAC.- [Show abstract] [Hide abstract] ABSTRACT: As increasing numbers of individuals reach very advanced age, it is important to understand the influence of modifiable lifestyle factors such as diet and nutrition on both the achievement of exceptional longevity as well as the maintenance of optimal functional capacity. This includes determining the most appropriate biomarkers for monitoring changes in health and nutrition status and response to therapy in oldest old individuals. In an earlier work (Hausman et al., Maturitas 2011;68:203-9), we summarized studies of dietary intake and patterns of long-lived peoples and presented the current knowledge regarding vitamin B12, folate, 25(OH) vitamin D and other specific indicators of nutritional status in centenarians. The present review focuses on less specific biochemical indices of health and nutritional status and summarizes studies comparing protein, lipid and hematological biomarkers in centenarians and older adult controls. Such studies, from many countries worldwide, are often small, convenience samples of 'healthy' and/or community-dwelling centenarians, although a few population-based studies including participants with a broader range of physical and cognitive functioning are also presented. Though heterogeneous in design and demographic region, these studies typically show lower levels of protein and hematological indicators and improved levels of some lipid biomarkers in centenarians as compared with regionally matched older adult controls. As these biomarkers can be influenced by many factors interpretation of results must be approached with caution. Importantly, studies examining potential associations of these biomarkers with cognitive, mental and physical function must carefully control for potential confounders including genetics and chronic disease, an increasing burden at advanced age.
- [Show abstract] [Hide abstract] ABSTRACT: Insulin and the insulin-like growth factor (IGF) system regulate growth and are involved in determining muscle mass, strength and body composition. We hypothesised that IGF-I and IGF-II are associated with improved, and insulin with worse, physical performance in old age. Physical performance was measured using the get-up and go timed walk and flamingo balance test at 63-86 years. We examined prospective associations of insulin, IGF-I, IGF-II and IGFBP-3 with physical performance in the UK-based Caerphilly Prospective Study (CaPS; n = 739 men); and cross-sectional insulin, IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in the Boyd Orr cohort (n = 182 men, 223 women). In confounder-adjusted models, there was some evidence in CaPS that a standard deviation (SD) increase in IGF-I was associated with 1.5% faster get-up and go test times (95% CI: -0.2%, 3.2%; p = 0.08), but little association with poor balance, 19 years later. Coefficients in Boyd Orr were in the same direction as CaPS, but consistent with chance. Higher levels of insulin were weakly associated with worse physical performance (CaPS and Boyd Orr combined: get-up and go time = 1.3% slower per SD log-transformed insulin; 95% CI: 0.0%, 2.7%; p = 0.07; OR poor balance 1.13; 95% CI; 0.98, 1.29; p = 0.08), although associations were attenuated after controlling for body mass index (BMI) and co-morbidities. In Boyd Orr, a one SD increase in IGFBP-2 was associated with 2.6% slower get-up and go times (95% CI: 0.4%, 4.8% slower; p = 0.02), but this was only seen when controlling for BMI and co-morbidities. There was no consistent evidence of associations of IGF-II, or IGFBP-3 with physical performance. There was some evidence that high IGF-I and low insulin levels in middle-age were associated with improved physical performance in old age, but estimates were imprecise. Larger cohorts are required to confirm or refute the findings.
- [Show abstract] [Hide abstract] ABSTRACT: Background Insulin-like growth factor (IGF)-1 is a growth factor that can influence fibroblast functioning, with effects including the inhibition of collagenases and the induction of collagen expression. Objectives To assess whether serum IGF-1, IGF-binding protein (IGFBP)3 and the ratio between IGF-1 and IGFBP3, as a measure of IGF-1 bioavailability, are associated with facial ageing and skin wrinkling. Methods From a random sample comprising 617 subjects from the Leiden Longevity Study, perceived age and skin wrinkling were assessed from facial photographs, and IGF-1 and IGFBP3 were measured in serum. The associations were assessed using linear regression models, adjusted for chronological age, sex, body mass index, smoking and sun exposure. Results Across tertiles of the ratio of IGF-1 to IGFBP3, and after adjusting for all potential confounding factors, the mean perceived age decreased from 60·6 years in the lowest tertile to 59·5 years in the highest (Ptrend = 0·045). Similarly, the mean skin wrinkling grade decreased from 4·8 in the lowest tertile to 4·5 in the highest (Ptrend = 0·011). Adding skin wrinkling as a covariate in the analysis between IGF-1 and perceived age diminished this association. Conclusions This study demonstrates that a higher ratio of IGF-1 to IGFBP3 associates with a lower perceived age, via its association with reduced skin wrinkling. Whether high IGF-1 levels actually delay the accumulation of skin wrinkling now needs investigating.
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