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1 Department of Medicine, Gallagher, Dympna, Marjolein Visser, Ronald E. De Meersman,
Dennis Sepúlveda, Richard N. Baumgartner, Richard N. Pierson, Tamara Harris, and Steven B. Heymsfield. Appendicular skeletal muscle mass: effects of age, gender, and ethnicity. J. Appl. Physiol. 83(1): 229-239, 1997.
body composition; total body potassium; aging
AGING IN BOTH ANIMALS AND HUMANS is associated with a
loss of skeletal muscle mass and a decline in muscle function (3, 32).
Skeletal muscle atrophy and functional impairment with senescence in
humans may be associated with osteoporotic fractures (28), the
prolonged disability that accompanies hospitalizations for acute
illness, falls with subsequent injury, and the frailty with inactivity
often observed in geriatric populations (13).
Although skeletal muscle loss with aging in humans is well documented,
several unresolved questions remain that relate to the magnitude of
loss and whether gender and ethnic differences exist in the
age-associated muscle decline. The first concern is that earlier
investigations of skeletal muscle in humans were based largely on
methods of questionable validity (14, 33). Two such methods, urinary
creatinine excretion and total body potassium (TBK), assume that muscle
is the sole or main source of intracellular creatine (30) and potassium
(31), respectively. Recent studies challenge these assumptions (14, 33)
and raise concerns related to the use of these methods in estimating
age-related muscle loss.
An attempt was made to improve the use of TBK as a marker of skeletal
muscle by devising a two-compartment method based on TBK and total body
nitrogen (TBN) (5). This method assumes that the TBK-to-TBN ratios in
skeletal muscle and nonskeletal muscle lean tissues are known and
constant (6). A recent study suggests, however, that skeletal muscle
mass estimates derived from the TBK-TBN method are substantially lower
than that observed by using whole body multislice computerized
tomography (33).
Much of the present understanding of skeletal muscle mass and aging is
based on studies of urinary creatinine (33) and TBK (10, 22, 23) in
adult populations. Questions surrounding the validity of these methods
in accurately quantifying skeletal muscle mass raise concerns about the
interpretation of earlier studies of skeletal muscle in relation to
aging, gender, and ethnicity.
A second limitation associated with earlier investigations of changes
in skeletal muscle mass with aging is the inadequate control of factors
known to influence muscle, such as body weight and stature. Older
subjects in some studies were shorter and weighed more or less than
their younger counterparts (7, 22, 23). The independent influence of
these important factors on skeletal muscle mass is usually not
considered, and the prevailing hypothesis is that skeletal muscle mass
is relatively reduced in the elderly. A related concern is that little
is known about how women and men compare across the age span with
regard to loss in muscle mass. Women on average weigh less and are
shorter than men (19), and, in most previous studies, between-gender
comparisons of skeletal muscle did not adequately control for body
weight, stature, and age differences (7).
The third concern is that much of what is documented about skeletal
muscle mass was derived from persons of Caucasian ethnicity, and there
is relatively little information available on other ethnic groups.
African-Americans may have different total amounts of skeletal muscle
at any given age compared with Caucasian subjects (12, 21), and there
may be ethnic differences in the relative loss of skeletal muscle with
aging as there are with bone mineral (20).
The recent introduction of dual-energy X-ray absorptiometry (DEXA)
provides a new opportunity to study the appendicular portion of
skeletal muscle mass in vivo. Appendicular skeletal muscle accounts for
>75% of total body skeletal muscle (31) and is the primary portion
of skeletal muscle involved in ambulation and physical activities.
Earlier studies from our laboratory (15, 33) and from other research
groups (17) support the validity of DEXA estimates of appendicular
skeletal muscle. An important advantage of DEXA over previous skeletal
muscle mass-measuring methods is its capability of providing separate
estimates of lower and upper extremity appendicular muscle components
(17).
The primary purpose of this study was to test the hypothesis that
skeletal muscle is reduced in the elderly after appropriate control for
body weight and stature. A second study aim was to test the hypothesis
that TBK reliably represents skeletal muscle mass.
Study Design
Examination of TBK was intended to bridge the many earlier studies of
skeletal muscle based on TBK to the present research effort. The
analysis was carried out in two stages. First, we examined the
independent effect of age on TBK in the cross-sectional cohort after
controlling first for stature and body weight. The independent effects
on TBK of gender and ethnicity were also examined as they were for
appendicular skeletal muscle mass. In the second stage of analysis, we
established in our cohort how much of the observed variation in TBK
could be explained by total appendicular skeletal muscle (TASM) mass
and other potential independent TBK determinants such as age, gender,
and ethnicity.
Subjects
This study
tested the hypothesis that skeletal muscle mass is reduced in elderly
women and men after adjustment first for stature and body weight. The
hypothesis was evaluated by estimating appendicular skeletal muscle
mass with dual-energy X-ray absorptiometry in a healthy adult cohort. A
second purpose was to test the hypothesis that whole body
40K counting-derived total body
potassium (TBK) is a reliable indirect measure of skeletal muscle mass.
The independent effects on both appendicular skeletal muscle and TBK of
gender (n = 148 women and 136 men) and
ethnicity (n = 152 African-Americans and 132 Caucasians) were also explored. Main findings
were 1) for both appendicular
skeletal muscle mass (total, leg, and arm) and TBK, age was an
independent determinant after adjustment first by stepwise multiple
regression for stature and weight (multiple regression model
r2 = ~0.60);
absolute decrease with greater age in men was almost double that in
women; significantly larger absolute amounts were observed in men and
African-Americans after adjustment first for stature, weight, and age;
and >80% of within-gender or -ethnic group between-individual
component variation was explained by stature, weight, age, gender, and
ethnicity differences; and 2) most
of between-individual TBK variation could be explained by total
appendicular skeletal muscle
(r2 = 0.865),
whereas age, gender, and ethnicity were small but significant additional covariates (total
r2 = 0.903). Our
study supports the hypotheses that skeletal muscle is reduced in the
elderly and that TBK provides a reasonable indirect assessment of
skeletal muscle mass. These findings provide a foundation for
investigating skeletal muscle mass in a wide range of health-related conditions.
Body Composition
Appendicular skeletal muscle. Body weight was measured to the nearest 0.1 kg (Weight Tronix, New York, NY) and height to the nearest 0.5 cm by using a stadiometer (Holtain; Crosswell, Wales). Total body fat, fat-free body mass, and TASM were measured with whole body DEXA (DPX, Lunar Radiation, Madison, WI). Software version 3.4 was used to analyze all of the DEXA scans. The calculation of appendicular skeletal muscle mass has been previously described in detail (15). With the use of specific anatomic landmarks, the legs and arms are isolated on the skeletal X-ray planogram (anterior view). The arm encompasses all soft tissue extending from the center of the arm socket to the phalange tips, and contact with the ribs, pelvis, or greater trochanter is avoided. The leg consists of all soft tissue extending from an angled line drawn through the femoral neck to the phalange tips. The system software provides the total mass, ratio of soft tissue attenuations, and bone mineral mass for the isolated regions. The ratio of soft tissue attenuation for each region was used to divide bone mineral-free tissue of the extremities into fat and fat-free components. The fat and bone mineral-free portion of the extremities were assumed to represent appendicular skeletal muscle mass along with a small and relatively constant amount of skin and underlying connective tissues. Leg skeletal muscle (LSM) mass and arm skeletal muscle (ASM) mass represent the sum of both right and left extremities, respectively. TASM was taken as the combined sum of LSM and ASM. Repeated daily measurements over 5 days in four subjects showed a coefficient of variation (CV; means ± SD) of 2.4 ± 0.5% for LSM, 7.0 ± 2.4% for ASM, and 3.0 ± 1.5% for TASM. Earlier studies indicate that African-American subjects have significantly greater skeletal muscle mass (12) and longer appendicular bone lengths (1, 12, 21) compared with Caucasian subjects. The possibility therefore exists that longer extremities in African-American subjects might explain their greater appendicular skeletal muscle mass after adjustment for covariates such as height, weight, age, and gender. We therefore also included in our multiple-regression models measurements of appendicular bone lengths. The skeletal X-ray planogram generated by the DEXA scan was used specifically to measure tibia length, femur length, humerus length, and total subject skeletal lengths. All dimensions were measured in millimeters by a single reader by using an engineering caliper (Staedtler, Frankfurt, Germany). Total skeletal length was measured as the distance from the apex of the cranium to the plantar surface of the calcaneus bone. Appendicular bone lengths were measured from the proximal to the distal end of the bones; tibia length from the lateral condyle to the medial malleolus; femoral length from the greater trochanter to the lateral epicondyle; and humerus length from the greater tubercle to the lateral epicondyle. These dimensions do not correspond precisely to anatomic bone lengths, although all measurements were consistent among subjects. The ratio of tibia plus femur length to total subject skeletal length was used as an index of relative leg length. The ratio of humerus length to total subject skeletal length was used as an index of relative arm length.TBK
The St. Luke's 4-
whole body counter was used to measure
40K (25). The
40K raw counts accumulated over 9 min were adjusted for body size on the basis of a
42K calibration equation (26). The
within-subject CV in our laboratory for
40K counting is 4% (26). TBK was
calculated as TBK (mmol) = 40K
(mmol)/0.0118.
Statistical Analysis
Data were analyzed by using the Statistical Analysis System (SAS; release 6.10, SAS Institute, Cary, NC). Differences between ethnic groups were tested by using Student's t-tests. Pearson's correlation coefficients were used to establish the univariate relationships between total and regional skeletal muscle mass and age. Pearson's correlation coefficients adjusted for age were used to establish the relationships between total and regional skeletal muscle mass and other body composition components, as well as subject demographic characteristics. The relationships between skeletal muscle measurements and height, weight, age, and ethnicity were investigated by using multiple-regression analysis. TASM, LSM, and ASM were used as dependent variables and height, weight, age, ethnicity, and extremity lengths were used as independent variables in the multiple-regression models. In addition, potential interaction terms and nonlinear relationships were explored for selected variables. Statistical significance was set at P < 0.05 by using a two-sided P value. Group subject data are expressed as means ± SD.Baseline Characteristics
The baseline subject characteristics are summarized in Table 1. The African-American women as a group were older (P = 0.04), weighed more (P = 0.0003), and had a higher BMI (P = 0.0001) compared with the Caucasian women. There were no significant differences in height between African-American and Caucasian women. Relative leg length was significantly (P = 0.0001) greater in African-American women compared with their Caucasian counterparts.
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African-American men were, on average, older (P = 0.009) and shorter (P = 0.05) compared with Caucasian men. There were no significant differences between the two groups of men in body weight and BMI. African-American men had relatively longer legs (P < 0.0001) compared with Caucasian men.
Age-Adjusted Appendicular Skeletal Muscle Associations
There were significant negative correlations between most of the appendicular skeletal muscle components and age in all four groups (Table 2). After adjustment for the effects of age, TASM mass, LSM, and ASM were all significantly and positively correlated with body weight (all P = 0.001) and fat-free body mass (all P = 0.001) in African-American and Caucasian women and men. TASM and LSM were also positively correlated with height (P = 0.001) in African-American and Caucasian women and men. ASM mass was positively correlated with height in African-American women and men (P = 0.001) and in Caucasian women (P = 0.005).
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TASM and LSM were negatively associated with age in African-American (P = 0.01) and Caucasian (P = 0.001) women and men. ASM was negatively associated with age in Caucasian men (P = 0.0002) only.
TBK was also negatively associated with age in both African-American (P = 0.001) and Caucasian women (P = 0.01) and men (P = 0.001). After adjustment for the effects of age, TBK was positively correlated with TASM (P = 0.001) in all four subgroups.
Appendicular Skeletal Muscle Mass Models
In each of the following sections we develop appendicular skeletal muscle mass (TASM, LSM, and ASM) multiple-regression models. A composite analysis section is then provided that summarizes the salient features of the three appendicular skeletal muscle multiple regression models. TASM mass. TASM mass multiple-regression models for the four subgroups (African-American women and men; Caucasian women and men) and two combined groups (total women and men; total African-American and Caucasian subjects) are presented in Table 3. These models explore the independent effects on TASM of height, weight, age, gender, and ethnicity.
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), African-American women (AAW;
), Caucasian men (CM;
),
and African-American men (AA:
). Linear regression lines (top to bottom): dashed line, AA; dotted line,
CM; solid line, AAW; dashed line, CW. CW: TASM =
0.06 (age) + 21.37 kg, r = 0.43, n = 68. AAW: TASM =
0.07 (age) + 23.87 kg, r = 0.37, n = 80. CM: TASM =
0.10 (age) + 32.52 kg, r = 0.52, n = 64. AAM: TASM =
0.10
(age) + 32.07 kg, r = 0.33, n = 72.
GENDER. After adjustment for height, body weight, and age, men had larger TASM compared with women in both African-American and Caucasian subjects (P = 0.0001) across the entire age range studied. The interaction term age × gender contributed significantly to the model containing height, body weight, and age in Caucasian subjects (P = 0.02), suggesting that the decrease in TASM with greater age is larger in men than in women. The age × gender interaction was of borderline significance (P = 0.13) in African-American subjects. ETHNICITY. After adjustment for height, body weight, age, and gender, African-American women and men had greater TASM compared with Caucasian women and men (both P = 0.0001). The lower TASM with greater age was, however, not significantly different among African-American and Caucasian women (P = 0.94) and men (P = 0.52). LSM mass. LSM mass multiple-regression models for the subgroups and combined groups are presented in Table 4. These models explore the independent effects on LSM of height, weight, age, gender, and ethnicity.
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0.05 (age) + 16.75 kg,
r = 0.48, n = 68. AAW: LSM =
0.05 (age) + 18.38 kg, r = 0.42, n = 80. CM: LSM =
0.07 (age) + 23.92 kg, r = 0.48, n = 64. AAM: LSM =
0.08 (age) + 25.79 kg, r = 0.33, n = 72.
GENDER. In African-American and Caucasian subjects, men had greater LSM compared with women (P = 0.0001), independent of height, weight, and age. Gender tended to interact with age in Caucasian (P = 0.09) and African-American subjects (P = 0.15), suggesting a greater magnitude reduction in LSM with older age in men compared with women. ETHNICITY AND LOWER LIMB LENGTHS. After adjustment for height, body weight, and age, African-American subjects had more LSM than Caucasian subjects (women, P = 0.0001; men, P = 0.0004). Relative leg length alone was significantly correlated with LSM in women (r = 0.30, P < 0.001), and this association was of borderline significance (r = 0.14, P < 0.10) in men. When relative leg length was added to the multiple-regression model, it contributed significantly (P = 0.02) in men. African-American men thus had greater LSM than Caucasian men (P = 0.0034) after adjustment for ethnic differences in lower limb length. The decrease in LSM with greater age was similar in African-American and Caucasian men and women. ASM mass. ASM mass multiple-regression models for the subgroups and combined groups are presented in Table 5. The models presented explore the independent effects on ASM of height, weight, age, gender, and ethnicity.
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0.01 (age) + 4.61 kg,
r = 0.23, n = 68. AAW: ASM =
0.01 (age) + 5.50 kg, r = 0.53, n = 80. CM: ASM =
0.04 (age) + 8.61 kg, r = 0.46, n = 64. AAM: ASM =
0.02 (age) + 8.72 kg, r = 0.23, n = 72.
GENDER. After adjustment for body weight and age, men had more ASM compared with women in both ethnic groups (P = 0.0001). In Caucasian subjects the interaction term gender × age was significant (P = 0.005), once again suggesting a larger magnitude decrease in muscle mass with greater age in Caucasian men compared with Caucasian women (Fig. 3). The age-gender interaction term was not statistically significant in African-American subjects. ETHNICITY AND ARM LENGTH. After adjustment for body weight and age, African-American women and men had significantly more ASM than did Caucasian subjects. Relative arm length alone was not significantly correlated with ASM in either women or men. Relative arm length contributed significantly to the multiple regression model in women (P = 0.03) and was of borderline significance in men (P = 0.07). That is, ethnic differences in ASM were still apparent in women and men after adjustment for relative arm length, with African-American subjects having more ASM compared with Caucasian subjects. The decrease in ASM with greater age was not significantly different between African-American and Caucasian women (P = 0.59). Composite summary. For TASM and LSM, height, body weight, age, gender, and ethnicity each contributed independently to the respective multiple-regression models. ASM was similar, except that height did not contribute significantly to the models. After adjustment for height and body weight, men had greater TASM, LSM, and ASM (all P = 0.001) than women across the entire age span. Within each ethnic group, height, body weight, age, and gender accounted for 80-88% of between-subject differences in appendicular skeletal muscle. African-American subjects had greater TASM, LSM, and ASM than Caucasian subjects of equivalent height, body weight, age, and gender. This is shown for the hypothetical Reference Woman and Reference Man (see Table 7). The table provides appendicular skeletal muscle mass estimates for subjects ages 20-70 yr on the basis of data presented in Tables 3-5. After adjustment for height (TASM and LSM only), weight, and age, 20-yr-old African-American women have ~1.4 (7.3%), 1.0 (6.3%), and 0.4 kg (9.6%) more TASM, LSM, and ASM, respectively, than their Caucasian counterparts. Similarly, African-American men have 2.0 (7.4%), 1.3 (6.6%), and 0.72 kg (9.8%) more TASM, LSM, and ASM, respectively, than Caucasian men. The ethnic differences in appendicular skeletal muscle mass persisted even after adjustment for the significantly longer appendicular lengths in African-American subjects.
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0.08,
0.05, and
0.03 kg/yr for TASM, LSM, and ASM, respectively) than in women
(
0.04,
0.03, and
0.01 kg/yr) (see Table 7). The
Reference Woman would have a 2.0 kg or ~10.8% (in both ethnic
groups) decrease in appendicular skeletal muscle between the ages of 20 and 70 yr. The decrease in TASM between the ages of 20 and 70 yr for the Reference Man is 4.0 kg or ~14.7%. The absolute decrease in appendicular skeletal muscle mass with greater age is thus larger in
men than in women, whereas, in relative terms, the gender differences persisted but were smaller in magnitude.
The multiple-regression models also suggest a gender difference in
skeletal muscle distribution. This observation is evident in the
appendicular skeletal muscle mass estimates for the Reference Woman and
Reference Man (see Table 7). LSM is ~80 and 73% of TASM in women and
men, respectively. The ratio of LSM to ASM for the Reference Woman and
Reference Man is ~3.6 and ~2.6, respectively. Accordingly, it would
appear that women have a larger proportion of their appendicular
skeletal muscle located in the lower extremities than men.
TBK Models
The TBK multiple regression models for the subgroups and combined groups are shown in Table 6. The models presented explore the independent effects on TBK of height, weight, age, gender, and ethnicity.
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9.30
(age) + 2,781 meq, r = 0.53, n = 68. AAW: TBK =
13.34 (age) + 3,173 meq, r = 0.54, n = 80. CM: TBK =
16.23 (age) + 4,487 kg, r = 0.63, n = 64. AAM: TBK =
20.20 (age) + 4,734 meq, r = 0.51, n = 72.
Gender. Men had relatively more TBK than women in both African-American and Caucasian subjects (P = 0.0001). The interaction term gender × age contributed significantly to the regression model in both African-American (P = 0.020) and Caucasian (P = 0.004) subjects, indicating a larger reduction in TBK with greater age in men compared with women. Ethnicity. A significant ethnic difference in TBK, after adjustments for other covariates, was apparent in women (P = 0.0053). According to the model, African-American women had a larger TBK compared with Caucasian women. The lower TBK with greater age was similar for African-American and Caucasian women (P = 0.12) and men (P = 0.34). African-American men also had a greater TBK than Caucasian men, although the difference was not statistically significant (P = 0.29). Composite summary. Unlike TASM models, the TBK models showed no significant dependency on body weight within three of the four subgroups. Like TASM models, the TBK models showed significant dependencies on age, gender, and ethnicity (women only), and the decrease in TBK with increasing age was greater in men than in women. Within each ethnic group, height, weight, age, and gender accounted for 81-87% of between-individual TBK differences.
TBK-Appendicular Skeletal Muscle Comparison
TBK was strongly correlated with TASM. For example, in all subjects combined, simple linear regression of TBK vs. TASM gave an r of 0.93 (P < 0.001; standard error of the estimate = 87 meq), indicating that TASM explained 86.5% of between-individual differences in TBK. Three independent variables added significantly to the model, i.e., age, gender, and ethnicity, although the increase in r (to 0.95) and explained variance (90.3%) was not very large.The primary purpose of the present study was to quantitatively test the hypothesis that, after adjustment for stature and body weight, skeletal muscle is significantly lowered in the elderly. To accomplish this purpose and to explore other independent determinants of skeletal muscle, we developed age-, gender-, and ethnic-specific appendicular skeletal muscle mass multiple-regression models that appropriately adjust for subject height and weight.
An additional purpose was to test the hypothesis that TBK provides an indirect measurement of appendicular skeletal muscle mass in vivo. This hypothesis is based on the observation that a large proportion of TBK (~60%) is found in skeletal muscle tissue. Many earlier studies evaluated TBK as a measure of skeletal muscle mass, and our purpose in developing TBK multiple- regression models was twofold. Our first question was whether these models gave a qualitatively similar view of skeletal muscle determinants like TASM. A second, and related, concern was how comparable our TBK models were to those developed over the past four decades in both cross-sectional and longitudinal cohorts.
Our results indicate that, after adjustment for stature and body weight, age is a significant independent determinant of appendicular skeletal muscle mass. Additionally, we found that gender and ethnicity (i.e., African-American and Caucasian) also independently determine an individual's appendicular skeletal muscle mass. A qualitatively similar pattern is observed with TBK, although our findings suggest that, to a certain extent, age, gender, and ethnicity moderate the TBK-TASM relationship.
Skeletal Muscle Mass and TBK Determinants
Height and weight. Our observations indicate that height and weight are the main determinants of appendicular skeletal muscle mass. Although there was some variation between the four subgroups, height and weight together explained almost two-thirds of between-individual variation in TASM. Height alone was a stronger determinant of TBK within each of the subgroups, explaining from one-fourth to one-half of between-individual variation. It is reasonable that stature and appendicular skeletal muscle mass are closely related. Taller subjects with longer extremity bones would be expected to have greater muscle weights. Similarly, heavier subjects, who require greater appendicular skeletal muscle mass for extremity movement, would be expected to have more muscle than their lean counterparts. Our modeling results suggest that linear relationships exist among the mass of appendicular skeletal muscles, stature, and body weight. Age. Our findings with respect to age were twofold: after adjustment for stature and weight within each subgroup, older subjects had less appendicular skeletal muscle than younger subjects, and, in absolute terms, the decrease in appendicular skeletal muscle mass with increasing age was greater in men than in women. These findings, in a relatively large cross-sectional cohort, corroborate a substantial body of earlier literature indicating reductions in or loss of lean body mass, fat-free body mass, and skeletal muscle as indicated by elemental analysis (TBK and/or TBN) (4, 6, 8, 10, 23), urinary creatinine excretion (10, 32), and anthropometry (26). Our findings suggest a linear decline in TASM of ~0.4 kg/decade in women and 0.8 kg/decade in men (Table 7). A significant reduction in TBK with greater age was also observed (78 and 163 meq/decade in women and men, respectively). Linkage with earlier studies. The TBK observations are notable because a large body of earlier studies inferred an age-related loss in skeletal muscle or lean mass. Unfortunately, most of these studies did not control adequately for covariates such as stature and body weight so that quantitative estimates cannot be made for the independent effects of aging on body composition. We reasoned that the results of these earlier studies might be similar to our own, and thus findings across studies might be generalizable. To explore this possibility, we used our TBK regression models to estimate TBK on the basis of height, weight, and subject age as published in relevant earlier cross-sectional studies (Table 8). We then compared TBK estimates from our models to measured TBK in each of the studies as a means of establishing whether similar findings apply across all investigations. The earlier studies were selected from a broad body of literature extending from 1965 to the present and are intended to be representative of both American (7, 8, 22) and European (4, 23) populations on whom TBK data are available. As shown in Table 8, the observed TBK ranged from 1 to 22% and from 1 to 8% of values derived by using TBK regression models in the present study for women and men, respectively. Older persons in earlier studies had less TBK (8-33%) than younger persons, this being true for both women (8-15%) and men (17-33%). Similar consistencies were observed between studies with regard to gender differences in TBK, with men having greater absolute amounts (31-46%) compared with women.
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