The Author Published by Oxford University Press on behalf of The Gerontological Society of America.

Journal of Gerontology: MEDICAL SCIENCES The Author 2011. Published by Oxford University Press on behalf of The Gerontological Society of America. Cite journal as: J Gerontol A Biol Sci Med Sci. 2012 May;67A(5):523 529 All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. doi:10.1093/gerona/glr183 Advance Access published on October 19, 2011 Mobility-Related Fatigue, Walking Speed, and Muscle Strength in Older People Minna Mänty, 1,2 Carlos F. Mendes de Leon, 3 Taina Rantanen, 4 Pertti Era, 4,5,6 Agnes N. Pedersen, 7 Anette Ekmann, 8 Marianne Schroll, 9 and Kirsten Avlund 1,2,8 1 Section of Social Medicine, Department of Public Health and 2 Center for Healthy Aging, University of Copenhagen, Denmark. 3 Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA. 4 Gerontology Research Centre, Department of Health Sciences, University of Jyväskylä, Finland. 5 GeroCenter Foundation for Research and Development, Kinkomaa, Finland. 6 Department of Rehabilitation, Central Finland Health Care District, Jyväskylä, Finland. 7 Department of Nutrition, National Food Institute, Technical University of Denmark, Copenhagen, Denmark. 8 Danish Aging Research Center, Universities of Odense, Aarhus, and Copenhagen, Denmark. 9 Research Centre for Prevention and Health, Glostrup University Hospital, Denmark. Address correspondence to Minna Mänty, PhD, Section of Social Medicine, Department of Public Health, University of Copenhagen, Øster Farimagsgade 5, PO Box 2099, DK-1014 Copenhagen K, Denmark. Email: mrma@sund.ku.dk Background. Fatigue is an important early marker of functional decline among older people, but the mechanisms underlying this association are not fully understood. The purpose of the present study was to examine the association between mobility-related fatigue and walking speed and to test the degree to which muscle strength accounts for this association. Methods. The study is based on baseline (n = 523) and 5-year follow-up data (n = 292) from a cohort of 75-year-old persons. Standardized assessments include self-report measures of mobility-related fatigue (score range 0 6) and medical history, as well as performance-based assessment of walking speed and maximal isometric strength of knee extension, body extension, and handgrip. Results. In the cross-sectional baseline analysis, one unit increase in fatigue score was associated with 0.03 m/s (b =.03, p <.001) and 0.05 m/s (b =.05, p <.001) slower maximum walking speed among women and men, respectively, while adjusting for important covariates. Among women, muscle strength accounted up to 21% and among men up to 24% for the association. In the prospective analysis, fatigue at baseline was predictive of change in walking speed among men (b =.04, p <.001) but not among women (b =.005, p =.64). Among men, muscle strength accounted up to 15% for the association between baseline fatigue and change in maximum walking speed. Conclusions. Mobility-related fatigue is associated with slower walking speed in older adults. The results suggest that muscle strength is one of the underlying factors explaining this association. Key Words: Fatigue Aging Walking Mobility limitation Muscle strength. Received May 30, 2011; Accepted September 8, 2011 Decision Editor: Luigi Ferrucci, PhD THERE has been a growing interest in fatigue as an early marker of aging-related declines in health and functional abilities (1 3). Fatigue is a commonly reported symptom in older people (1), which has been associated with sedentary lifestyle, poor functional performance and higher levels of disability (4 10). In addition, several prospective studies have shown that perceived fatigue in daily activities is a robust predictor of subsequent functional decline in older adults (11 15). Despite the predictive value of selfreported fatigue, there is a limited understanding of the mechanisms that underlie the association between fatigue and functional decline in old age. Impaired mobility is another important risk factor for functional decline. Walking is a fundamental part of everyday living, and limitations in walking increase the risk for disability (16), dependency (17,18), and mortality (17,19). Sufficient muscle strength is an essential prerequisite for walking (20 25), and declining muscle strength is considered an important component in the causal pathway between impaired mobility and the development of functional limitations, frailty, and disability (26 29). Reduced muscle function may also contribute to feelings of fatigue when performing mobility-related tasks, such as walking and climbing stairs. This raises the possibility that declining muscle strength accounts for part of the association between fatigue and functional limitations. However, few studies to date have addressed muscle strength as an underlying factor for fatigue (5,30,31), and the role of muscle strength in the 523

524 MÄNTY ET AL. association between fatigue and functional limitations is unknown. In this study, we first examine the association between mobility-related fatigue and walking speed, a key indicator of overall mobility (16 19), and then test the degree to which muscle strength accounts for this association. Methods Study Design and Participants This observational study is based on the baseline and 5-year follow-up data of the Nordic Research on Aging Study (NORA) (32). The original study population (n = 835, 59% women) consisted of a random sample of 75-yearold persons living in Glostrup, a suburban area of Copenhagen, Denmark (n = 480), and of all 75-year-old citizens living in Jyväskylä, Finland (n = 355). During the 5-year follow-up, a total of 213 persons died (26%) and 95 persons (11%) were lost for other reasons, mostly due to refusal. The study design, participation rates in different parts of the study, as well as drop-out analyses have been published in detail elsewhere (32). The present study is conducted among participants with full information on all the variables used and those who reported having independent mobility at baseline, leaving a total of 523 participants (55% women) for the baseline and 292 participants (57% women) for the prospective analyses. In this study sample, participants who did not complete the follow-up measurements tended to have slightly poorer health and physical function as compared with those who completed the follow-up analyses (data not shown). Measurements At both sites, all assessments were carried out using identical standard protocols. The outcome measure, maximum walking speed, and specific tests of muscle strength were measured in a laboratory at each site. Face-to-face interviews were conducted at participants homes and included structured questions on perceived fatigue and other covariates. All measurements were done at baseline and maximum walking speed again at 5-year follow-up. Maximum walking speed. The outcome measure, maximum walking speed, was assessed over a distance of 10 m. Participants were allowed 5 m for acceleration before the start line, and they were encouraged to walk as fast as possible. Participants wore walking shoes or sneakers, and use of a walking aid was allowed if needed. Walking time was measured with a stopwatch, and maximal walking speed was calculated by dividing distance over time (meters per second). Fatigue. Mobility-related fatigue was defined as a subjective feeling of fatigue in mobility tasks required for independent community living. It was measured using a structured and previously validated instrument, the Avlund Mobility-Tiredness scale (33,34). Participants were first asked whether they were able to perform the following six mobility tasks with or without help of another person: (a) rising from a chair or bed, (b) walking indoors, (c) getting outdoors, (d) walking outdoors in a nice weather, (e) walking outdoors in a bad weather, and (f) climbing stairs. Participants who were able to manage the tasks independently were further asked if they felt fatigued after performing them. Fatigue on individual tasks were summed for a total fatigue score (range 0 6), with higher scores indicating higher levels of fatigue. Participants who were unable to manage the tasks independently were excluded from the current study (n = 72). Muscle strength. Measures of muscle strength included tests of grip strength, knee extension, and trunk extension that were carried out at both centers using identical adjustable dynamometers and standard protocols (35,36). Maximum isometric handgrip strength and knee extension strength were measured on the side of the dominant hand in a sitting position. Grip strength was measured using a dynamometer fixed to the arm of the adjustable chair. Maximum isometric knee extension strength was measured at an angle of 60 degrees from fully extended knee joint toward flexion. Maximum isometric trunk extension strength was measured in a standing position with a shoulder-level strain-gauge system. Participants were allowed up to three practice trials, followed by three measurements with an intertrial test period of 1 minute. The best result of the three trials was used for analysis (Newton). Each measure of muscle strength was converted to a z score based on the genderand site-specific distribution of the muscle strength data. For descriptive purposes only, muscle strength variables were coded as low (below the median) versus high (above the median). Covariates. Information on the number of chronic diseases was collected during the face-to-face interviews at baseline. The answers were checked during the medical examination by a physician and coded using the World Health Organization s International Classification of Diseases (ICD-8). The presence of depressive symptoms was assessed using the Center for Epidemiologic Studies Depression scale (score range 0 60). For descriptive purposes, a cutoff score of 16 was used to identify subjects with depressed mood (37). Physical activity was evaluated with a single question about the frequency of participation in sports, and responses were categorized into sedentary (monthly or less often) or active (more often). Income was defined as low (only old age pension) versus high (old age pension plus other sources of income). Body weight and height were measured at the laboratory. For descriptive purposes, body mass index (BMI, kilograms per square meter) was calculated, and participants with a BMI 30 were considered obese.

FATIGUE, WALKING SPEED, AND MUSCLE STRENGTH 525 Statistical Analyses The role of muscle strength in the association between fatigue and walking speed was examined using linear regression models. Each of the three muscle strength variables was added into a model adjusted for important covariates and percent reduction in the fatigue estimate was calculated. A gender- and site-specific z score for each of the muscle strength variable was used. In addition to cross-sectional associations, predictive values of fatigue and muscle strength on aging-related changes in walking speed were studied using prospective 5-year follow-up data. Change in walking speed from baseline to follow-up was calculated, and all models were adjusted for walking speed at baseline. We tested for potential bias regarding baseline adjustment in the analyses of change (38) by replicating our follow-up analyses without adjusting for baseline walking speed. The effects observed in these analyses suggested no substantial differences due to baseline adjustment, supporting the reliability of the results presented in this article. Gender-by-fatigue and gender-by-muscle strength interactions on maximum walking speed at baseline and follow-up were found to be nonsignificant (p values >.05). However, all analyses were performed stratified by gender due to previously observed significant gender differences in the prevalence of mobility-related fatigue (1) and the incidence of walking restrictions in this study population (39). Analyses were performed using SAS software version 9.2 (SAS Institute Inc., Cary, NC). Results Baseline descriptive data are presented in Table 1. More than half (56%) of the participants were women. Among women and men, mean maximum walking speed at baseline was 1.5 ± 0.3 (SD) and 1.7 ± 0.4 m/s, respectively. Around two thirds of women (62%) and half of men (49%) reported fatigue in at least one mobility task. The mean values for knee extension, body extension, and grip strengths among women were 259 ± 76, 335 ± 135, and 247 ± 68 N, respectively, and among men 408 ± 106, 589 ± 193, and 421 ± 94 N, respectively. Walking speed was higher in men, in those with high income, in physically active participants, in participants without obesity or depressive symptoms, and those with fewer chronic conditions, lower levels of fatigue, and higher muscle strength (Table 1). Cross-Sectional Analyses Mobility-related fatigue was significantly associated with maximum walking speed at baseline (Table 2). Among women and men, one unit increase in the fatigue score was associated with 0.03 and 0.05 m/s slower maximum walking speed (b =.034, p <.001 and.051, p <.001), respectively, while adjusting for site, chronic diseases, depressive symptoms, physical activity, income, weight, and height (Model 3). Table 1. Maximum Walking Speed (meters per second) at Baseline According to Descriptive Baseline Data Characteristic N (%) Women Walking Speed (m/s) (SD) N (%) Men Walking Speed (m/s) (SD) Total 289 (100) 1.52 (0.29) 234 (100) 1.74 (0.39) Study site Glostrup, Denmark 142 (49) 1.49 (0.27) 159 (68) 1.69 (0.37) Jyväskylä, Finland 147 (51) 1.54 (0.31) 75 (32) 1.84 (0.41) Income High 262 (91) 1.53 (0.29) 209 (89) 1.75 (0.39) Low 27 (9) 1.42 (0.34) 25 (11) 1.64 (0.37) Physical activity Active 120 (42) 1.57 (0.26) 105 (45) 1.81 (0.37) Sedentary 169 (58) 1.47 (0.31) 129 (55) 1.68 (0.39) Obesity* No 223 (77) 1.56 (0.28) 207 (88) 1.76 (0.39) Yes 66 (23) 1.37 (0.32) 27 (12) 1.62 (0.39) Number of chronic conditions 0 72 (25) 1.58 (0.26) 87 (37) 1.85 (0.34) 1 95 (33) 1.54 (0.25) 75 (32) 1.70 (0.37) 2 122 (42) 1.46 (0.33) 72 (31) 1.64 (0.43) Depressive symptoms No 204 (71) 1.54 (0.27) 188 (80) 1.75 (0.39) Yes 85 (29) 1.45 (0.33) 46 (20) 1.68 (0.39) Fatigue No fatigue 108 (38) 1.61 (0.30) 120 (51) 1.86 (0.35) Fatigue in 1 3 102 (35) 1.53 (0.23) 58 (25) 1.70 (0.41) activities Fatigue in 4 6 79 (27) 1.37 (0.31) 56 (24) 1.53 (0.35) activities Muscle strength Knee extension High 145 (50) 1.58 (0.27) 117 (50) 1.80 (0.36) Low 144 (50) 1.45 (0.30) 117 (50) 1.67 (0.41) Body extension High 144 (50) 1.63 (0.25) 116 (50) 1.89 (0.38) Low 145 (50) 1.40 (0.29) 118 (50) 1.60 (0.35) Grip strength High 144 (50) 1.56 (0.30) 117 (50) 1.78 (0.39) Low 145 (50) 1.48 (0.29) 117 (50) 1.70 (0.38) Note: *Body mass index (BMI, kilograms per square meter) 30. CES-D score 16, CES-D = Center for Epidemiological Studies Depression scale. Muscle strength, High = above the median, Low = below the median. To test the role of muscle strength between the association of fatigue and walking speed, each muscle strength variable was added one at the time into Model 3 and percent reductions in the fatigue estimate were calculated. Among women, knee extension strength accounted for 12% (Model 4), body extension strength 18% (Model 5), and grip strength 6% (Model 6) of the association between mobility-related fatigue and maximum walking speed. The corresponding numbers for men were 12%, 28%, and 4%. In all these models, fatigue remained significantly associated with maximum walking speed (Table 2). Finally, we added all three muscle strength variables in the same model (Model 7). Among women and men, the reduction in the fatigue estimate was 21% and 24%, respectively, whereas fatigue remained significantly associated

526 MÄNTY ET AL. Table 2. Cross-Sectional Association of Mobility-Related Fatigue and Muscle Strength With Maximum Walking Speed (meters per second) at Baseline Women (n = 289) Men (n = 234) b SE p Value Change (%)* b SE p Value Change (%)* Model 1 Fatigue.047 0.008 <.001.066 0.011 <.001 Model 2 Fatigue.047 0.008 <.001.062 0.011 <.001 Model 3 Fatigue.034 0.008 <.001.051 0.011 <.001 Model 4 Fatigue.030 0.008 <.001 12.045 0.011 <.001 12 Knee extension strength.084 0.016 <.001.114 0.023 <.001 Model 5 Fatigue.028 0.007 <.001 18.037 0.010 <.001 28 Body extension strength.128 0.015 <.001.185 0.021 <.001 Model 6 Fatigue.032 0.008 <.001 6.049 0.011 <.001 4 Grip strength.041 0.017.008.117 0.025 <.001 Model 7 Fatigue.027 0.008 <.001 21.039 0.010 <.001 24 Knee extension strength.026 0.018.156.018 0.025.486 Body extension strength.115 0.017 <.001.162 0.027 <.001 Grip strength.002 0.016.912.033 0.026.204 Notes: Model 1 = Nonadjusted; Model 2 = Adjusted for site; Model 3 = Model 2 + number of chronic diseases, depressive symptoms (CES-D score), physical activity, income, weight, and height; Model 4 = Model 3 + knee extension strength; Model 5 = Model 3 + body extension strength; Model 6 = Model 3 + grip strength; Model 7 = Model 3 + knee extension strength, body extension strength, and grip strength. CES-D = Center for Epidemiological Studies Depression scale. * Change (%) of the estimate b from the Model 3. Fatigue score (range 0 6). Gender- and site-specific z score for muscle strength. with maximum walking speed (b =.027, p <.001 and.039, p <.001). Prospective Analyses Among women and men, mean change in maximum walking speed during the 5-year follow-up was 0.23 ± 0.24 and 0.20 ± 0.28 m/s, respectively. Mobility-related fatigue at baseline was significantly associated with decline in maximum walking speed during 5-year follow-up among men but not among women (Table 3). Among men, one unit increase in the fatigue score measured at baseline was associated with 0.04 m/s decline in maximum walking speed (b =.041, p <.001) during follow-up while adjusting for site, walking speed at baseline, chronic diseases, physical activity, income, weight, and height (Model 3). Knee extension strength accounted for 12% (Model 4), body extension strength 7% (Model 5), and grip strength 10% (Model 6) of the association between mobility-related fatigue at baseline and change in maximum walking speed during follow-up. Among men, all three muscle strength variables combined in the Model 7 reduced the fatigue estimate by 15%. In all these models, fatigue remained significantly associated with change in maximum walking speed during follow-up (Table 3). Discussion Considering that muscle strength is an important determinant of the ability to walk (20 25) and that weakening muscle strength might be an underlying factor for fatigue (5,30,31), we hypothesized that muscle strength may partly explain the association between mobility-related fatigue and functional decline. Our results support this hypothesis by showing that in older adults, mobility-related fatigue is associated with declines in walking speed and that muscle strength is one of the underlying factors explaining this association. Knee extension, body extension, and grip strength measures were studied as potential factors explaining the association between fatigue and walking speed. Sufficient knee extension strength is needed for mobility and body strength to give postural stability. Both can be considered as good measures to identify high-functioning people from their frail counterparts. For example, higher knee extension strength has been shown to be associated with better walking ability (20,22,23,40) and together with good balance protective of the development of severe walking limitations (21) and further disability (35). Grip strength has often been used as an indicator of overall body strength, and it is considered a useful measure to identify frail older adults at risk for further functional decline (35,41). Our results further suggest that knee and body extension strengths explain a greater amount of the cross-sectional relationship between fatigue and walking speed than grip strength. All three strength measures were found to be strong determinants of walking speed. Although grip strength has been shown to be a predictor of functional

FATIGUE, WALKING SPEED, AND MUSCLE STRENGTH 527 Table 3. The Association of Fatigue and Muscle Strength Measured at Baseline With Change in Maximum Walking Speed (meters per second) During 5-year Follow-up Women (n = 167) Men (n = 125) b SE p Value Change (%)* b SE p Value Change (%)* Model 1 Fatigue.003 0.010.751.038 0.012.001 Model 2 Fatigue.008 0.010.452.042 0.011 <.001 Model 3 Fatigue.005 0.010.642.041 0.012 <.001 Model 4 Fatigue.009 0.011.371.036 0.012.003 12 Knee extension strength.031 0.021.142.036 0.024.139 Model 5 Fatigue.005 0.010.617.038 0.012.002 7 Body extension strength.060 0.021.005.062 0.026.021 Model 6 Fatigue.004 0.011.693.037 0.012.003 10 Grip strength.015 0.021.488.062 0.028.027 Model 7 Fatigue.005 0.010.615.035 0.012.005 15 Knee extension strength.018 0.023.444.011 0.027.677 Body extension strength.055 0.023.020.046 0.029.112 Grip strength.006 0.022.773.048 0.029.098 Notes: Model 1 = nonadjusted; Model 2 = adjusted for baseline maximum walking speed and site; Model 3 = Model 2 + number of chronic diseases, depressive symptoms (CES-D score), physical activity, income, weight, and height; Model 4 = Model 3 + knee extension strength; Model 5 = Model 3 + body extension strength; Model 6 = Model 3 + grip strength; Model 7 = Model 3 + knee extension strength, body extension strength, grip strength. CES-D = Center for Epidemiological Studies Depression scale. * Change (%) of the estimate b from the Model 3 (was not calculated for women due to nonsignificant association). Fatigue score (range 0 6). Gender- and site-specific z score for muscle strength. decline (35,41), it does not involve musculature that is directly related to walking. Our results corroborate the previous research findings on the importance of fatigue as an early indicator of functional decline (11,12) and muscle strength as a strong predictor of walking ability (20 23). For example, in the cross-sectional analyses, a single-unit increase in the 6-item fatigue score was associated with 0.03 and 0.05 m/s slower walking speed among women and men, respectively. These results are highly comparable to the previously reported estimates for small (0.05 m/s) and substantial (0.10 m/s) meaningful changes in walking speed in older adults (42). However, our follow-up results also indicate that there might be important gender differences regarding mobility-related fatigue and its association to functional decline. One previous study (43) on 15- to 64-year-old general practice patients has suggested that fatigue among women is typically associated with psychosocial and sociodemographic factors, whereas among men, fatigue is more strongly related on physical aspects of health. Because our outcome was walking speed, a measure of physical function, it is plausible that the differences observed in our prospective analyses may partly reflect the potential gender differences in the factors underlying self-reported mobility-related fatigability. However, these gender differences have rarely been investigated and need to be clarified in future studies. In the perspective of disability prevention, it is essential to gain a better understanding of the factors explaining the association between fatigue and functional decline (44). The present results indicate that muscle strength is one of the potentially modifiable factors affecting this association. Physical exercise, in particular progressive resistance training, has been shown to be effective in increasing muscle strength and promoting physical functioning among older people (45). However, further research is needed to confirm the effectiveness of strength training among older adults with fatigue. In addition, knowledge of other factors that may mediate the relationship between fatigue and functional decline would help to develop more effective multidisciplinary interventions to prevent and alleviate mobility decline among those reporting fatigue. For example, other physiological factors, such as poor cardiovascular function, chronic pain, or declined energy availability (46), as well as various biological, cognitive, and psychosocial mechanisms should be investigated (1 3). Furthermore, the associations between depressive symptoms, mobility-related fatigue, and functional decline need to be clarified. The NORA data set used in this study consists of participants from two Nordic towns, Jyväskylä, Finland, and Glostrup, Denmark. It has been reported earlier (39) that there are no significant differences between these two samples in physical performance measured at baseline or in the rate of

528 MÄNTY ET AL. decline observed during follow-up. However, the proportion of participants reporting fatigue has been shown to be somewhat higher among the Danish than in the Finnish study participants (47). When we repeated the present analysis after stratifying by site, we found essentially the same results in each sample (data not shown), supporting the reliability of our results obtained from the analysis of combined data set. When interpreting the results, some limitations and strengths of the study should be considered. We used cross-sectional data for our primary analysis because of the larger sample size. The follow-up data provided an opportunity to analyze the degree to which muscle strength accounts for the association between mobility-related fatigue and change in walking speed. Although these prospective analyses may be more informative from an inferential perspective, they are limited by the relatively high degree of attrition in this cohort during the 5-year follow-up, and we therefore consider these more as exploratory analyses. Furthermore, the exact causal associations between declining muscle strength, fatigue, and loss of function are likely to be complex, and studies with more frequent assessments are needed to delineate the exact mechanisms by which fatigue leads to declining mobility. The study was conducted among relatively highfunctioning older women and men in a cohort from a single birth year from two Nordic localities, and further studies are needed to examine the generalizability of our findings to a wider age range and other populations. The strengths of the study are a well-characterized cohort with standardized measures of mobility-related fatigue, muscle strength, and performance-based physical function. In conclusion, the present findings suggest that mobilityrelated fatigue is associated with slower walking speed in older men and women and that muscle strength is one of the underlying factors explaining this association. Furthermore, our longitudinal findings indicate that there might be important gender differences regarding mobility-related fatigue and its association to future functional decline. Other potential factors contributing to this association as well as gender differences need to be addressed in future studies. Funding Nordea-fonden, The Danish Medical Research Council, Denmark; Academy of Finland, Ministry of Education, Ministry of Social Affairs and Health, Social Insurance Institution, City of Jyväskylä, Finland. Acknowledgments All authors report no financial or personal conflicts of interest. References 1. Avlund K. Fatigue in older adults: an early indicator of the aging process? Aging Clin Exp Res. 2010;22:100 115. 2. Alexander NB, Taffet GE, Horne FM, et al. 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