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1 Department of Epidemiology, University of Pittsburgh, Pennsylvania.
2 New England Research Institutes, Watertown, Massachusetts.
3 Institute for Research in Extramural Medicine, VU Medical Center, and Institute of Health Sciences, Vrije Universiteit, Amsterdam, The Netherlands.
4 Laboratory for Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland.
5 Department of Medicine, University of Pittsburgh, Pennsylvania.
6 Wake Forest University School of Medicine, Winston-Salem, North Carolina.
7 Department of Preventive Medicine, University of Tennessee, Memphis.
8 Prevention Sciences Group, University of California, San Francisco.
Address correspondence to Anne B. Newman, MD, MPH, University of Pittsburgh, Department of Epidemiology, 130 N. Bellefield Avenue, Room 532, Pittsburgh, PA 15213. E-mail: newmana{at}edc.pitt.edu
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Methods. Total mortality rates were examined in the Health, Aging and Body Composition (Health ABC) Study in 2292 participants (aged 70–79 years, 51.6% women, and 38.8% black). Knee extension strength was measured with isokinetic dynamometry, grip strength with isometric dynamometry. Thigh muscle area was measured by computed tomography (CT) scan, and leg and arm lean soft tissue mass were determined by dual energy x-ray absorptiometry (DXA). Both strength and muscle size were assessed as in gender-specific Cox proportional hazards models, with age, race, comorbidities, smoking status, level of physical activity, fat area by CT or fat mass by DXA, height, and markers of inflammation, including interleukin-6, C-reactive protein, and tumor necrosis factor-
considered as potential confounders.
Results. There were 286 deaths over an average of 4.9 (standard deviation = 0.9) years of follow-up. Both quadriceps and grip strength were strongly related to mortality. For quadriceps strength (per standard deviation of 38 Nm), the crude hazard ratio for men was 1.51 (95% confidence interval, 1.28–1.79) and 1.65 (95% confidence interval, 1.19–2.30) for women. Muscle size, determined by either CT area or DXA regional lean mass, was not strongly related to mortality. In the models of quadriceps strength and mortality, adjustment for muscle area or regional lean mass only slightly attenuated the associations. Further adjustment for other factors also had minimal effect on the association of quadriceps strength with mortality. Associations of grip strength with mortality were similar.
Conclusion. Low muscle mass did not explain the strong association of strength with mortality, demonstrating that muscle strength as a marker of muscle quality is more important than quantity in estimating mortality risk. Grip strength provided risk estimates similar to those of quadriceps strength.
Strength might also predict mortality because it is reduced with disease and deconditioning. For example, lower extremity arterial ischemia can cause lower muscle strength and function (13). Pain from osteoarthritis may prevent activity resulting in atrophy from disuse. Intervention studies show the potential for large improvements in strength with small increases in lean mass (14), illustrating the importance of activity and exercise. Markers of inflammation are also related to lower strength (15) and lean mass, as well as to a decline in strength (16). However, in the Women's Health and Aging Study, comorbidity and inflammatory markers did not explain the association of lower grip strength with mortality (3).
The Health, Aging and Body Composition (Health ABC) Study was designed to determine the role of body composition changes in the risk of poor health outcomes including death and functional limitation in older adults. In this report, we sought to determine whether low muscle mass, measured with computed tomography (CT) scanning and dual energy x-ray absorptiometry (DXA), would explain an association of strength with mortality with and without adjusting for hypothesized causes of sarcopenia, including physical activity, disease, and inflammatory markers. Finally, we were able to compare associations on the basis of isokinetic quadriceps strength versus isometric grip strength.
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Outcome
Total mortality was assessed over 6 years with a mean follow-up of 4.9 (standard deviation [SD] 0.9) years. Surveillance was conducted by in-person examination or telephone interview every 6 months. Hospital records, death certificates, informant interviews, and autopsy data were reviewed by committee to adjudicate immediate and underlying causes of death. The number of individual causes of death was too low to have adequate power to assess risk for cause-specific mortality at this time.
Strength Assessments
Strength was measured using an isokinetic Kin-Com dynamometer (model 125 AP; Chattanooga, TN) for knee extension and an isometric dynamometer (Jaymar, Bolingbrook, IL) for grip strength. For knee extension, the right leg was used unless contraindicated by pain or history of joint replacement. Participants with uncontrolled hypertension, stroke, bilateral knee replacement, or severe bilateral knee pain were excluded from the test (7). Isometric grip strength was assessed for each hand. Participants with severe hand pain or recent surgery were excluded. The vast majority (96%) who had leg strength testing also had grip strength testing. For these analyses, we used the maximum of the force from two trials for the right upper extremity. The ratio of muscle size to strength (specific torque or force) (7) was calculated as a marker of the quality of the muscle and was also considered as a predictor of mortality (7,17).
Body Composition
Lean mass of the upper and lower extremities as well as the total body were assessed using DXA (Hologic QDR 4500, software version 8.21; Waltham, MA). Bone mineral content was subtracted from the total and regional lean mass to define total nonbone lean mass, which represents primarily skeletal muscle in the extremities (18). Fat mass was estimated for the whole body as well. Both the percent fat and total fat were examined in these analyses. With the participant in a hospital gown and no shoes, body weight and height were measured by calibrated balance beam scale and stadiometer, respectively. Body mass index (BMI) in kilograms per meter squared was also examined as a measure of body composition. Analyses of the lower extremities were repeated using cross-sectional muscle and fat areas of the mid-thigh assessed by CT scan (in Pittsburgh: 9800 Advantage, General Electric, Milwaukee, WI; in Memphis: Somatom Plus 4, Siemens, Erlangen, Germany, and PQ 2000S, Marconi Medical Systems, Cleveland, OH) (17). All images were network transferred (Transmission Controlled Protocol/Internet Protocol) and analyzed by a single observer using a Sun workstation (SPARC station II; Sun Microsystems, Mountain View, CA) and proprietary Interactive Data Language development software (RSI Systems, Boulder, CO).
Other Covariates
Age, race, level of physical activity, total number of chronic conditions, smoking status, and field site were all considered as possible confounders of the association between strength and mortality. Physical activity was assessed by self-report as total kilocalories/week spent walking and exercising (19,20). Smoking status was assessed by questionnaire, and participants were classified as current, past, or never smokers. Depression score, assessed with the Center for Epidemiologic Studies-Depression (CES-D) scale (21), was examined as a potential marker of motivation because voluntary assessment of strength was used. Using self-report with confirmation by treatment and medications, we assessed comorbidity as the total number of 11 chronic health conditions. These conditions included cancer, myocardial infarction, congestive heart failure, depression, diabetes, hypertension, knee osteoarthritis, osteoporosis, peripheral arterial disease, pulmonary disease, and stomach and/or duodenal ulcer. Inflammatory markers were assessed from stored fasting blood specimens. Interleukin-6 (IL-6) and tumor necrosis factor- (TNF-) were measured in duplicate using enzyme-linked immunosorbent assay kits (R&D Systems, Minneapolis, MN). C-reactive protein serum levels were also measured in duplicate using enzyme-linked immunosorbent assay based on purified protein and polyclonal anti-C-reactive protein antibodies (Calbiochem, San Diego, CA) (22).
Analysis
Means and proportions were used to describe demographic and key clinical characteristics of the study population. Because there was minimal overlap in strength or body composition between men and women, all analyses were stratified by gender. Quadriceps and grip strength were examined as continuous variables. After assessing the proportionality assumption, we used the Cox proportional hazards model to assess the association between strength and mortality. Hazard ratios (HR) and 95% confidence intervals (CI) are reported. Results were expressed in the full cohort's SD for each strength measure to allow a comparison of the HR for quadriceps strength and for grip strength and between men and women. Separate models were used to first adjust for CT and then DXA body composition measures. Additional potential factors were considered using a forward stepwise procedure to adjust for age, race, height, inflammatory markers, smoking status, comorbidity count, level of physical activity, education, and depression score. Alternative models adjusting for individual health conditions were also examined, but did not change the main findings. Models were also examined with adjustment for BMI as an alternative to the more direct measures of lean and fat mass.
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For both quadriceps and grip strength, the HRs for mortality appeared to be a little higher in women than in men. The CIs overlapped, and there was no evidence for a significant interaction between gender and strength on mortality. Adjustment for BMI yielded risk estimates similar to those shown for adjustment for lean and fat mass by DXA or for muscle and fat areas by CT scan.
Separate models for muscle size by DXA or CT scan were examined to further evaluate the lack of attenuation of strength by muscle size. In men, a lower leg muscle area on CT scan was related to a higher risk of mortality (adjusted HR = 1.26; 95% CI, 1.02–1.55) (Table 3). This was not the case in the women. Lean mass by DXA, either for the lower or the upper extremity, was not related to mortality in men or women. As would be expected from these results, the risks for specific torque or force (Table 4) were similar to those based on strength alone, showing adjusted relative risks 25%–40% higher per SD in both men and women.
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To illustrate the patterns of association between strength and mortality, Kaplan–Meier survival curves were drawn for intervals of both quadriceps (Figures 1 and 2) and grip strength (Figures 3 and 4). The intervals of strength were chosen to approximate a gender-specific SD of strength to provide stable estimates of risk within gender. These figures show that the relationship of strength to mortality could be seen across the range of strength in this nondisabled cohort. There was no statistical evidence of any threshold in the association of either quadriceps strength or grip strength with mortality. Patterns of association were quite similar for both grip strength and quadriceps strength and in both men and women.
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In epidemiological studies, grip strength has been assessed more widely than has leg strength and has been shown to be less strongly associated with age itself than has leg strength (7,8). Nevertheless, grip strength has been shown to be a robust predictor of mortality, even when measured in middle age (23). Grip strength is currently much easier to measure, thus has greater potential than would isokinetic dynamometry for incorporating into clinic practice. However, most studies report HRs based on cohort-specific lowest versus highest tertile or quartile of grip strength, so the exact magnitude of risk is difficult to evaluate across studies. Because there appears to be no threshold in this relationship, it may be helpful to report risk for standard intervals in future studies.
Previous studies have examined only men (1,2), or women (3); most have examined only grip strength, and none has adjusted for direct quantification of muscle area or lean mass as measures of sarcopenia. Nevertheless, all of these studies show consistent findings that suggest that muscle strength is a very important marker of mortality risk in old age. This association remains unexplained by sarcopenia, disease, activity level, and inflammatory markers in this study and in the Women's Health and Aging Study (3). This might be due to inadequate assessment of these factors, but more likely suggests that muscle strength may capture important aspects of the aging process that were not included in this analysis or in other studies. Potentially, strength-related hormonal factors such as testosterone (24) and insulin-like growth factor-I (25,26), which decline with age and strength, might explain why strength appears to be such a powerful marker of risk. Assessment of these factors is in progress in the Health ABC Study.
The loss of motor neurons with aging results in an increase in size of remaining motor units, but with greater preservation of type 1 fibers, resulting in preservation of mass with relatively fewer type 2 fibers, thus lower strength (27). This neurogenic aspect of muscle aging is difficult to study without muscle biopsy, thus we are unable to determine whether this would explain the associations of strength but not mass with mortality.
The strengths of this study are the comparison of men and women and both upper and lower extremity strength, the use of state-of-the-art assessment of regional body composition, and the large number of minorities. DXA lean mass may overestimate lean mass in obese individuals because it includes intermuscular fat as lean mass. The similarity in the DXA and CT results suggests that this potential bias is not a major factor in these associations. To our knowledge, this is the first large epidemiologic study of African Americans. Strength has been shown previously to predict mortality in Caucasians (1), Hispanics, and Asians (2).
There are important characteristics of this study which limit the generalization of these findings. First, the Health ABC Study cohort was nondisabled at baseline. It is quite possible that measures of lean mass may be more important in individuals who are more disabled. Second, only 85% of this cohort was eligible for the isokinetic strength test. Analysis of these findings in the full cohort with grip strength alone was virtually identical, thus the exclusions do not appear to have biased the findings reported.
This study has important implications for clinical practice and future research. First, it shows that muscle function can be used to assess mortality risk without accounting for muscle size, and validates the use of grip strength against leg strength, which better isolates a specific muscle group but is harder to measure. Second, it demonstrates clearly that lower lean mass is not a predictor of mortality, thus cannot explain the strength–mortality association. These results do not explain why strength predicts mortality. More detailed assessment of lifelong activity; subclinical diseases; perhaps cognition, hormonal, or genetic factors; and of the primary changes in muscle with age are needed.
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Received January 28, 2005
Accepted July 30, 2005
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170 Nm). Intervals of 40 Nm of quadriceps strength were used to approximate men's standard deviation = 33.8 and to distribute the number of events
