Background Decreased handgrip strength has been reported to be a risk factor for all-cause death among the elderly. However, it is unclear whether handgrip strength measured in midlife is associated with risk of all-cause and cause-specific death in the general population.
Methods We followed, prospectively, a total of 2527 community-dwelling Japanese (1064 men and 1463 women) aged ≥40 years for 19 years. Participants were divided into three groups according to the age-specific and sex-specific tertiles of handgrip strength (T1, lowest; T3, highest).
Results During the follow-up period, 783 participants died, of whom 235 died of cardiovascular disease, 249 of cancer, 154 of respiratory disease and 145 of other causes. In the middle-aged group (40–64 years), multivariable-adjusted HRs (95% CIs) for all-cause death were 0.75 (0.56 to 0.99) in T2 and 0.49 (0.35 to 0.68) in T3 compared with T1 as a reference. Corresponding HRs (95% CI) in the elderly group (≥65 years) were 0.50 (0.40 to 0.62) and 0.41 (0.32 to 0.51), respectively. As regards the cause of death, higher levels of handgrip strength were significantly associated with decreased risks of cardiovascular death, respiratory death and death from other causes, but not of cancer, in the middle-aged and the elderly.
Conclusions Our findings suggest that handgrip strength levels in midlife and late life are inversely associated with the risks of all-cause and non-cancer death in the general Japanese population.
- Cohort studies
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Handgrip strength, one of various indicators which reflect whole-body muscle strength, has been measured in many epidemiologic studies because it is a simple, easy and inexpensive way to evaluate muscle strength. Some population-based prospective studies have shown that handgrip strength levels were inversely associated with increased risks of all-cause death1–13 and cardiovascular death.1 ,2 Similarly, in a meta-analysis of observational studies, higher handgrip strength was associated with a lower risk of all-cause mortality.14 In general, handgrip strength reaches its peak in the decade between the ages of 30 and 39 years, and then decreases with age after the age of 40 years.15 ,16 Therefore, the association of handgrip strength levels with mortality risk may differ between midlife and late life. However, most previous studies have reported the influence of late-life handgrip strength in an elderly population (approx ≥65 years),2–8 ,17 and only a small number of studies have examined the association between midlife handgrip strength and mortality risk.1 ,10–13 ,18 Moreover, the influence of midlife handgrip strength on the risk of cause-specific death is still unclear.
The aims of the present study were to investigate the association of levels of handgrip strength with the risks of all-cause and cause-specific death in a general Japanese population, and to compare the influence of handgrip strength in the middle-aged (40–64 years old) and in the elderly (≥65 years old).
A population-based prospective study of cardiovascular and malignant diseases has been underway since 1961 in the town of Hisayama, a suburb of the Fukuoka metropolitan area of Kyushu Island in southern Japan. In 1988, a baseline examination for the present study was performed in this town. A total of 2742 residents aged ≥40 years (80.9% of the total population in this age group) participated in the examination. Excluded from the study were 168 individuals with a history of stroke, coronary heart disease, or cancer; 45 individuals in whom handgrip strength was not measured; and two individuals who died before follow-up; the remaining 2527 participating individuals (1064 men and 1463 women) were enrolled in the present study.
At baseline examination, handgrip strength was measured using the Smedley Hand Dynamometer (MIS, Tokyo, Japan) according to instructions provided by a public health nurse. The width of the handle was adjusted such that the second phalanx was against the inner stirrup. The participants were encouraged to exert maximal handgrip strength. Two trials were allowed for each hand alternately, and the maximum value among four measurements was used for the analyses.
Each participant completed a self-administrated questionnaire covering medical history, treatments for hypertension and diabetes, smoking status, alcohol intake and leisure-time physical activity. Smoking status was classified into never smokers, former smokers, current light smokers (<20 cigarettes/day), and current heavy smokers (≥20 cigarettes/day). Alcohol intake was categorised into never drinkers, former drinkers, current light drinkers (ethanol intake <34 g/day), and current heavy drinkers (≥34 g/day). Leisure-time physical activity was quantified by the sum of activity time (hours per week) multiplied by the metabolic equivalents (MET) intensity for each activity.19
Resting blood pressure was measured three times with the subject in a sitting position, with a mercury sphygmomanometer at the right upper arm after at least five minutes of rest; the mean of the three measurements was used in the analysis. Diabetes was determined by the administration of antidiabetic treatment, plasma glucose levels (fasting glucose level ≥7.0 mmol/L or postprandial glucose level ≥11.1 mmol/L), or a 75 g oral glucose tolerance test using the 1998 WHO criteria,20 with plasma glucose measured by the glucose-oxidase method. Total cholesterol was determined by an enzymatic autoanalyser. Body height and weight were measured while the subject was wearing lightweight clothing without shoes, and body mass index (BMI) was calculated. Electrocardiogram abnormalities were defined as left ventricular hypertrophy (Minnesota code 3-1), ST segment depression (4-1, 2, or 3), or atrial fibrillation (8-3).
The participants were followed prospectively for 19 years from December 1988 to November 2007 by repeated health examinations and by a daily monitoring system established by the study team, local physicians and members of the town's Health and Welfare Office. Vital status was checked annually by mail or telephone for any subjects who did not undergo regular examination or who moved out of town. Information about death was received via this follow-up system. When a resident died, all medical information related to a participant's illness and death, including hospital charts, physician's records and death certificate, were collected. Moreover, autopsy was performed at the Kyushu University Departments of Pathology, provided if consent for autopsy had been obtained. All medical information and autopsy findings were scrutinised, and the underlying causes of death were determined according to the International Classification of Diseases, 10th Revision (ICD-10). Cause of death was classified into the following categories: cardiovascular death (ICD-10 code of I00-I99), cancer death (C00-C97), respiratory death (J00-J99.8), and death from other causes. During the follow-up period, 783 participants (397 men and 386 women) died, of whom 564 (72.0%) underwent autopsy. Of the deceased persons, 235 (106 men and 129 women) died of cardiovascular disease, 249 (149 men and 100 women) of cancer, 154 (81 men and 73 women) of respiratory disease, and 145 (61 men and 84 women) of other causes. All individuals were completely followed-up for 19 years or until death.
All statistical analyses were performed with SAS V.9.3 software (SAS Institute, Cary, North Carolina, USA). The participants were divided into three groups on the basis of age-specific and sex-specific tertiles of handgrip strength (T1: 12.0 to 39.5, T2: 40.0 to 46.5, and T3: 47.0 to 64.0 kg for middle-aged (40–64 years) men; T1: 0.5 to 18.5, T2: 19.0 to 23.5, and T3: 24.0 to 27.5 kg for middle-aged women; T1: 3.0 to 29.5, T2: 30.0 to 36.5, and T3: 37.0 to 52.0 kg for elderly (≥65 years) men; T1: 0.5 to 16.0, T2: 16.5 to 20.5, T3: 21.0 to 39.0 kg for elderly women). Age- and sex-adjusted mean values of possible risk factors taken as continuous variables were estimated across handgrip strength levels using analysis of covariance, and the prevalence of risk factors taken as categorical variables were adjusted for age and sex by means of the direct method, where overall study population was used as the standard population. Linear trends in the mean values or prevalence of risk factors across handgrip strength levels were tested using linear or logistic regression analysis. The mortality rate was calculated by the person-year method and adjusted for either age or sex using the direct method. The HR and its 95% CI across the tertiles or per 1 SD increment of handgrip strength were estimated using the Cox proportional hazards model with adjustment for potential confounding factors at baseline, namely, systolic blood pressure, use of antihypertensive agents, diabetes, total cholesterol, BMI, smoking status, alcohol intake and leisure-time physical activity, as well as either age or sex. Here, SD of handgrip strength was 7.5 kg for middle-aged men, 5.5 kg for middle-aged women, 8.4 kg for elderly men and 5.7 kg for elderly women. Heterogeneity in the relationship between men and women or between age groups was tested by adding a multiplicative interaction term to the relevant Cox model. Proportions of missing values were less than 1% for all variables in the multivariable model. A two-sided p<0.05 was considered to be statistically significant in all analyses.
This study was conducted with the approval of Kyushu University Institutional Review Board for Clinical Research, and written informed consent was obtained from the participants.
Baseline characteristics of the study population are shown in table 1. Higher handgrip strength levels were associated with younger age, higher diastolic blood pressure, higher total cholesterol, higher BMI, lower prevalence of electrocardiogram abnormalities and increased leisure-time physical activity level.
Table 2 shows the association of all-cause and cause-specific death according to handgrip strength level by sex. In both sexes, the age-adjusted all-cause mortality in the second tertile (T2) and the highest tertile (T3) of handgrip strength was significantly lower compared to the lowest tertile (T1) (all p<0.05). Handgrip strength was inversely associated with the risk of all-cause death, even after adjustment for potential confounding factors. Compared with the T1 of handgrip strength, the multivariable-adjusted HR (95% CI) for all-cause death was 0.81 (0.64 to 1.03) for T2 and 0.70 (0.53 to 0.92) for T3 in the men, and 0.66 (0.52 to 0.85) for T2 and 0.65 (0.50 to 0.84) for T3 in the women. The HR (95% CI) for all-cause death per 1 SD increment of handgrip strength was 0.72 (0.64 to 0.81) in the men and 0.74 (0.66 to 0.82) in the women. Similar associations were observed for cardiovascular death, respiratory death and death from other causes, but not for cancer death. There was no evidence of heterogeneity in the association between men and women (all P for heterogeneity >0.2).
Next, we examined the association between handgrip strength and the risks of all-cause and cause-specific death in the middle-aged (40–64 years) and the elderly (≥65 years) groups (table 3). Here, the men and women were analysed together due to limited statistical power. The all-cause mortality in T2 and T3 was significantly decreased compared to T1 in both age groups (all p<0.05). These associations remained significant even after adjustment for multiple confounding factors. The multivariable-adjusted HR (95% CI) for all-cause death was 0.75 (0.56 to 0.99) for T2 and 0.49 (0.35 to 0.68) for T3 in the middle-aged group and 0.50 (0.40 to 0.62) for T2 and 0.41 (0.32 to 0.51) for T3 in the elderly group. The HR (95% CI) per 1 SD increment for handgrip strength was 0.72 (0.63 to 0.81) in the middle-aged group and 0.63 (0.58 to 0.69) in the elderly group. We observed similar associations for cause-specific mortality, with the exception of cancer death. There was no evidence of heterogeneity in the association between age groups (all p for heterogeneity >0.4).
The sensitivity analysis, which excluded participants who died within 5 years of follow-up, did not generate any substantial discrepancies with the study conclusions (data not shown).
Using data from a 19-year follow-up study of a general Japanese population, we demonstrated that greater handgrip strength levels were associated with a reduced risk of all-cause death in men and women, even after adjustments were made for other conventional risk factors. With regard to the causes of death, handgrip strength levels were inversely associated with the risk of cardiovascular death, respiratory death, and death from other causes, but not with the risk of cancer death. These associations were observed in the middle-aged group as well as in the elderly group.
Many prospective studies in Western2–8 10–13 ,18 and Asian countries1 ,9 ,17 have examined the association between handgrip strength and the risk of all-cause mortality. Most previous studies have reported that handgrip strength is associated with all-cause death in men1 ,2 ,4 ,6 ,9–12 and in women.1 ,4–6 ,8 However, only a few population-based prospective studies have reported the association of handgrip strength levels with risk of cause-specific deaths.1 ,2 ,9 The Adult Health Study in Hiroshima, Japan1 and a cohort study in the UK2 found that elevated levels of handgrip strength were associated with a decreased risk of cardiovascular death, while a similar but non-significant association was found in another Japanese study.9 The Adult Health Study1 also observed a significantly inverse association between handgrip strength and the risk of death from pneumonia. Our findings are in agreement with those of these previous studies. On the other hand, there is no consensus on the association between handgrip strength and cancer death.1 ,2 ,9 While the study in the UK2 observed a significantly inverse association between handgrip strength and cancer death, our study and two other Japanese cohort studies1 ,9 did not observe any such association.
The inverse associations were recognised concerning lower handgrip strength levels and all-cause death in observational studies of elderly populations.2–8 By contrast, there have been a small number of studies on this issue in middle-aged populations, and the findings were inconsistent.1 ,10–13 ,18 The Honolulu Heart Program,10 ,12 which observed Japanese–American men, and the Adult Health Study in Hiroshima, Japan,1 showed a significant inverse association of handgrip strength levels with all-cause death in middle-aged populations. The Mini-Finland Health Examination Survey13 and our present study showed a similar inverse association in the middle-aged and elderly group. On the other hand, the Baltimore Longitudinal Study of Aging11 and the Canadian Fitness Survey18 failed to show a significant association in middle-aged populations. The discrepancy between results for middle-aged populations may be due to differences in background characteristics, such as ethnicity and other confounding factors, and differences between statistical methods used.
To the best of our knowledge, there has been no previous study which examined the association of midlife handgrip strength with the risk of cause-specific mortality. In our study, the level of handgrip strength measured in midlife was associated with the risks of cardiovascular, respiratory and other non-cancer death, as was handgrip strength measured in late life. Therefore, even though the absolute risk of death (shown as mortality rates in table 3) among the middle-aged was much lower than that of the elderly, handgrip strength measured in midlife may be a good predictive marker that could be used to identify people at higher risk of non-cancer diseases, and subsequent risk of mortality.
The mechanisms underlying the association between handgrip strength and risk of all-cause and cause-specific death have not been clearly defined, but a lower level of handgrip strength, which reflects a weaker whole-body muscle strength, is known to be associated with traditional risk factors for death or cardiovascular disease, that is, lower body weight,21 physical inactivity22 and chronic diseases, such as diabetes and hypertension.23 However, our findings showed that the association of handgrip strength levels with all-cause and cardiovascular death remained significant, even after adjustment for these factors. A population-based study reported a positive correlation of handgrip strength with the serum concentration of insulin-like growth factor 1 (IGF-1),24 which is a key regulator of muscle cell proliferation and differentiation, and an inhibitor of cell apoptosis and necrosis.25 Other epidemiological studies have shown an association between decreased IGF-1 concentration and elevated risk of insulin resistance,26 impaired glucose tolerance including type 2 diabetes,27 ischaemic heart disease,28 and mortality.29 Therefore, IGF-1 may potentially mediate the association between muscle strength and risk of cardiovascular death. The mechanisms which account for the link between handgrip strength and respiratory death remain unclear, but a case-control study30 demonstrated that patients with chronic obstructive pulmonary disease, a common cause of respiratory death, had decreased expiratory muscle endurance and lower handgrip strength, compared to control subjects with normal lung function, indicating that weaker handgrip strength may be a marker of reduced respiratory muscle function. In our cohort, pneumonia was also an important cause of respiratory death, and death from other causes primarily included infectious diseases such as sepsis. Lower handgrip strength may reflect lower body weight,21 and may be associated with higher risk of pneumonia and sepsis due to undernourished and immunocompromised conditions.
The strengths of the present study include a longitudinal population-based design, long duration of follow-up, perfect follow-up of the participants, and accurate diagnosis for cause of death on the basis of medical information and autopsy. However, some limitations should be noted. First, handgrip strength levels were determined on the basis of measurements at baseline examination only. Possible changes in handgrip strength levels during the follow-up period were not taken into consideration. Therefore, the risk estimates reported in this study might be underestimated. Second, socioeconomic information, such as educational level and occupation, which might affect the association between handgrip strength and the risk of death, was not available in our cohort. Third, we could not determine the cut-off level of handgrip strength to predict the mortality risk (which might be clinically useful information), because we did not have an adequate number of mortality events to analyse.
In conclusion, handgrip strength levels were associated with the risk of all-cause and cause-specific mortality, except for cancer mortality, in middle-aged and elderly subjects in a Japanese population. Our results suggest that handgrip strength measured in midlife may be a good predictive marker that could be used to identify individuals at high risk for death from non-cancer diseases.
What is already known on this subject
Most previous studies have reported an inverse association between handgrip strength and all-cause mortality in elderly populations (approx 65 years or older).
A small number of studies have evaluated the association of handgrip strength with all-cause mortality in a middle-aged population, and their findings have been inconsistent.
The association of handgrip strength with cause-specific mortality in the middle-aged population has been unknown.
What this study adds
Handgrip strength measured in midlife, as well as in late life, was significantly and inversely associated with the risk of cardiovascular, respiratory and other non-cancer death, and these associations were independent of other potential risk factors.
Handgrip strength levels in midlife may be a good predictive marker for the future risk of non-cancer death.
The authors thank the staff of the Division of Health and Welfare of the Hisayama Town Office for their cooperation in the present study.
Contributors We would like to include nine authors as listed in the title page of the manuscript. This study was a collaboration study among three institutes, and each author made an important and remarkable contribution to this study. With regard to author's contributions, Hiro Kishimoto contributed to the study concept, design, data collection, interpretation of data, statistical analysis, and writing the manuscript. Jun Hata contributed to study concept, design, data collection, interpretation of data, and revising the manuscript. Toshiharu Ninomiya, Hajnalka Nemeth, Yoichiro Hirakawa, and Daigo Yoshida contributed to data collection, interpretation of data, and revising the manuscript. Shuzo Kumagai, Takanari Kitazono, and Yutaka Kiyohara were study coordinators and contributed to the study performance, obtaining funding, study concept, design, interpretation of data, and revising of manuscript.
Funding This study was supported in part by Grants-in-Aid for Scientific Research on Innovative Areas (22116010) and for Scientific Research (A) (25253048 and 22240073), (B) (25293428), and (C) (23590797, 23590798, 23500842, 24590797, 24590796, and 25460758) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by Health and Labour Sciences Research Grants of the Ministry of Health, Labour and Welfare of Japan (Comprehensive Research on Life-Style Related Diseases including Cardiovascular Diseases and Diabetes Mellitus: H22-Junkankitou (Seishuu)-Ippan-005, H23-Junkankitou (Seishuu)-Ippan-005, H25-Junkankitou (Seishuu)-Ippan-005, H25-Junkankitou (Seishuu)-Ippan-009, and H25-Junkankitou (Seishuu)-Sitei-022; and Comprehensive Research on Dementia: H25-Ninchisho-Ippan-004).
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of Kyushu University Institutional Review Board for Clinical Research, and written informed consent was obtained from the participants.
Provenance and peer review Not commissioned; externally peer reviewed.
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