Gender differences in the association between grip strength and mortality in older adults: results from the KORA-age study

The results of our study demonstrate that low handgrip strength is associated with all-cause mortality among older men and women from the general population after controlling for significant confounders, including age, nutritional status, number of prescribed drugs, diseases and level of physical activity. Further, we observed gender-specific differences with HRs being more than twice as high in women than in men. However, gender differences were not statistically significant, possibly because of the relatively small number of deaths especially in women.

Few studies have examined the effect of gender on the association between muscle strength and mortality with inconsistent findings [7, 10, 13, 14, 21, 22]. In three of them, muscle strength was not predictive of mortality in women [7, 14, 22], whereas three other studies [10, 13, 21] reported a significantly increased risk of mortality for women in the lowest quartile of grip strength. In the above studies, only three studies adjusted for physical activity [7, 21, 22]. We included level of physical activity, medical status and number of prescribed drugs, and we also accounted for nutritional status, all of which are independent predictors of mortality, in our final model. Although nutritional status was significantly associated with mortality (p-value = 0.01) and with grip strength (p-value = 0.0014), it was only a modest confounder of the association between grip strength and mortality. The HR in the full model without adjustment for nutritional status was 3.21 (1.48–6.98) for the first tertile versus the third tertile. Our results extend the limited literature by showing that, compared with men, it appears to be more important for older women to enhance their levels of muscular strength in order to reduce the risk of all-cause mortality [10, 13, 21]. The presence of chronic diseases commonly underlying death, nutritional status and physical activity did not explain the association, indicating that muscle strength may predict mortality through other mechanisms, such as factors secreted from the muscle cells, classified as myokines, which may protect against premature death [23].

In addition, little is known about the level of muscular strength required to protect against the risk of premature death. Data from the Aerobic Center Longitudinal Study, a prospective study of 8,762 men aged between 20 and 80 years, reported similar risk reductions in people with medium versus high muscular strength [9, 12], suggesting that having high levels in comparison with moderate levels of muscular strength does not provide additional protection. Indeed, in our study, men showed an elevated risk of mortality only when they had low levels of muscular strength (<30 kg), whereas women tended to show a higher risk of all-cause mortality with moderate muscular strength (between 18 and 24 kg) compared with those in the highest tertile of muscular strength. However, it has to be kept in mind that none of the individual HRs was statistically significant and, therefore, larger studies examining possible dose–response relationships and gender differences are urgently needed. The question arises whether the initial level or the rate of change in grip strength is more predictive of mortality. Danish data revealed significantly greater change for grip strength in men compared with women in later life, whereas the decline in grip strength was non-linear in women with a more pronounced decline with increasing age [24]. The data further suggested that the initial level of grip strength was more predictive of mortality than the rate of change, and the predictive effects were similar in men and women.

Our results suggest that older women are more sensitive to muscle strength alterations throughout ageing, probably as a result of sex differences in muscle mass as well as hormonal factors [25, 26]. It seems to be particularly important for the weakest to enhance their levels of muscular strength and build up muscle mass early in life, where targeted preventative efforts may be launched, to reduce their risk of premature death. On the other side, however, small improvements in strength levels (moving from the low to the middle tertile) may translate into great benefits in mortality risk reduction. Ultimately, randomized clinical trials with interventions aiming to increase muscular strength have to demonstrate whether increases in muscle strength at older ages indeed translate into reduced mortality rates.

The underlying mechanisms behind the benefits of muscular strength on mortality are still unclear but appear to be multifactorial. As there is a strong association between muscle strength and skeletal muscle mass, which is unquestionably a major tissue responsible for blood glucose disposal on account of its sheer size and ability to respond to insulin, the decline in muscle mass with age is linked to an increased risk of metabolic diseases such as type 2 diabetes associated with substantial premature death [27]. The findings of a recent study of 4,066 individuals, aged 20–85 years, revealed that, for every 0.05 decrement in grip strength (normalized as strength per body mass), there was a 1.26 times increased adjusted odds of diabetes in men and women [28]. The gender- and age-specific weakness thresholds to detect diabetes were lower in women than in men. In the past few years, skeletal muscle has been identified as a secretory organ producing and releasing several cytokines in response to contraction, which have been named myokines; these can influence the metabolism and function of muscle tissue and may counteract the harmful effects of proinflammatory adipokines [23]. Indeed, associations between chronic low-grade inflammation and sarcopenia are observed quite consistently, and inflammatory markers showed negative associations with both muscle mass [29] and strength [30, 31], as well as physical function [32]. Recent findings from the KORA-Age Study demonstrate higher concentrations of interleukin-6 and hs-CRP in older individuals with lower levels of muscular strength, independent of disease state, suggesting that the muscular system per se is effective in reducing low-grade inflammation [33]. Visceral fat has a high metabolic activity with deleterious effects on health contributing to muscle weakness and the frailty syndrome [34]. For example, the Baltimore Longitudinal Study of Aging has demonstrated in 786 individuals with a mean age of 66.3 years that adiposity is a significant predictor of lower muscle quality and strength [35]. The Toledo Study for Healthy Aging, a prospective study of 1,741 individuals aged ≥65 years, found a gender-specific nonlinear relationship between waist to hip ratio (WHR, a measure of central adiposity) and muscle strength [36]. In women, a normal BMI combined with either high or low WHRs were associated with a decrease or increase in strength, respectively. In contrast, men achieved their maximum strength at a WHR around 1 and the highest BMI. Thus, muscle strength may be determined by the relationship between WHR and BMI depending on gender. According to the Falls Risk and Osteoporosis Longitudinal Study in 171 men and women, aged 60–88 years old, better diet quality in females is associated with lower BMI and fat mass and higher lean mass, compared with males who appear to have better physical function, are less likely to self-report falls risk and have a better fat distribution, i.e. a lower android/gynoid ratio, which was significantly associated with better diet quality [37]. Moreover, low handgrip strength is a strong predictor of falls [38] and osteoporotic fractures [39], physical disability and frailty [40], which in turn have been found to be related to increased mortality risk [41]. It is, therefore, important for clinicians to be able to identify patients for whom low muscle strength is an important cause of their weakness because they are the most likely to benefit from therapies such as resistance training through enhanced muscle mass but also improved neural factors including motor unit recruitment and synchronization [42]. Thus, the assessment of grip strength could be a useful tool in clinical practice to identify older people with very low muscle strength at the greatest risk of all-cause mortality.

This study has several strengths and limitations. A major strength of this study was the prospective design, the inclusion of a number of participants aged ≥80 years and the use of an objective and standardized test for the assessment of maximal muscular strength. Limitations of the study are the relatively small sample size and short follow-up time. However, in old age, muscle atrophy can proceed dramatically, and even relatively small changes in muscle strength may have a significant impact on predictors of mortality such as glucose disposal, low-grade inflammation and osteoporotic fractures. Although we have adjusted for several confounding factors such as age, nutritional status, physical activity and chronic diseases, we were unable to adjust for cardiorespiratory fitness, which has been shown to be an independent predictor of all-cause mortality. Finally, as this is an observational study, we could only assess statistical associations and not causal relationships. Ultimately, randomized intervention studies aiming to increase muscular strength in older adults have to show whether the observed associations are causal and whether premature death can be prevented by increasing muscular strength.

The findings of this study suggest that low muscle strength is inversely associated with mortality in old age, independent of potential confounders including age, nutritional status, number of prescribed drugs, chronic diseases and level of physical activity. This association tended to be stronger in women. Thus, the implementation of resistance exercise training for the weakest may be a promising means of reducing the adverse effects of low muscle strength on mortality and should be further tested in randomized clinical trials.