We examined associations between inflammatory biomarkers and physical function in older adults with various diseases/conditions. Our data show that increased CRP and IL-6 were associated with poorer physical function, independent of age, gender, race, and body composition. Most importantly, the associations between physical function and inflammation were generally independent of disease status. Specifically, these associations were consistent among individuals with COPD, CHF, high cardiovascular risk, and self-reported disability, but no major illnesses, with a few exceptions where the relationship between inflammation and physical function was not uniform across studies. Of note, the relationship between CRP and SPPB was different in the POWER study (disease-free participants at risk for disability), whereas the relationships between TNF-α and SPPB and chair rise time were different in the PIE study (CHF patients). The reasons for these differences are not readily apparent. Nevertheless, although previous cross-sectional studies show that increased inflammatory biomarker concentrations in the elderly are related to impaired physical function (15
), this study is the first to report an association between inflammation and physical function using standardized measures across multiple study populations.
There is substantial evidence of an association between physical function and inflammation in a number of chronic disorders of the elderly. For example, muscle loss and wasting are associated with chronic systemic inflammation in COPD (21
). Similarly, elevated cytokine concentrations in CHF patients are associated with reduced muscle mass and strength (22
). Additionally, inflammatory biomarkers are strong independent risk factors for cardiovascular disease and predict cardiovascular outcomes, disability, and mortality in older persons (23
). By performing uniform clinical assessments across multiple study populations, our results provide further evidence that chronic inflammation and impaired physical function are strongly related in various age-related diseases/health conditions.
In the present study, we could not reject the null hypothesis that TNF-α was not associated with physical function. Given that TNF-α was not measured in the TRAIN study (n
= 289), the sample size for TNF-α was smaller than the other two biomarkers (IL-6 and CRP). The highest partial correlation we found between TNF-α and physical function was −.08 after adjusting for age, gender, race, and study; thus, we would need at least 1,250 participants in order to have adequate power to detect the effect of TNF-α. We calculated confidence intervals for the regression coefficient estimates so as to gain some insight on interpreting the results (data not shown). We found that the associations with TNF-α were generally much smaller than those for CRP and IL-6, suggesting that the relationship between TNF-α and physical function may simply be weaker in our study population. In patients with knee osteoarthritis, associations with physical function have been reported to be stronger for circulating levels of TNF-α receptors than for TNF-α itself (17
). Soluble TNF-α receptors are able to modulate TNF-α activity (24
) and may therefore modify its association with physical function and disease severity indicators. Because cytokines such as TNF-α are generally less stable in circulation over time than their receptors (25
), soluble cytokine receptors could potentially be more reliable markers of the inflammatory response.
The association between inflammation and functional impairment may be partially due to the catabolic effect of inflammatory cytokines on muscle. For example, in humans, there is a positive correlation between whole-body protein breakdown and TNF-α production (26
). Additionally, myosin heavy chain protein synthesis rates are inversely correlated with muscle TNF-α expression (27
), as well as plasma levels of CRP and IL-6 (28
). In rats, direct infusion of TNF-α induces skeletal muscle protein degradation (8
). Similarly, IL-6 infusion results in muscle atrophy and a loss of myofibrillar protein (9
). Thus, elevated inflammatory biomarkers may contribute to functional decline and physical disability via decreases in skeletal muscle protein content and loss of muscle mass and strength.
Inflammatory biomarkers may also have an effect on physical function by promoting age-related changes in body composition, primarily fat gain and muscle loss. It was previously reported that the relationship between inflammation and sarcopenia was mostly explained by obesity (14
). Although increased fat mass contributes to increased production of inflammatory cytokines, which in turn contribute to muscle catabolism and loss of muscle mass, we found that the associations between inflammation and physical function generally remained significant even after adjusting for lean mass, fat mass, percent body fat, or BMI. These results indicate that inflammatory biomarkers have an independent effect on physical function.
The major limitation of this study is that it is cross-sectional, and therefore, we cannot determine the underlying mechanisms for the observed association between inflammatory biomarkers and physical function. In addition, we were not able to fully account for anti-inflammatory medication use, although participants in the TRAIN study (more than half of the combined study population) were not on these medications. Moreover, although we studied patients with diseases/health conditions that are common in older individuals, these findings may not be applicable to all aging-related diseases. Nevertheless, the strength of the current investigation lies in the use of standardized measures and common resources across multiple study populations.
In conclusion, we found that increased concentrations of CRP and IL-6 were associated with impaired physical function in older adults with various diseases/conditions. Our data suggest that higher levels of inflammatory cytokines may be a marker of functional limitations in older persons across several diseases/health conditions. It is also possible that elevated inflammatory cytokine concentrations are markers of increased disease severity or other underlying factors that may drive the association between inflammation and physical function. Given the prevalence of low-grade inflammation in older persons, interventions aimed at reducing inflammatory biomarker concentrations may help slow the decline of physical function with age and disease.