Frailty has a stronger association with inflammation than age in older veterans
In the present study we sought to determine the relative effect of age compared with frailty on markers of inflammation and coagulation in older adults. We observed significant elevations in pro-inflammatory cytokines as well as the inflammatory index among older adults who were pre-frail or frail. While age was associated with some of the markers studied, in particular the inflammatory index, these associations were not present within frailty groups. Additionally we also observed that the variability in inflammatory markers was explained to a much greater extent by frailty status than age. Coagulation markers fibrinogen and D-dimer, on the other hand, were not significantly different among frailty groups but did correlate with age. These correlations persisted among those with intact functional status. Age appeared to explain the variability in coagulation markers more than frailty.
Similar to prior studies we found elevations in IL-6, SAA, TNFR1 and TNFR2 levels among those with functional decline [4, 12, 14, 24, 25]. A measure validated in older adults, the inflammatory index, which incorporates two of these markers, has recently been shown to be independently associated with frailty among aging HIV-infected and uninfected injection drug users [26]. We also found the inflammatory index scores to be significantly increased in frail and pre-frail older adults. Interestingly, unlike a previous report where the greatest differences between IL-6, TNF-? and CRP levels were seen between the pre-frail and frail adults [27], we did not see any significant differences between PF and frail subjects. In our cohort, pre-frail inflammatory profile more closely resembled that of frail subjects than those that were still functionally intact. While both the PF and frail groups were significantly older than NF group, we showed that in fact age did not explain variations in inflammatory markers as much as frailty status. This finding may indicate that even before functional decline becomes clinically apparent, the pro-inflammatory phenotype has already been set in motion.
Age was associated with increased TNFR1 and TNFR2, but unlike previously cited studies we did not find IL-6 or CRP levels to be significantly associated with age in this cohort over 60 years of age. The data presented in this study focused on those over the age of 60. When subjects of all ages were included in the analysis, IL-6 did correlate with age. Aging was associated with increasing inflammatory index score in our study, as has previously been shown [19]. However, age was not associated with the inflammatory index, or any other markers, when frailty groups were examined separately. This finding was confirmed by comparing the percentage of variability in markers explained by age vs. frailty. Frailty status had consistently greater association with inflammation than did age. Interestingly, this trend seemed to persist for most inflammatory markers, particularly IL-6, inflammatory index and CRP, even after controlling for comorbid conditions. This suggests that while chronic inflammation is a feature of aging looking over the entire age span, the inflammatory milieu is closely linked with frailty such that irrespective of chronologic age, frailty phenotype maybe a stronger predictor of chronic inflammation. However, as with other cross-sectional studies demonstrating association between frailty and inflammation, our study provides no insights into causality. It has been hypothesized that chronic inflammation may be the driving force behind functional decline and may form the biologic basis of age-associated conditions including frailty [28, 29]. Elevated levels of IL-6 have been linked to multiple age-associated conditions, such as atherosclerosis [30], dementia [31] and frailty [32], however causality and pathogenesis is yet to be proven. It is also plausible that increased levels of inflammatory cytokines maybe a compensatory mechanism in frailty and other age-associated conditions. Inflammatory response maybe triggered by chronic viral infections such as cytomegalovirus or other herpes viruses [33]. We were unable to link CMV chronic infection to inflammation due to very low numbers of seronegative subjects in our study. It is also possible that markers of inflammation are simply a byproduct of another causal mechanism of frailty such as excessive oxidative stress. Frailty in older adults has been associated with superoxide anion overproduction by nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase and low-grade chronic inflammation [2]. Biomarkers of oxidative stress have also been associated with frailty in the Framingham Offspring Study, suggesting oxidative stress as the underlying mechanism contributing to frailty [34]. Whether targeted interventions at preventing functional decline may result in an improved pro and anti-inflammatory balance, regardless of age of the patient remains to be established.
We also tested the associations between frailty and age among markers of coagulation. In the present cohort there were no differences between D-dimer and fibrinogen levels among frailty groups. Prior studies have linked D-dimer and other markers of activated coagulation with limitation in functional abilities [4, 35]. It has been proposed that aging represents a pro-thrombotic state and that some of the markers of coagulation and thrombosis begin to rise early during the process of aging, suggesting a potential usefulness as markers for frailty [3]. We did find aging to be not only associated with both these coagulation markers but also more strongly associated with a pro-thrombotic state than frailty status. This association was present even after controlling for comorbid conditions. Surprisingly, when age was examined within frailty groups, the association remained very strong but only among non-frail subjects. This suggests that while aging results in a pro-thrombotic state, its effect maybe less pronounced in those who already have evidence of functional decline.
This study not only provides further evidence of association between frailty and inflammation but also demonstrates that chronological age maybe less important than functional ability when it comes to chronic inflammation among older adults. Further studies are not only needed to establish the nature of this association but also to investigate the effects of interventions to prevent functional decline or modulate the inflammatory cytokines in an effort to prevent age-associated conditions.