In this study, we have observed, for the first time, a significant association of elevated serum neopterin levels with prevalent frailty in community-dwelling older adults, adjusting for age, race, sex, education and BMI. Moreover, the observed association is independent of IL-6 levels, a pro-inflammatory cytokine that is known for its association with frailty.
Neopterin is a marker of monocyte/macrophage-mediated immune activation in humans. We have recently shown that neopterin level increases with age [13
]. An Austrian study in a large cohort of healthy blood donors has suggested the mean value ±standard deviation (SD) of serum neopterin levels of 9.7 ±5.0 nM in persons aged 75 years and above [12
]. Consistent with these reports, older adults included in the present study had a mean ±SD of 9.66 ±4.21 nM. The currently observed results—that frail participants had significantly higher neopterin levels than non-frail controls after adjusting for age and other potential confounding factors—indicate further elevation of neopterin levels in the syndrome of frailty above and beyond age-related changes. The observed elevation in neopterin levels suggests immune activation and increased monocyte/macrophage activities in frailty. Such monocyte–macrophage-mediated immune activation is supported, at least in part, by our previous findings that compared with their age-, race- and sex-matched non-frail controls; frail older adults had high monocyte counts and upregulated ex vivo
expression of pro-inflammatory chemokine CXCL10 by unstimulated monocytes and several additional stress-responsive genes after brief ex vivo
stimulation with LPS [8
]. The neopterin levels observed in the frail elderly in this study appeared to be not as markedly elevated as those reported in acute viral infections, such as acute cytomegalovirus infection (>13 nM) [25
] and human immunodeficiency virus infection (>16 nM) [26
] or in active systemic lupus erythematosus (>15 nM) [27
]. Additional studies are needed to further investigate the mechanism and regulation of neopterin production and monocyte/macrophage-mediated immune regulation in frailty.
A number of studies have observed significant association of elevated IL-6 levels with frailty in older adults [5
]. Results from the present study were consistent with this observation (Table , Model II). IL-6 is a well-known pro-inflammatory that is produced by the immune system cells including monocytes and macrophages and a variety of other cell types [29
]. Significant correlation between neoperin and IL-6 levels identified in this study, coupled with age-related increase in neopterin or IL-6 levels observed in other studies [13
], may suggest monocyte/macrophage activation leading to increased production of both neopterin and IL-6 in older adults. The results that the association of neopterin with frailty remained significant after adjusting for IL-6 (Table , Model III) indicates that such association is independent of IL-6. On the other hand, the data that the association between IL-6 and frailty was no longer statistically significant after adjusting for neopterin may suggest monocyte/macrophage-mediated immune activation marked by elevated neopterin levels as a potentially important mechanism that mediates IL-6-marked inflammation and its contribution to frailty.
The following limitations should be considered. First, the relatively small sample size may limit the study power. For example, that the ORs of being frail had large 95% CIs when log(neopterin) and log(IL-6) modelled as continuous variables is likely due to a limited sample size and data variability. This was partly addressed by modelling neopterin and IL-6 levels in tertiles. In addition, that the OR of being prefrail for top tertile of neopterin was marginally significant is also likely due to the limited sample size. Secondly, except for the pre-established exclusion criteria, other medical conditions that are common in older adult population were not excluded and they were not included in the statistical models. However, as this study was designed to evaluate associations of immune activation and inflammation with frailty, it was not intended to adjust for common comorbid conditions, because they may have significant contributions to immune activation and inflammation in frail older adults. Lastly, the directionality of the observed associations between elevated neopterin and frailty could not be determined in this cross-sectional study. Despite these limitations, results from this study support the original hypothesis and suggest significant monocyte/macrophage-mediated immune activation in frail elderly living in the community, independent of IL-6 levels. These findings provide a basis for further mechanistic and longitudinal investigations into the underlying immune mechanisms that contribute to frailty, based on which potential interventional strategies can be developed for the prevention and treatment of this important and common geriatric syndrome in the future.