The Association of Olfactory Dysfunction, Frailty, and Mortality Is Mediated by Inflammation: Results from the InCHIANTI Study

Abstract

Background. Olfactory dysfunction might unveil the association between ageing and frailty, as it is associated with declining cognitive function, depression, reduced physical performance, reduced dietary intake, and mortality; all these conditions are characterized by increased levels of inflammatory parameters. The present study is aimed at evaluating the association between olfactory dysfunction, frailty, and mortality and whether such association might be mediated by inflammation. Methods. We analysed data of 1035 participants aged 65+ enrolled in the “InCHIANTI” study. Olfactory function was tested by the recognition of the smells of coffee, mint, and air. Olfactory dysfunction was defined as lack of recognition of at least two smells. Considering the items “shrinking,” “exhaustion,” “sedentariness,” “slowness,” and “weakness” included in the Fried definition, frailty was defined as the presence of at least three criteria, prefrailty of one or two, and robustness of none. Serum interleukin-6 (IL-6) was measured in duplicate by high-sensitivity enzyme-linked immunosorbent assays. Logistic regression was adopted to assess the association of frailty with olfactory function, as well as with the increasing number of olfactory deficits. Cox regression was used to test the association between olfactory dysfunction and 9-year survival. Results. Olfactory dysfunction was associated with frailty, after adjusting (OR 1.94, 95% CI=1.07-3.51; P=.028); analysis of the interaction term indicated that the association varied according to interleukin-6 levels (P for interaction=.005). Increasing levels of olfactory dysfunction were associated with increasing probability of being frail. Also, olfactory dysfunction was associated with reduced survival (HR 1.52, 95% CI=1.16-1.98; P=.002); this association varied according to the presence of frailty (P for interaction=.017) and prefrailty status (P for interaction=.046), as well as increased interleukin-6 levels (P for interaction = .011). Conclusions. Impairment of olfactory function might represent a marker of frailty, prefrailty, and consequently reduced survival in an advanced age. Inflammation might represent the possible link between these conditions.

Predictors of Olfactory Decline in Aging: A Longitudinal Population-Based Study

“…As such, gait speed may reflect overall health in a similar manner as the state of the olfactory system ( 40 ). Indeed, some previous findings suggest a significant overlap between frailty, inflammatory markers, and OD ( 41 , 42 ). Note, however, that gait speed was not associated with olfactory change in multi-adjusted models, again indicating significant overlap with comorbidities.…”

The association between olfactory dysfunction and cardiovascular disease and its risk factors in middle-aged and older adults

“…A decrease in basal cell proliferation with age can be explained by decreased expression of cyclin D, a transcription factor for cell proliferation, and decreased expression of growth factors such as epidermal growth factor, insulin-like growth factor-1, and neuropeptide Y signalling 16,17 The repeated damage of olfactory receptor neurons might also be associated with decreased proliferation of basal cells after excessive www.nature.com/scientificreports/ basal cell divisions 18 . In addition, pro-inflammatory cytokines from senescent cells may induce the suppression of basal cell proliferation and loss of olfactory receptor neurons as aging-related physiological changes 19,20 . Several previous studies have proposed possible mechanisms for association of CVD and its risk factors with olfactory dysfunction 12,[21][22][23] .…”

Mechanisms Linking Olfactory Impairment and Risk of Mortality

“…Controlling for smoking or alcohol abuse did not attenuate the link between OI and mortality (Pinto et al, 2014;Devanand et al, 2015). Some authors also suggested that high levels of inflammatory markers (interleukin-6, C-reactive protein) could be associated with frailty, atherosclerosis and also with OI (Schubert et al, 2011;Henkin et al, 2013;Laudisio et al, 2019). However, adjusting for these variables did not attenuate the link between OI and mortality (Schubert et al, 2016).…”