Longitudinal Relationship Between Interleukin-6 and Perceived Fatigability Among Well-Functioning Adults in Mid-to-Late Life

Background: Chronically elevated interleukin-6 (IL-6) levels contribute to fatigue and functional decline via multiple pathways that often lead to frailty. Lesser known is the contribution of IL-6 to fatigue in relation to a standardized workload (fatigability), a precursor to functional decline. Therefore, the purpose of this study was to examine the longitudinal relationship between IL-6 and fatigability. Methods: About 985 participants from the Baltimore Longitudinal Study of Aging (mean age: 70 +/- 10 years) were evaluated every 1-4 years. IL-6 was measured in fasting serum samples at each visit and log-transformed for analyses. Perceived fatigability (PF) was defined as self-reported exertion (rate of perceived exertion; RPE) after a 5-min, 0.67 m/s, 0% grade treadmill walk. Continuous and categorical associations between IL-6 (baseline and repeated measures) and PF were assessed using generalized estimating equations, adjusting for demographics, behavioral factors, and comorbid conditions. Results: In fully adjusted continuous models, twofold higher baseline IL-6 was associated with a 0.28 higher RPE (p =.03). This relationship tended to remain constant annually (baseline log IL-6 by time interaction p =.29). To provide clinical relevance, the sample median (3.7 pg/mL) was used to examine high versus low IL-6 levels. Over time, the high group reported an average 0.25 higher RPE (p =.03) than the low group. Annual change in logged IL-6 was not associated with annual change in PF (p =.48). Conclusion: Findings suggest that elevated IL-6 is a biomarker of physiological dysregulation associated with greater fatigability, but there is no longitudinal association between IL-6 and fatigability. Future studies should evaluate whether interventions that aim to reduce inflammation also attenuate fatigability.