Circulating interleukin-37 declines with aging in healthy humans: relations to healthspan indicators and IL37 gene SNPs

Abstract

Aging is characterized by declines in physiological function that increase risk of age-associated diseases and limit healthspan, mediated in part by chronic low-grade inflammation. Interleukin (IL)-37 suppresses inflammation in pathophysiological states but has not been studied in the context of aging in otherwise healthy humans. Thus, we investigated associations between IL-37 and markers of healthspan in 271 young (18–39 years; n = 41), middle-aged (40–64 years; n = 162), and older (65 + years; n = 68) adults free of overt clinical disease. After conducting a thorough validation of AdipoGen’s IL-37 ELISA, we found that plasma IL-37 is lower in older adults (young: 339 ± 240, middle-aged: 345 ± 234; older: 258 ± 175 pg/mL; P = 0.048), despite elevations in pro-inflammatory markers. As such, the ratios of circulating IL-37 to pro-inflammatory markers were considerably lower in older adults (e.g., IL-37 to C-reactive protein: young, 888 ± 918 vs. older, 337 ± 293; P = 0.02), indicating impaired IL-37 responsiveness to a pro-inflammatory state with aging and consistent with the notion of immunosenescence. These ratios were related to multiple indicators of healthspan, including positively to cardiorespiratory fitness ( P < 0.01) and negatively to markers of adiposity, blood pressure, and blood glucose (all P < 0.05). Lastly, we correlated single-nucleotide polymorphisms (SNPs) in the IL37 and ILR8 (the co-receptor for IL-37) genes and found that variants in IL37 SNPs tended to be associated with blood pressure and adiposity ( P = 0.08–0.09) but did not explain inter-individual variability in circulating IL-37 concentrations across age ( P ≥ 0.23). Overall, our findings provide novel insights into a possible role of IL-37 in biological aging in humans. Supplementary Information The online version contains supplementary material available at 10.1007/s11357-022-00587-3.

Circulating interleukin-38 concentrations in healthy adults

“…Based on the available data, it was not possible to define a reliable refence range for IL-38 in healthy volunteers, as was possible for the IL-37 data extracted from literature ( 13 ). This is remarkable as IL-37 has several isoforms that will probably not be determined by all ELISA kits ( 50 , 51 ). However, to give an estimation of a potential direction of a reference range of IL-38 we could rely on the data generated after exclusion of outliers.…”

Effect of Physical Activity/Exercise on Oxidative Stress and Inflammation in Muscle and Vascular Aging

“…In fact, the concept of inflammaging which was adopted by Ferrucci recognizes that the chronic low-grade inflammation milieu observed in older adults contributes to cardiovascular risk [ 133 ], and seems to play a role in the development of multiple age-related diseases and conditions, including frailty [ 134 ]. However, the pathways linking inflammaging to physiological function and healthspan in humans are not well-known [ 135 ].…”

A Critical Appraisal of the Diagnostic and Prognostic Utility of the Anti-Inflammatory Marker IL-37 in a Clinical Setting: A Case Study of Patients with Diabetes Type 2

“…Notably, a negative direction of associations of pre-frailty/frailty with IL-37, which was stably maintained across the regression models, is suggestive of the suppressive effect of pre-frailty/frailty on circulating levels of IL-37. Some clarifications come from the recent study, where it was found that plasma levels of IL-37 are lower in healthy elderly individuals than in middle-aged and young ones, despite elevations in proinflammatory markers [ 63 ]. These results suggest that IL-37 responsiveness to proinflammatory stimuli declines with age.…”