Chandler Herring
Research Mentor: Xinna Li
Mentor Department: Pathology, Medicine
Author(s): Not Available
Session: Session 2 (10:00 AM – 10:50 AM)
Presentation Type: Poster 61
Abstract
Lifespan-extending interventions inhibited consistent expression patterns of IL-11 signaling across mouse livers and adipose tissues Xinna Li1,2, Christopher Adam3, Leanne Mercier3, Kennedy Kuchinski3, Alexander Voorhees 3, Jackson Yang3, Richard A Miller1,2 1 Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA 2 University of Michigan Geriatrics Center, Ann Arbor, Michigan 48109, USA 3 College of Literature, Sciences, & the Arts, University of Michigan, Ann Arbor, Michigan 48109, USA Abstract The emergence of a chronic, low-intensity systemic inflammatory state, commonly referred to as “inflammagingâ€, is a defining characteristic of the aging process. This contributes to the pathogenesis of age-related disorders, such as neurodegenerative, cardiometabolic, and musculoskeletal dysfunction, alongside generalized physiological frailty and cancer. Inflammaging is multifactorial, involving an assortment of secreted molecules originating from multiple sources, and operates through an established signaling mechanism. Considering the multifaceted and complex nature of the aging process, there is a critical need to structurally delineate and reduce the complexity of inflammaging-related signaling networks. Recent studies have implicated interleukin-11 (IL-11), a cytokine within the IL-6 cytokine family characterized by pro-inflammatory and pro-fibrotic properties, as a crucial regulator of molecular pathways governing aging. IL-11 acts through the modulation of signalling nodes, including AMPK, ERK, JAK-STAT3, and mTOR. Previous studies indicate that IL-11 inhibition may result in enhancements in both health span and lifespan in animal models, with potential translational relevance in humans. In this study, we hypothesized that systemic changes in IL-11 signaling across liver and adipose tissues are correlated with lifespan-extending interventions (16a-hydroxyestradiol (OH_Est), canagliflozin (Cana), astaxanthin (Asta), and meclizine (Mec)). We have identified that canagliflozin (Cana), started at 16 months of age, and 16-hydroxy-estradiol (OH_Est), started at 12 months of age, each led to significant increases in lifespan in male UM-HET3 mice. In contrast, both interventions led to a significant decrease among their female counterparts. Astaxanthin and meclizine were also found to extend the lifespan of UM-HET3 male mice. Our data showed consistent inhibition of IL-11 signaling in the liver and adipose tissue of mice with lifespan-extending interventions. We observed no alteration in IL-11 protein expression across liver samples, but saw a decrease in IL-11 levels in the inguinal adipose tissue of the slow-aging mouse models, without differences between sexes. In perigonadal adipose tissue from mice treated with OH_Est and Cana, IL-11 protein levels decreased in males, in contrast to the increase of IL-11 protein expression in females. No change of IL-11 protein levels was detected in the perigonadal adipose tissue of mice treated with Asta or Mec. These findings highlight that pharmacologic interventions on lifespan may also be partially mediated by reductions in inflammaging. Keywords: Longevity; Astaxanthin (Asta); Meclizine (Mec); 16a-hydroxyestradiol (OH_Est); canagliflozin (Cana); adipocyte; IL-11, inflammaging
