Interleukin-6 Drives Mitochondrial Dysregulation and Accelerates Physical Decline: Insights From an Inducible Humanized IL-6 Knock-In Mouse Model

Abstract Chronic activation of inflammatory pathways (CI) and mitochondrial dysfunction are independently linked to age-related functional decline and early mortality. Interleukin 6 (IL-6) is among the most consistently elevated chronic activation of inflammatory pathways markers, but whether IL-6 p...

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Published in:The journals of gerontology. Series A, Biological sciences and medical sciences Biological sciences and medical sciences, 2023-10, Vol.78 (10), p.1740-1752
Main Authors: Nidadavolu, Lolita S, Cosarderelioglu, Caglar, Merino Gomez, Alessandra, Wu, Yuqiong, Bopp, Taylor, Zhang, Cissy, Nguyen, Tu, Marx-Rattner, Ruth, Yang, Huanle, Antonescu, Corina, Florea, Liliana, Talbot, Conover C, Smith, Barbara, Foster, D Brian, Fairman, Jennifer E, Yenokyan, Gayane, Chung, Tae, Le, Anne, Walston, Jeremy D, Abadir, Peter M
Format: Article
Language:English
Subjects:
Age
Animals
Cell proliferation
Cytokines
Disease Models, Animal
Editor's Choice
Energy utilization
Frailty
Gerontology
Humans
Inflammation
Interleukin 6
Interleukin-6 - genetics
Interleukin-6 - metabolism
Metabolic pathways
Mice
Mitochondria
Mitochondria - genetics
Mitochondria - metabolism
Mitophagy
Muscle, Skeletal - metabolism
Quality control
Skeletal muscle
THE JOURNAL OF GERONTOLOGY: Biological Sciences
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Summary:Abstract Chronic activation of inflammatory pathways (CI) and mitochondrial dysfunction are independently linked to age-related functional decline and early mortality. Interleukin 6 (IL-6) is among the most consistently elevated chronic activation of inflammatory pathways markers, but whether IL-6 plays a causative role in this mitochondrial dysfunction and physical deterioration remains unclear. To characterize the role of IL-6 in age-related mitochondrial dysregulation and physical decline, we have developed an inducible human IL-6 (hIL-6) knock-in mouse (TetO-hIL-6mitoQC) that also contains a mitochondrial-quality control reporter. Six weeks of hIL-6 induction resulted in upregulation of proinflammatory markers, cell proliferation and metabolic pathways, and dysregulated energy utilization. Decreased grip strength, increased falls off the treadmill, and increased frailty index were also observed. Further characterization of skeletal muscles postinduction revealed an increase in mitophagy, downregulation of mitochondrial biogenesis genes, and an overall decrease in total mitochondrial numbers. This study highlights the contribution of IL-6 to mitochondrial dysregulation and supports a causal role of hIL-6 in physical decline and frailty. Graphical Abstract
ISSN:1079-5006
1758-535X
DOI:10.1093/gerona/glad147