Interleukin-6 Drives Mitochondrial Dysregulation and Accelerates Physical Decline: Insights from an Inducible Humanized IL-6 Knock-In Mouse Model.
Lolita S NidadavoluCaglar CosardereliogluAlessandra Merino GomezYuqiong WuTaylor BoppCissy ZhangTu NguyenRuth Marx-RattnerHuanle YangCorina AntonescuLiliana D FloreaConover C TalbotBarbara SmithD Brian FosterJennifer E FairmanGayane YenokyanTae ChungAnne LeJeremy D WalstonPeter M AbadirPublished in: The journals of gerontology. Series A, Biological sciences and medical sciences (2023)
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 CI 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-6 mitoQC) that also contains a mitochondrial-quality control reporter. Six weeks of hIL-6 induction resulted in upregulation of pro-inflammatory 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 post-induction 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.