Imperfect Repair in Aging: Uncovering the Fibrotic Niche and Metabolic Vulnerability
Chuna Kim
1Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea
2Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea
Aging is a nonlinear process characterized by a spatial mosaic pattern. Because organs constantly strive to maintain homeostasis despite continuous exposure to diverse external stimuli, aging does not occur at a constant rate. While the exact spatial origins and specific triggers of aging within organs remain elusive, various omics studies point to chronic inflammation and fibrosis as universal consequences. We interpret this phenomenon as a state of "imperfect repair," where unresolved tissue damage persists in aged tissues. Therefore, to fully comprehend this process, it is essential to spatially define the pathological niches created by imperfect repair and simultaneously uncover the stimuli and mechanisms that drive it.
To first understand the spatial architecture of these unresolved niches, we developed a novel method termed fibrotic niche enrichment sequencing (FiNi-seq). Through this approach, we revealed the presence of a fibrotic niche within the aged liver, densely populated by specific cell types analogous to those found in patients with liver cirrhosis. Notably, this pathological microenvironment is orchestrated by senescent-like endothelial cells, Smoc1+ fibroblasts, and exhausted T cells—populations absent in the corresponding niches of young tissues.
Furthermore, to investigate how specific stimuli construct this aging environment and alter its responsiveness, we conducted multi-omics analysis on lungs exposed to a sublethal dose of lipopolysaccharide (LPS). We discovered that alterations in macrophages, driven by itaconate accumulation, act as a core mechanism inducing inflammatory hypersensitivity in the aged lung.
In conclusion, to fundamentally understand organ aging, it is imperative to trace the 'footprints' left by incoming stimuli and elucidate how they culminate in imperfect repair and long-term tissue dysfunction.
