Integrative cross‐tissue analysis unveils complement‐immunoglobulin augmentation and dysbiosis‐related fatty acid metabolic remodeling during mammalian aging

Abstract Aging‐related decline and adaptation are complex, multifaceted processes that affect various tissues and increase risk of chronic diseases. To characterize key changes in cross‐tissue aging, we performed comprehensive proteomic and metabolomic analyses across 21 solid tissues and plasma samples, alongside shotgun metagenomic profiling of fecal microbial communities in young and aged mice. Our findings revealed widespread aging‐rewired chronic inflammation, characterized by complement system activation in plasma and universal immunoglobulins accumulation across multiple solid tissues. This inflammatory remodeling significantly enhanced vulnerability to aging‐related tissue injury. Moreover, we identified organ‐specific and organ‐enriched proteins with high functional specificity. Among these, aging‐related proteins were closely linked to disorders arising from lipid metabolism dysfunction. Analysis of multi‐tissue metabolomic and fecal metagenomic profiles revealed that aging significantly disrupted inter‐tissue metabolic coupling, activities of polyunsaturated fatty acids metabolism, and gut microbiota homeostasis. Aged mice exhibited a marked decrease in Escherichia and an increase in Helicobacter , strongly correlating with alterations in omega‐3 and omega‐6 fatty acid abundances. Through multi‐omics integration, we identified key molecular hubs driving organismal responses to aging. Collectively, our study uncovers extensive aging‐associated alterations across tissues, emphasizing the interplay between systemic inflammation and dysbiosis‐driven fatty acid remodeling. These findings provide deeper insights into the development of healthy aging from a cross‐tissue perspective.