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To characterize key changes in cross\u2010tissue 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\u2010rewired 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\u2010related tissue injury. Moreover, we identified organ\u2010specific and organ\u2010enriched proteins with high functional specificity. Among these, aging\u2010related proteins were closely linked to disorders arising from lipid metabolism dysfunction. Analysis of multi\u2010tissue metabolomic and fecal metagenomic profiles revealed that aging significantly disrupted inter\u2010tissue metabolic coupling, activities of polyunsaturated fatty acids metabolism, and gut microbiota homeostasis. Aged mice exhibited a marked decrease in <jats:italic>Escherichia<\/jats:italic> and an increase in <jats:italic>Helicobacter<\/jats:italic>, strongly correlating with alterations in omega\u20103 and omega\u20106 fatty acid abundances. Through multi\u2010omics integration, we identified key molecular hubs driving organismal responses to aging. Collectively, our study uncovers extensive aging\u2010associated alterations across tissues, emphasizing the interplay between systemic inflammation and dysbiosis\u2010driven fatty acid remodeling. 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