Molecular Axis of Healthy Aging Supplementary Materials

Background Aging is a complex systemic process detectable by high-throughput omics technologies. A critical challenge lies in distinguishing biomarkers of physiological aging from those of age-related diseases. Research design and methods We processed nine curated databases and eleven peer-reviewed publications encompassing integrated lists of protein identifiers associated with aging and age-related diseases. This study identified molecular signatures specifically associated with healthy aging by integrating proteomic and pathway-inferred metabolite associations from multiple databases. Results We identified distinct molecular profiles: 5,036 proteins and 1,141 metabolites were specifically associated with healthy aging, while 969 proteins and 350 metabolites were linked to age-related diseases. Functional enrichment analysis revealed differential distribution of hallmarks of aging. Network analysis of healthy aging proteins revealed modular organization and led us to hypothesize an integrative molecular axis of healthy aging, centered on key regulatory nodes (ATF4, CEBPB, NFKB1, TRAF6, ULK1, PRKACA/G, PKM, PCK1, MDH2, ATP5F1B/C, MT-ATP6, RPS3). This axis integrates mitochondrial function, metabolic adaptation, proteostasis, and immune regulation into a coordinated network ensuring stress resistance. Conclusions Our findings demonstrate that healthy aging represents a distinct biological trajectory governed by balanced immune-metabolic and mitochondrial processes, whereas age-related diseases are characterized by hormonal-cardiometabolic and xenobiotic dysregulation.