Systems Biochemistry of Cellular Aging: Integrating Metabolic, Epigenetic, and Oxidative Stress Pathways

Background: Cellular aging is a complex, multifactorial process that results from the cumulative interplay between metabolic dysfunction, epigenetic remodeling, and oxidative stress. These interconnected biochemical pathways contribute to the progressive decline in cellular homeostasis, increased susceptibility to disease, and loss of regenerative capacity observed with aging. A systems biochemistry approach is essential for unraveling the dynamic interactions among these hallmarks and identifying integrative targets for therapeutic intervention. Methods and Results: This review synthesizes recent advances in the systems-level understanding of cellular aging, highlighting how disruptions in mitochondrial metabolism, redox signaling, and epigenetic regulation converge to drive senescence and functional decline. Key features include decreased NAD⁺ levels impairing sirtuin activity, mitochondrial DNA damage fueling ROS production, and altered one-carbon metabolism affecting DNA and histone methylation. Epigenetic drift manifests through global hypomethylation alongside focal hypermethylation of stress-response genes, reinforcing pro-aging transcriptional programs. Integrated omics technologies, such as metabolomics, epigenomics, and redox proteomics, have revealed feedback loops between oxidative stress and metabolic rewiring, emphasizing the role of AMPK, mTOR, and PARP in age-related signaling. Computational network modeling has further enabled the mapping of cross-regulatory nodes and potential intervention points. Pharmacological modulation of NAD⁺ biosynthesis, histone deacetylation, and mitochondrial quality control has demonstrated lifespan and healthspan extension in preclinical models. Conclusion: A systems biochemistry framework provides a powerful lens through which to decode the multilayered processes of cellular aging.