Molecular mechanisms of cellular aging: A systems physiology perspective

Abstract

Cellular aging is a complex biological process characterized by a gradual decline in the ability of cells to maintain homeostasis, respond to stress, and sustain tissue function. This phenomenon is driven by the accumulation of interacting molecular and physiological changes, ultimately contributing to impaired organ function and increased susceptibility to age-related diseases. Although reductionist approaches have revealed key pathways and molecules involved in aging, they have not fully explained the dynamics of interactions across levels of biological organization that make aging a systemic phenomenon. This review aimed to integrate the molecular mechanisms of cellular aging within the framework of systems physiology, emphasizing the interconnectedness of molecular changes, cell function, and physiological regulation at the tissue and organism levels. The literature was obtained through a search of major scientific databases with a focus on experimental and computational studies addressing cellular aging, hallmarks of aging, and systems and multi-omics approaches. The synthesis of results demonstrates that key mechanisms of aging—such as genomic instability, mitochondrial dysfunction, impaired proteostasis, deregulated nutrient sensing, cellular senescence, and altered intercellular communication—form a dynamic and interconnected regulatory network. The nonlinear interactions between these pathways explain variations in aging across tissues and individuals, while emphasizing the importance of physiological context in determining biological outcomes. A systems physiology approach provides a more comprehensive understanding of how changes at the molecular level translate into systemic decline. Overall, a systems-based perspective offers a robust conceptual framework for integrating molecular findings on aging and supporting the development of more effective, predictive, and physiologically relevant intervention strategies to maintain health across the lifespan.