Frontiers in Aging · Jun 2, 2026

Physiological amplitude: a systems-level framework for adaptive capacity in aging and metabolism

By Sepczynska G

BACKGROUND: Aging is characterized by progressive loss of physiological complexity, inter-system coordination, and adaptive capacity. While mitochondrial dysfunction, metabolic inflexibility, impaired stress responses, and circadian dysregulation are well established, an integrative systems-level construct linking these processes remains lacking. OBJECTIVE: To introduce physiological amplitude as a unifying framework describing the bounded dynamic range of coordinated variability across interacting physiological systems. METHODS: We develop a conceptual, hypothesis-generating framework grounded in network physiology and systems biology, integrating mitochondrial function, metabolic flexibility, hormetic stress responses, and circadian regulation into a unified architecture of system-level adaptation. RESULTS: Physiological amplitude is defined as the bounded dynamic range within which coordinated multiscale physiological dynamics are maintained. Aging is conceptualized as a progressive contraction of this accessible range across interconnected biological networks. This framework distinguishes physiological amplitude from variability and resilience by positioning it as a higher-order property emerging from constraint-defined interactions across physiological systems. CONCLUSION: Physiological amplitude provides an integrative framework for interpreting multiscale physiological dynamics and generates testable hypotheses for quantification using continuous monitoring and network-based analysis. As a candidate systems-level descriptor, it may support the development of integrative biomarkers of aging and metabolic decline, pending empirical validation.

doi.org/10.3389/fragi.2026.1837722 Open access PubMed 42311339 Mechanisms