The fibrosis-plasticity axis (FPA) and ionic resilience: a systems framework for understanding adverse drug reactions in ageing populations

Background: Older adults frequently develop disabling adverse drug reactions (ADRs) from standard-dose medications despite lacking clear organ pathology and presenting with normal serum electrolyte values. Traditional explanations focusing on altered pharmacokinetics or pharmacodynamics inadequately explain why adverse effects often span multiple organ systems and resist prediction by standard clinical parameters. Objective: To develop a unified theoretical framework-the Fibrosis-Plasticity Axis (FPA)-that integrates mechanotransduction theory, allostatic load concepts, network physiology, and electrolyte-dependent ionic resilience to explain system-level drug intolerance in ageing. Methods: We synthesize evidence from mechanobiology, ion transport physiology, autonomic function research, and geriatric pharmacology to develop an integrated framework linking tissue-level stabilization to system-level pharmacological vulnerability. Results: We identify six functional vulnerability domains where plasticity loss manifests clinically and propose that ionic resilience-the capacity to maintain electrolyte-dependent cellular functions under stress-represents a critical, yet under-measured, determinant of drug tolerance. We introduce the Composite Plasticity Index (CPI), combining dynamic capacity measures (heart rate variability, gait variability) with stabilization markers (pulse wave velocity, inflammatory markers), as a conceptual biomarker for adaptive capacity. Conclusion: The FPA framework provides mechanistic coherence for multisystem vulnerability patterns and generates testable predictions about adverse effect clustering. By shifting focus from concentration-based to capacity-based assessment, this framework may improve prediction of drug tolerance and identify targets for plasticity-restoring interventions, including the emerging paradigm of repairing without fibrosis.